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FDA lifts partial hold on tazemetostat trials
The U.S. Food and Drug Administration has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas, according to a press release from the drug’s developer Epizyme.
The patient had been on study for approximately 15 months and had achieved a confirmed partial response. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.
“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” Robert Bazemore, president and chief executive officer of Epizyme, said in a webcast on Sept. 24.
Epizyme assessed the risk of secondary malignancies, including T-LBL, as well as the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials. A panel of external scientific and medical experts who reviewed the findings concluded that T-LBL risks appear to be confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.
“The team at Epizyme has worked diligently in collaboration with external experts and the FDA over the past several months,” Mr. Bazemore said.
The company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials. However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies. Mr. Bazemore said Epizyme hopes to submit a New Drug Application for tazemetostat in the treatment of epithelioid sarcoma.
Tazemetostat is under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid-tumor malignancies. The drug is also being studied as part of combination therapy for non–small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).
In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.
Epizyme is now working to resolve partial clinical holds placed on tazemetostat in France and Germany in order to resume trial enrollment in those countries.
The U.S. Food and Drug Administration has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas, according to a press release from the drug’s developer Epizyme.
The patient had been on study for approximately 15 months and had achieved a confirmed partial response. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.
“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” Robert Bazemore, president and chief executive officer of Epizyme, said in a webcast on Sept. 24.
Epizyme assessed the risk of secondary malignancies, including T-LBL, as well as the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials. A panel of external scientific and medical experts who reviewed the findings concluded that T-LBL risks appear to be confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.
“The team at Epizyme has worked diligently in collaboration with external experts and the FDA over the past several months,” Mr. Bazemore said.
The company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials. However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies. Mr. Bazemore said Epizyme hopes to submit a New Drug Application for tazemetostat in the treatment of epithelioid sarcoma.
Tazemetostat is under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid-tumor malignancies. The drug is also being studied as part of combination therapy for non–small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).
In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.
Epizyme is now working to resolve partial clinical holds placed on tazemetostat in France and Germany in order to resume trial enrollment in those countries.
The U.S. Food and Drug Administration has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas, according to a press release from the drug’s developer Epizyme.
The patient had been on study for approximately 15 months and had achieved a confirmed partial response. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.
“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” Robert Bazemore, president and chief executive officer of Epizyme, said in a webcast on Sept. 24.
Epizyme assessed the risk of secondary malignancies, including T-LBL, as well as the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials. A panel of external scientific and medical experts who reviewed the findings concluded that T-LBL risks appear to be confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.
“The team at Epizyme has worked diligently in collaboration with external experts and the FDA over the past several months,” Mr. Bazemore said.
The company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials. However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies. Mr. Bazemore said Epizyme hopes to submit a New Drug Application for tazemetostat in the treatment of epithelioid sarcoma.
Tazemetostat is under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid-tumor malignancies. The drug is also being studied as part of combination therapy for non–small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).
In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.
Epizyme is now working to resolve partial clinical holds placed on tazemetostat in France and Germany in order to resume trial enrollment in those countries.
PARP inhibitor plus trabectedin shows promise for sarcoma
A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma, the recent TOMAS trial found.
High PARP1 expression was associated with treatment response, reported Giovanni Grignani, MD, of the Medical Oncology_Sarcoma Unit at Istituto di Ricovero e Cura a Carattere Scientifico in Candiolo, Italy, and his colleagues.
PARP inhibitors prevent repair of DNA damage, suggesting potential synergisms with DNA-damaging anticancer agents. Preclinical models support this strategy; however, clinical trials have found that toxicities restrict doses below antitumor activity levels.
“In view of these findings, trabectedin could be an ideal drug to use in combination with PARP1/2 inhibitors for two reasons: its favourable haemopoietic toxicity profile and its unique mechanisms of action,” the authors wrote in The Lancet Oncology. Trabectedin bends the minor groove of DNA toward the major groove, which activates PARP1 in an attempt to repair the damage. Preclinical trials showed that a PARP inhibitor such as olaparib would block this PARP1 activation, ultimately resulting in a more robust response than with either drug alone.
The phase 1b, open-label TOMAS trial involved 50 patients with sarcoma who had experienced disease progression after standard therapy. The study was divided into two cohorts: dose-escalation and dose-expansion. Patients received a median of four cycles of therapy with a median follow-up of 10 months (some patients are still undergoing treatment). The primary endpoint was maximum tolerated dose. The investigators also evaluated pharmacokinetics, pharmacodynamics, and various response measures.
Although adverse events occurred, these were manageable, and the authors concluded that the combination is safe for further investigation. The most common grade 3 or higher adverse events were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase elevation (18%). The maximum tolerated dose (recommended phase 2 dose) was olaparib 150 mg twice daily and trabectedin 1.1 mg/m2 every 3 weeks.
“These doses allowed us to minimize the need for dose reductions and continue treatment for as long as tumour control was maintained,” the authors wrote. Previous treatments impacted tolerability. The researchers noted that “patients who had received more than two lines of therapy had a higher risk of developing dose-limiting toxicities than those patients who had been treated with only one line of therapy.”
Overall, 14% of patients responded to therapy. Six-month progression-free survival was more common in patients with soft tissue sarcoma (38%) than other tumor types. More patients with high PARP1 expression achieved 6-month PFS compared with patients who had low PARP1 expression (59% vs. 8%; P = .01).
“The combination of olaparib and trabectedin exploits the potential of two different first-in-class drugs and shows tolerability and activity in homologous repair-proficient tumors,” the authors concluded.
They are planning two phase 2 studies in the future; one “comparing trabectedin alone versus the combination of trabectedin and olaparib, stratifying patients according to PARP1 expression,” and an “after-platinum-failure study of patients with ovarian cancer regardless of patients’ BRCA1/2 and BRCAness status.”
The TOMAS trial was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.
SOURCE: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.
The phase 1b TOMAS trial by Grignani et al. showed that PARP inhibitor combination therapy may be a safe and effective option for patients with sarcoma, and a phase 2 study is warranted, according to Benjamin A. Nacev, MD, and William D. Tap, MD.
PARP inhibitors mitigate DNA damage repair, suggesting potential for synergistic combinations with DNA-damaging anticancer agents. Unfortunately, previous combinations have revealed toxicity issues.
“The first clinical example of this approach was the combination of the alkylating drug temozolomide and the PARP inhibitor rucaparib, which was hampered by dose-limiting myelosuppression,” Dr. Nacev and Dr. Tap wrote in an editorial in The Lancet Oncology.
In the TOMAS trial, Grignani et al. assessed a combination of trabectedin and the PARP inhibitor olaparib. Preclinical data showed synergistic activity in sarcoma cell lines, and the authors predicted tolerable myelosuppression with trabectedin.
Their predictions yielded promising results: Approximately one-third of patients with soft-tissue sarcoma were progression free at 6 months. Although myelosuppression did occur, the adverse event profile was tolerable.
As drug synergisms are biologically complex, “a key success of the TOMAS trial is the effective use of exploratory pharmacodynamic endpoints including PARP1 expression, PARylation, and mutational status of the DNA damage repair pathway.”
“For example, efficacy in the TOMAS trial correlated with PARP1 expression, with greater 6-month progression-free survival in the high PARP1 expression group than the low expression group.”
“The TOMAS investigators should be commended for doing the important bench-to-bedside approach of rationally designing and testing a drug combination to leverage available active drugs. We agree with the authors’ call for further investigation of trabectedin and olaparib in a randomised phase 2 trial in soft tissue sarcoma.”
William D. Tap, MD is chief of the Sarcoma Medical Oncology Service and Benjamin A. Nacev, MD is a third-year medical oncology/hematology fellow at Memorial Sloan Kettering Cancer Center in New York. Dr. Tap reported personal fees from Eli Lilly, Novartis, Eisai, and others. These comments are adapted from their accompanying editorial .
The phase 1b TOMAS trial by Grignani et al. showed that PARP inhibitor combination therapy may be a safe and effective option for patients with sarcoma, and a phase 2 study is warranted, according to Benjamin A. Nacev, MD, and William D. Tap, MD.
PARP inhibitors mitigate DNA damage repair, suggesting potential for synergistic combinations with DNA-damaging anticancer agents. Unfortunately, previous combinations have revealed toxicity issues.
“The first clinical example of this approach was the combination of the alkylating drug temozolomide and the PARP inhibitor rucaparib, which was hampered by dose-limiting myelosuppression,” Dr. Nacev and Dr. Tap wrote in an editorial in The Lancet Oncology.
In the TOMAS trial, Grignani et al. assessed a combination of trabectedin and the PARP inhibitor olaparib. Preclinical data showed synergistic activity in sarcoma cell lines, and the authors predicted tolerable myelosuppression with trabectedin.
Their predictions yielded promising results: Approximately one-third of patients with soft-tissue sarcoma were progression free at 6 months. Although myelosuppression did occur, the adverse event profile was tolerable.
As drug synergisms are biologically complex, “a key success of the TOMAS trial is the effective use of exploratory pharmacodynamic endpoints including PARP1 expression, PARylation, and mutational status of the DNA damage repair pathway.”
“For example, efficacy in the TOMAS trial correlated with PARP1 expression, with greater 6-month progression-free survival in the high PARP1 expression group than the low expression group.”
“The TOMAS investigators should be commended for doing the important bench-to-bedside approach of rationally designing and testing a drug combination to leverage available active drugs. We agree with the authors’ call for further investigation of trabectedin and olaparib in a randomised phase 2 trial in soft tissue sarcoma.”
William D. Tap, MD is chief of the Sarcoma Medical Oncology Service and Benjamin A. Nacev, MD is a third-year medical oncology/hematology fellow at Memorial Sloan Kettering Cancer Center in New York. Dr. Tap reported personal fees from Eli Lilly, Novartis, Eisai, and others. These comments are adapted from their accompanying editorial .
The phase 1b TOMAS trial by Grignani et al. showed that PARP inhibitor combination therapy may be a safe and effective option for patients with sarcoma, and a phase 2 study is warranted, according to Benjamin A. Nacev, MD, and William D. Tap, MD.
PARP inhibitors mitigate DNA damage repair, suggesting potential for synergistic combinations with DNA-damaging anticancer agents. Unfortunately, previous combinations have revealed toxicity issues.
“The first clinical example of this approach was the combination of the alkylating drug temozolomide and the PARP inhibitor rucaparib, which was hampered by dose-limiting myelosuppression,” Dr. Nacev and Dr. Tap wrote in an editorial in The Lancet Oncology.
In the TOMAS trial, Grignani et al. assessed a combination of trabectedin and the PARP inhibitor olaparib. Preclinical data showed synergistic activity in sarcoma cell lines, and the authors predicted tolerable myelosuppression with trabectedin.
Their predictions yielded promising results: Approximately one-third of patients with soft-tissue sarcoma were progression free at 6 months. Although myelosuppression did occur, the adverse event profile was tolerable.
As drug synergisms are biologically complex, “a key success of the TOMAS trial is the effective use of exploratory pharmacodynamic endpoints including PARP1 expression, PARylation, and mutational status of the DNA damage repair pathway.”
“For example, efficacy in the TOMAS trial correlated with PARP1 expression, with greater 6-month progression-free survival in the high PARP1 expression group than the low expression group.”
“The TOMAS investigators should be commended for doing the important bench-to-bedside approach of rationally designing and testing a drug combination to leverage available active drugs. We agree with the authors’ call for further investigation of trabectedin and olaparib in a randomised phase 2 trial in soft tissue sarcoma.”
William D. Tap, MD is chief of the Sarcoma Medical Oncology Service and Benjamin A. Nacev, MD is a third-year medical oncology/hematology fellow at Memorial Sloan Kettering Cancer Center in New York. Dr. Tap reported personal fees from Eli Lilly, Novartis, Eisai, and others. These comments are adapted from their accompanying editorial .
A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma, the recent TOMAS trial found.
High PARP1 expression was associated with treatment response, reported Giovanni Grignani, MD, of the Medical Oncology_Sarcoma Unit at Istituto di Ricovero e Cura a Carattere Scientifico in Candiolo, Italy, and his colleagues.
PARP inhibitors prevent repair of DNA damage, suggesting potential synergisms with DNA-damaging anticancer agents. Preclinical models support this strategy; however, clinical trials have found that toxicities restrict doses below antitumor activity levels.
“In view of these findings, trabectedin could be an ideal drug to use in combination with PARP1/2 inhibitors for two reasons: its favourable haemopoietic toxicity profile and its unique mechanisms of action,” the authors wrote in The Lancet Oncology. Trabectedin bends the minor groove of DNA toward the major groove, which activates PARP1 in an attempt to repair the damage. Preclinical trials showed that a PARP inhibitor such as olaparib would block this PARP1 activation, ultimately resulting in a more robust response than with either drug alone.
The phase 1b, open-label TOMAS trial involved 50 patients with sarcoma who had experienced disease progression after standard therapy. The study was divided into two cohorts: dose-escalation and dose-expansion. Patients received a median of four cycles of therapy with a median follow-up of 10 months (some patients are still undergoing treatment). The primary endpoint was maximum tolerated dose. The investigators also evaluated pharmacokinetics, pharmacodynamics, and various response measures.
Although adverse events occurred, these were manageable, and the authors concluded that the combination is safe for further investigation. The most common grade 3 or higher adverse events were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase elevation (18%). The maximum tolerated dose (recommended phase 2 dose) was olaparib 150 mg twice daily and trabectedin 1.1 mg/m2 every 3 weeks.
“These doses allowed us to minimize the need for dose reductions and continue treatment for as long as tumour control was maintained,” the authors wrote. Previous treatments impacted tolerability. The researchers noted that “patients who had received more than two lines of therapy had a higher risk of developing dose-limiting toxicities than those patients who had been treated with only one line of therapy.”
Overall, 14% of patients responded to therapy. Six-month progression-free survival was more common in patients with soft tissue sarcoma (38%) than other tumor types. More patients with high PARP1 expression achieved 6-month PFS compared with patients who had low PARP1 expression (59% vs. 8%; P = .01).
“The combination of olaparib and trabectedin exploits the potential of two different first-in-class drugs and shows tolerability and activity in homologous repair-proficient tumors,” the authors concluded.
They are planning two phase 2 studies in the future; one “comparing trabectedin alone versus the combination of trabectedin and olaparib, stratifying patients according to PARP1 expression,” and an “after-platinum-failure study of patients with ovarian cancer regardless of patients’ BRCA1/2 and BRCAness status.”
The TOMAS trial was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.
SOURCE: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.
A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma, the recent TOMAS trial found.
High PARP1 expression was associated with treatment response, reported Giovanni Grignani, MD, of the Medical Oncology_Sarcoma Unit at Istituto di Ricovero e Cura a Carattere Scientifico in Candiolo, Italy, and his colleagues.
PARP inhibitors prevent repair of DNA damage, suggesting potential synergisms with DNA-damaging anticancer agents. Preclinical models support this strategy; however, clinical trials have found that toxicities restrict doses below antitumor activity levels.
“In view of these findings, trabectedin could be an ideal drug to use in combination with PARP1/2 inhibitors for two reasons: its favourable haemopoietic toxicity profile and its unique mechanisms of action,” the authors wrote in The Lancet Oncology. Trabectedin bends the minor groove of DNA toward the major groove, which activates PARP1 in an attempt to repair the damage. Preclinical trials showed that a PARP inhibitor such as olaparib would block this PARP1 activation, ultimately resulting in a more robust response than with either drug alone.
The phase 1b, open-label TOMAS trial involved 50 patients with sarcoma who had experienced disease progression after standard therapy. The study was divided into two cohorts: dose-escalation and dose-expansion. Patients received a median of four cycles of therapy with a median follow-up of 10 months (some patients are still undergoing treatment). The primary endpoint was maximum tolerated dose. The investigators also evaluated pharmacokinetics, pharmacodynamics, and various response measures.
Although adverse events occurred, these were manageable, and the authors concluded that the combination is safe for further investigation. The most common grade 3 or higher adverse events were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase elevation (18%). The maximum tolerated dose (recommended phase 2 dose) was olaparib 150 mg twice daily and trabectedin 1.1 mg/m2 every 3 weeks.
“These doses allowed us to minimize the need for dose reductions and continue treatment for as long as tumour control was maintained,” the authors wrote. Previous treatments impacted tolerability. The researchers noted that “patients who had received more than two lines of therapy had a higher risk of developing dose-limiting toxicities than those patients who had been treated with only one line of therapy.”
Overall, 14% of patients responded to therapy. Six-month progression-free survival was more common in patients with soft tissue sarcoma (38%) than other tumor types. More patients with high PARP1 expression achieved 6-month PFS compared with patients who had low PARP1 expression (59% vs. 8%; P = .01).
“The combination of olaparib and trabectedin exploits the potential of two different first-in-class drugs and shows tolerability and activity in homologous repair-proficient tumors,” the authors concluded.
They are planning two phase 2 studies in the future; one “comparing trabectedin alone versus the combination of trabectedin and olaparib, stratifying patients according to PARP1 expression,” and an “after-platinum-failure study of patients with ovarian cancer regardless of patients’ BRCA1/2 and BRCAness status.”
The TOMAS trial was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.
SOURCE: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.
FROM THE LANCET ONCOLOGY
Key clinical point: A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma.
Major finding: Of those with high PARP1 expression, 59% were progression free 6 months after treatment.
Study details: TOMAS was an open-label phase 1b trial involving 50 patients with sarcoma who had disease progression after standard therapy.
Disclosures: The study was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.
Source: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.
Novel molecular assay: Promising results in bone and soft tissue tumor evaluation
, according to researchers.
The technique of anchored multiplex polymerase chain reaction (AMP)–based targeted next-generation sequencing (NGS) had a failure rate of 14% but, nonetheless, worked favorably when compared with conventional techniques, which were associated with several false positives in this study, the researchers reported in the Journal of Molecular Diagnostics.
Two new fusion partners for the USP6 gene were found using AMP-based targeted NGS in this study, which thus contributed to the “further unraveling of the molecular landscape” for these tumors, added corresponding author Judith V.M.G. Bovée, MD, PhD, of the department of pathology at Leiden (the Netherlands) University Medical Center and her colleagues.
While the genetics of bone and soft tissue tumors have diagnostic value in clinical practice, standard fluorescence in situ hybridization (FISH) and reverse transcriptase PCR are associated with several drawbacks, such as a high false negative rate in the case of FISH, Dr. Bovée and her coauthors wrote.
Accordingly, the researchers evaluated the applicability of a targeted sequencing assay (Archer FusionPlex Sarcoma kit, which was developed by ArcherDX) aimed at 26 genes relevant to bone and soft tissue tumor diagnostics.
Besides allowing for assessment of multiple target genes in a single assay, this technique circumvents the need to know both fusion partners for translocation detection, which opens up the possibility of identifying novel or rare fusion partners, investigators noted.
AMP-based targeted NGS was used to evaluate 81 bone and soft tissue tumor samples, and of those, 48 cases showed a fusion. For the remaining 33 cases in which no fusion was detected, 22 were considered truly negative because samples met all criteria for good quality, while the remaining 11 (14%) were considered not reliable because of insufficient quality, investigators reported.
The samples were also evaluated through use of FISH, reverse transcriptase PCR, or both in 58 cases and use of immunohistochemistry in 16 cases; for the remaining seven cases, no assay or immunohistochemistry could be applied because of a lack of availability, according to investigators.
Among the 48 entities that were fusion-positive according to AMP-based targeted NGS, 29 were validated using standard molecular assays, and of those, 25 had concordant results. Further analysis of the four discordant cases with a third independent technique confirmed the AMP-based targeted NGS findings, according to the published report.
Among the 22 fusion-negative high-quality samples, 19 were validated using FISH, and one case was found to be discordant; however, despite use of a third independent technique, this discrepancy could not be resolved, investigators said.
The AMP-based targeted NGS technique identified COL1A1 and SEC31A as novel fusion partners for USP6 in two cases of nodular fasciitis. Those fusion partners had been previously described in aneurysmal bone cysts, according to investigators.
Despite the promising results for the novel assay, conventional methods were sufficient in this study to confirm translocations in straightforward cases and ordinary rearrangements, according to the investigators.
“Both reverse transcription PCR and FISH are not only quick and easy to conduct but are also of low cost and high analytical validity and accuracy, which make them attractive methods,” they wrote.
The work by Dr. Bovée and her colleagues was supported by Leiden University Medical Center. The department of pathology and the department of cell and chemical biology at the medical center receive royalty payments from Kreatech/Leica, which provided a COL1A1/PDGFB fusion probe used in the research.
SOURCE: Lam SW et al. J Mol Diagn. 2018 Aug 20;20(5):653-63.
, according to researchers.
The technique of anchored multiplex polymerase chain reaction (AMP)–based targeted next-generation sequencing (NGS) had a failure rate of 14% but, nonetheless, worked favorably when compared with conventional techniques, which were associated with several false positives in this study, the researchers reported in the Journal of Molecular Diagnostics.
Two new fusion partners for the USP6 gene were found using AMP-based targeted NGS in this study, which thus contributed to the “further unraveling of the molecular landscape” for these tumors, added corresponding author Judith V.M.G. Bovée, MD, PhD, of the department of pathology at Leiden (the Netherlands) University Medical Center and her colleagues.
While the genetics of bone and soft tissue tumors have diagnostic value in clinical practice, standard fluorescence in situ hybridization (FISH) and reverse transcriptase PCR are associated with several drawbacks, such as a high false negative rate in the case of FISH, Dr. Bovée and her coauthors wrote.
Accordingly, the researchers evaluated the applicability of a targeted sequencing assay (Archer FusionPlex Sarcoma kit, which was developed by ArcherDX) aimed at 26 genes relevant to bone and soft tissue tumor diagnostics.
Besides allowing for assessment of multiple target genes in a single assay, this technique circumvents the need to know both fusion partners for translocation detection, which opens up the possibility of identifying novel or rare fusion partners, investigators noted.
AMP-based targeted NGS was used to evaluate 81 bone and soft tissue tumor samples, and of those, 48 cases showed a fusion. For the remaining 33 cases in which no fusion was detected, 22 were considered truly negative because samples met all criteria for good quality, while the remaining 11 (14%) were considered not reliable because of insufficient quality, investigators reported.
The samples were also evaluated through use of FISH, reverse transcriptase PCR, or both in 58 cases and use of immunohistochemistry in 16 cases; for the remaining seven cases, no assay or immunohistochemistry could be applied because of a lack of availability, according to investigators.
Among the 48 entities that were fusion-positive according to AMP-based targeted NGS, 29 were validated using standard molecular assays, and of those, 25 had concordant results. Further analysis of the four discordant cases with a third independent technique confirmed the AMP-based targeted NGS findings, according to the published report.
Among the 22 fusion-negative high-quality samples, 19 were validated using FISH, and one case was found to be discordant; however, despite use of a third independent technique, this discrepancy could not be resolved, investigators said.
The AMP-based targeted NGS technique identified COL1A1 and SEC31A as novel fusion partners for USP6 in two cases of nodular fasciitis. Those fusion partners had been previously described in aneurysmal bone cysts, according to investigators.
Despite the promising results for the novel assay, conventional methods were sufficient in this study to confirm translocations in straightforward cases and ordinary rearrangements, according to the investigators.
“Both reverse transcription PCR and FISH are not only quick and easy to conduct but are also of low cost and high analytical validity and accuracy, which make them attractive methods,” they wrote.
The work by Dr. Bovée and her colleagues was supported by Leiden University Medical Center. The department of pathology and the department of cell and chemical biology at the medical center receive royalty payments from Kreatech/Leica, which provided a COL1A1/PDGFB fusion probe used in the research.
SOURCE: Lam SW et al. J Mol Diagn. 2018 Aug 20;20(5):653-63.
, according to researchers.
The technique of anchored multiplex polymerase chain reaction (AMP)–based targeted next-generation sequencing (NGS) had a failure rate of 14% but, nonetheless, worked favorably when compared with conventional techniques, which were associated with several false positives in this study, the researchers reported in the Journal of Molecular Diagnostics.
Two new fusion partners for the USP6 gene were found using AMP-based targeted NGS in this study, which thus contributed to the “further unraveling of the molecular landscape” for these tumors, added corresponding author Judith V.M.G. Bovée, MD, PhD, of the department of pathology at Leiden (the Netherlands) University Medical Center and her colleagues.
While the genetics of bone and soft tissue tumors have diagnostic value in clinical practice, standard fluorescence in situ hybridization (FISH) and reverse transcriptase PCR are associated with several drawbacks, such as a high false negative rate in the case of FISH, Dr. Bovée and her coauthors wrote.
Accordingly, the researchers evaluated the applicability of a targeted sequencing assay (Archer FusionPlex Sarcoma kit, which was developed by ArcherDX) aimed at 26 genes relevant to bone and soft tissue tumor diagnostics.
Besides allowing for assessment of multiple target genes in a single assay, this technique circumvents the need to know both fusion partners for translocation detection, which opens up the possibility of identifying novel or rare fusion partners, investigators noted.
AMP-based targeted NGS was used to evaluate 81 bone and soft tissue tumor samples, and of those, 48 cases showed a fusion. For the remaining 33 cases in which no fusion was detected, 22 were considered truly negative because samples met all criteria for good quality, while the remaining 11 (14%) were considered not reliable because of insufficient quality, investigators reported.
The samples were also evaluated through use of FISH, reverse transcriptase PCR, or both in 58 cases and use of immunohistochemistry in 16 cases; for the remaining seven cases, no assay or immunohistochemistry could be applied because of a lack of availability, according to investigators.
Among the 48 entities that were fusion-positive according to AMP-based targeted NGS, 29 were validated using standard molecular assays, and of those, 25 had concordant results. Further analysis of the four discordant cases with a third independent technique confirmed the AMP-based targeted NGS findings, according to the published report.
Among the 22 fusion-negative high-quality samples, 19 were validated using FISH, and one case was found to be discordant; however, despite use of a third independent technique, this discrepancy could not be resolved, investigators said.
The AMP-based targeted NGS technique identified COL1A1 and SEC31A as novel fusion partners for USP6 in two cases of nodular fasciitis. Those fusion partners had been previously described in aneurysmal bone cysts, according to investigators.
Despite the promising results for the novel assay, conventional methods were sufficient in this study to confirm translocations in straightforward cases and ordinary rearrangements, according to the investigators.
“Both reverse transcription PCR and FISH are not only quick and easy to conduct but are also of low cost and high analytical validity and accuracy, which make them attractive methods,” they wrote.
The work by Dr. Bovée and her colleagues was supported by Leiden University Medical Center. The department of pathology and the department of cell and chemical biology at the medical center receive royalty payments from Kreatech/Leica, which provided a COL1A1/PDGFB fusion probe used in the research.
SOURCE: Lam SW et al. J Mol Diagn. 2018 Aug 20;20(5):653-63.
FROM THE JOURNAL OF MOLECULAR DIAGNOSTICS
Key clinical point: Anchored multiplex PCR (AMP)-based targeted next-generation sequencing (NGS) may be superior to conventional molecular assays in the evaluation of bone and soft tissue tumor samples.
Major finding: Standard techniques yielded 4 false negatives out of 29 samples that were fusion-positive by AMP-based targeted NGS.
Study details: Analysis of 81 bone and soft tissue tumor samples evaluated by AMP-based targeted NGS and conventional techniques.
Disclosures: The research was supported by Leiden (the Netherlands) University Medical Center, which receives royalty payments from Kreatech/Leica.
Source: Lam SW et al. J Mol Diagn. 2018 Aug 20;20(5):653-63.
Addressing the rarity and complexities of sarcomas
The rarity and complexities of bone and soft tissue sarcomas pose a major challenge to effective treatment. Historically, there has been a blanket approach to treatment, but more recently that has begun to change thanks to genome profiling studies and novel clinical trial strategies. Here, we discuss the resulting enrichment of the therapeutic armamentarium with molecularly targeted and immune therapies.
A challenging tumor type
Sarcomas are a large group of histologically diverse cancers that arise in the mesenchymal cells. They can be broadly divided into bone and soft tissue sarcomas (STS) but are further subdivided according to the type of cell from which they derive; osteosarcomas in the bone, rhabdomyosarcomas in the skeletal muscle, liposarcomas in the fat tissues, leiomyosarcomas in the smooth muscle, and chondrosarcomas in the cartilaginous tissue, for example.
Each sarcoma subtype itself encompasses a range of different cancers with unique biology. Under the umbrella of liposarcoma, for example, are well/dedifferentiated liposarcomas and myxoid liposarcomas, which have very different pathologies and clinical courses.
As a whole, sarcomas are extremely rare tumors, accounting for less than 1% of all adult cancers, although they disproportionately affect children and young adults, with a prevalence closer to 15%.1,2 Certain sarcoma subtypes are exceptionally rare, with only a few cases diagnosed worldwide each year, whereas liposarcomas are at the other end of the spectrum, comprising the most common form of STS (Figure 1).3
In the early stages, sarcomas are generally highly treatable with a combination of surgical resection, chemotherapy, and radiation therapy. However, many patients develop advanced, metastatic disease, which presents much more of a challenge.4,5
Magic bullet for GIST
Despite their clear heterogeneity and complexity, sarcomas have tended to be treated as a single entity. Chemotherapy has played a central role in the treatment of advanced sarcomas and continues to do so, with 2 newer drugs approved by the United States Food and Drug Administration (FDA) in the past several years.6,7
The development of targeted therapy, on the other hand, for the most part proved unsuccessful. In general, studies examining the somatic mutation landscape in sarcomas found very few that were highly recurrent. The exception was gastrointestinal stromal tumors (GIST), which represent around 8% of STS.8 Frequent mutations in several highly targetable tyrosine kinases, notably KIT, which is mutated in around 85% of cases,9 and platelet-derived growth factor receptor alpha (PDGFRα) were identified in these tumors.10This prompted the development of tyrosine kinase inhibitors (TKIs), targeting these and other kinases, for the treatment of patients with GIST, and culminated in the approval of imatinib for this indication in 2002. This revolutionized the treatment of GIST, which had a poor prognosis and were resistant to chemotherapy, extending median overall survival in patients with metastatic disease almost to 5 years.11-13
Imatinib was also shown to benefit patients with surgically resectable disease and was subsequently approved in the adjuvant setting in 2008. A recent trial demonstrated that 3-year continuation of adjuvant imatinib resulted in a significantly longer progression-free survival (PFS) compared with 1 year of adjuvant imatinib, and even longer time periods are now being evaluated.14,15 The TKIs sunitinib and regorafenib have also been approved for the treatment of patients who become resistant to imatinib.16,17 Avapritinib, a newer, more specific inhibitor of KIT is also being evaluated in patients with GIST (Table).
Long-sought success for STS
Sunitinib and regorafenib include PDGFRα and the vascular endothelial growth factor receptors (VEGFRs) among their targets, receptors that play crucial roles in the formation of new blood vessels (angiogenesis). Many types of non-GIST sarcomas have been shown to be highly vascularized and express high levels of both of those receptors and other angiogenic proteins, which sparked interest in the development of multitargeted TKIs and other anti-angiogenic drugs in patients with STS.18
In 2012, pazopanib became the first FDA-approved molecularly targeted therapy for the treatment of non-GIST sarcomas. Approval in the second-line setting was based on the demonstration of a 3-month improvement in PFS compared with placebo.19 Four years later, the monoclonal antibody olaratumab, a more specific inhibitor of PDGFRα, was approved in combination with doxorubicin, marking the first front-line approval for more than 4 decades.20Numerous other anti-angiogenic drugs continue to be evaluated for the treatment of advanced STS. Among them, anlotinib is being tested in phase 3 clinical trials, and results from the ALTER0203 trial were presented at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO).21 After failure of chemotherapy, 223 patients were randomly assigned to receive either anlotinib or placebo. Anlotinib significantly improved median PFS across all patients, compared with placebo (6.27 vs 1.4 months, respectively; hazard ratio [HR], 0.33; P < .0001), but was especially effective in patients with alveolar soft part sarcoma (ASPS; mPFS: 18.2 vs 3 months) and was well tolerated.21
Sarcoma secrets revealed
Advancements in genome sequencing technologies have made it possible to interrogate the molecular underpinnings of sarcomas in greater detail. However, their rarity presents a significant technical challenge, with a dearth of samples available for genomic testing. Large-scale worldwide collaborative efforts have facilitated the collection of sufficiently large patient populations to provide statistically robust data in many cases. The Cancer Genome Atlas has established a rare tumor characterization project to facilitate the genomic sequencing of rare cancer types like sarcomas.
Genome sequencing studies have revealed 2 types of sarcomas: those with relatively stable genomes and few molecular alterations, exemplified by Ewing sarcoma, which has a mutational load of 0.15 mutations/Megabase (Mb); and those that are much more complex with frequent somatic mutations, the prime example being leiomyosarcoma. The latter are characterized by mutations in the TP53 gene, dubbed the “guardian of the genome” for its essential role in genome stability.
The 2 types are likely to require very different therapeutic strategies. Although genomically complex tumors offer up lots of potential targets for therapy, they also display significant heterogeneity and it can be challenging to find a shared target across different tumor samples. The p53 protein would make a logical target but, to date, tumor suppressor proteins are not readily druggable.
The most common type of molecular alterations in sarcomas are chromosomal translocations, where part of a chromosome breaks off and becomes reattached to another chromosome. This can result in the formation of a gene fusion when parts of 2 different genes are brought together in a way in which the genetic code can still be read, leading to the formation of a fusion protein with altered activity.22-25
In sarcomas, these chromosomal translocations predominantly involve genes encoding transcription factors and the gene fusion results in their aberrant expression and activation of the transcriptional programs that they regulate.
Ewing sarcoma is a prime example of a sarcoma that is defined by chromosomal translocations. Most often, the resulting gene fusions occur between members of theten-eleven translocation (TET) family of RNA-binding proteins and the E26 transformation-specific (ETS) family of transcription factors. The most common fusion is between the EWSR1 and FLI1 genes, observed in between 85% and 90% of cases.
Significant efforts have been made to target EWSR1-FLI1. Since direct targeting of transcription factors is challenging, those efforts focused on targeting the aberrant transcriptional programs that they initiate. A major downstream target is the insulin-like growth factor receptor 1 (IGF1R) and numerous IGF1R inhibitors were developed and tested in patients with Ewing sarcoma, but unfortunately success was limited. Attention turned to the mammalian target of rapamycin (mTOR) as a potential mechanism of resistance to IGF1R inhibitors and explanation for the limited responses. Clinical trials combining mTOR and IGF1R inhibitors also proved unsuccessful.26
Although overall these trials were deemed failures, they were notable for the dramatic responses that were seen in 1 or 2 patients. Researchers are probing these “exceptional responses” using novel N-of-1 clinical trial designs that focus on a single patient (Figure 2).27-30 More recently, the first drug to specifically target the EWSR1-FLI1 fusion protein was developed. TK216 binds to the fusion protein and prevents it from binding to RNA helicase A, thereby blocking its function.31
Another type of gene fusion, involving the neurotrophic tropomyosin receptor kinase (NTRK) genes, has recently come into the spotlight for the treatment of lung cancer. According to a recent study, NTRK fusions may also be common in sarcomas. They were observed in 8% of patients with breast sarcomas, 5% with fibrosarcomas, and 5% with stomach or small intestine sarcomas.32
The NTRK genes encode TRK proteins and several small molecule inhibitors of TRK have been developed to treat patients with NTRK fusion-positive cancers. Another novel clinical trial design – the basket trial – is being used to test these inhibitors. This type of trial uses a tumor-agnostic approach, recruiting patients with all different histological subtypes of cancer that are unified by the shared presence of a specific molecular alteration.33
Repurposing gynecologic cancer drugs
More recently, a third group of sarcomas was categorized, with intermediate genomic complexity. These tumors, including well/dedifferentiated liposarcomas, were characterized by amplifications of chromosome 12, involving genes such as cyclin-dependent kinase 4 (CDK4). In fact, more than 90% of patients with well/dedifferentiated sarcomas display CDK4 amplification, making it a logical therapeutic target.36
CDK4 encodes CDK4 protein, a cell cycle-associated protein that regulates the transition from G1-S phase, known as the restriction point, beyond which the cell commits to undergoing mitosis. Aberrant expression of CDK4 in cancer drives the hallmark process of unchecked cellular proliferation.
Some small molecule CDK4/6 inhibitors have been developed and have shown significant promise in the treatment of breast cancer. They are also being evaluatedin patients with sarcoma whose tumors display CDK4 overexpression. In a recently published phase 2 trial of palbociclib in 60 patients with well/dedifferentiated liposarcomas, there was 1 CR.37
Another group of drugs that has advanced the treatment of gynecologic cancers comprises the poly (ADP-ribose) polymerase (PARP) inhibitors. In this context, PARP inhibitors are used in patients with mutations in the breast cancer susceptibility genes, BRCA1/2. The BRCA and PARP proteins are both involved in DNA repair pathways and the inhibition of PARP in patients who already have a defective BRCA pathway renders a lethal double blow to the cancer cell. According to the Broad Institute Cancer Cell Line Encyclopedia, Ewing sarcomas express high levels of the PARP1 enzyme, which could render them sensitive to PARP inhibition. Preclinical studies seemed to confirm that sensitivity, however, so far this has yet to translate into success in clinical trials, with no objective responses observed as yet.38
Expanding the field
Other treatment strategies being tested in patients with sarcoma are moving the field beyond conventional targeted therapies. There has been substantial focus in recent years on epigenetic alterations and their potential role in the development of cancer. Epigenetics is the secondary layer of regulation that acts on the genome and directs the spatial and temporal expression of genes.
Both DNA and the histone proteins they are packaged up with to form chromatin in nondividing cells can be modified by the attachment of chemical groups, such as acetyl and methyl groups, which can alter access to the DNA for transcription.
EZH2 is an enzyme that participates in histone methylation and thereby regulates transcriptional repression. Some types of sarcoma are characterized by a loss of expression of the INI1 gene, also known as SMARCB1. The INI1 protein is part of a chromatin remodeling complex that relieves transcriptional repression and when INI1 is lost, cells become dependent upon EZH2.39Clinical trials of the EZH2 inhibitor tazemetostat are ongoing in several types of sarcoma. Results from a phase 2 study in adults with INI1-negative tumors were presented at ASCO in 2017. Among 31 patients treated with 800 mg tazemetostat in continuous 28-day cycles, mPFS was 5.7 months, disease control rate was 10%, and confirmed overall response rate was 13%. The FDA has granted tazemetostat orphan drug designation in this indication.40A pediatric basket trial of tazemetostat is also ongoing, but the FDA recently placed it under a clinical hold as a result of a safety update from the trial in which a pediatric patient with advanced poorly differentiated chordoma developed a secondary T-cell lymphoma.41
Targeting the unique metabolism of sarcomas may offer a promising therapeutic strategy, although this is in the preliminary stages of evaluation. A recent study showed that the expression of the argininosuccinate synthase 1 enzyme, which is involved in the generation of arginine through the urea cycle, was lost in up to 90% of STS. A pegylated arginine deaminase (ADI-PEG20), is being evaluated in a phase 2 clinical trial.42
Finally, the concept of using immunotherapy to boost the anti-tumor immune response is also being examined in sarcomas. A significant number of cases of STS, osteosarcoma and GIST have been shown to express programmed cell death protein-ligand 1, therefore the use of immune checkpoint inhibitors that block this ligand or its receptor and help to reactive tumor-infiltrating T cells, could be a beneficial strategy.
Limited activity has been observed in studies conducted to date, however combination therapies, especially with inhibitors of the indoleamine 2,3-dioxygenase (IDO) enzyme, which plays a key role in immunosuppression, could help to harness the power of these drugs. Studies have suggested that sarcomas may be infiltrated by immunosuppressive macrophages that express IDO.43
It is generally believed that immunotherapy is most effective in tumors that are highly mutated because that allows a large number of cancer antigens to provoke an anti-tumor immune response. However, a single highly expressed antigen can also be strongly immunogenic. Synovial sarcomas have a relatively low mutational burden but they do express high levels of the cancer testis antigen NY-ESO-1.
NY-ESO-1 has provided a useful target for the development of adoptive cell therapies and vaccines for the treatment of sarcomas. CMB305 is an NY-ESO-1 vaccine that also incorporates a toll-like receptor 4 agonist. It is being evaluated in the phase 3 Synovate study as maintenance monotherapy in patients with locally advanced, unresectable or metastatic synovial sarcoma. In a phase 1 study, at a median follow-up of just under 18 months, the median OS for all 25 patients was 23.7 months.44
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29.
2. Toro JR, Travis LB, Wu HJ, Zhu K, Fletcher CD, Devesa SS. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978-2001: An analysis of 26,758 cases. Int J Cancer. 2006;119(12):2922-2930.
3. Burningham Z, Hashibe M, Spector L, Schiffman JD. The epidemiology of sarcoma. Clin Sarcoma Res. 2012;2(1):14.
4. Italiano A, Mathoulin-Pelissier S, Cesne AL, et al. Trends in survival for patients with metastatic soft-tissue sarcoma. Cancer. 2011;117(5):1049-1054.
5. Savina M, Le Cesne A, Blay JY, et al. Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study. BMC Med. 2017;15(1):78.
6. Demetri GD, von Mehren M, Jones RL, et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol. 2016;34(8):786-793.
7. Schöffski P, Chawla S, Maki RG, et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet. 2016;387(10028):1629-1637.
8. Brennan MF, Antonescu CR, Moraco N, Singer S. Lessons learned from the study of 10,000 patients with soft tissue sarcoma. Ann Surg. 2014;260(3):416-421; discussion 421-412.
9. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21(23):4342-4349.
10. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299(5607):708-710.
11. Dagher R, Cohen M, Williams G, et al. Approval summary. Imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res. 2002;8(10):3034-3038.
12. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26(4):626-632.
13. Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364(9440):1127-1134.
14. Zhao R, Wang Y, Huang Y, et al. Adjuvant imatinib for patients with high-risk gastrointestinal stromal tumors: a retrospective cohort study. Scientific Reports. 2017;7:16834.
15. Raut C, Espat N, Maki R, Araujo D, Williams T, Wolff J. Extended treatment with adjuvant imatinib (IM) for patients (pts) with high-risk primary gastrointestinal stromal tumor (GIST): The PERSIST-5 study. J Clin Oncol. 2017;35(15_suppl):11009.
16. Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295-302.
17. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329-1338.
18. Versleijen-Jonkers YM, Vlenterie M, van de Luijtgaarden AC, van der Graaf WT. Anti-angiogenic therapy, a new player in the field of sarcoma treatment. Crit Rev Oncol Hematol. 2014;91(2):172-185.
19. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879-1886.
20. Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016;388(10043):488-497.
21. Chi Y, Yao Y, Wang S, et al. Anlotinib for metastatic soft tissue sarcoma: A randomized, double-blind, placebo-controlled and multi-centered clinical trial. J Clin Oncol. 2018;36(suppl):abstr 11503.
22. Brohl AS, Shah HR, Wang Y-C, Kasarskis A, Maki RG. The somatic mutational landscape in soft tissue sarcoma: Early results from TCGA data. J Clin Oncol. 2015;33(15_suppl):10508-10508.
23. Crompton BD, Stewart C, Taylor-Weiner A, et al. The genomic landscape of pediatric Ewing sarcoma. Cancer Discov. 2014;4(11):1326-1341.
24. Jour G, Scarborough JD, Jones RL, et al. Molecular profiling of soft tissue sarcomas using next-generation sequencing: a pilot study toward precision therapeutics. Hum Pathol. 2014;45(8):1563-1571.
25. Yang J-L. Investigation of osteosarcoma genomics and its impact on targeted therapy: an international collaboration to conquer human osteosarcoma. Chin J Cancer. 2014;33(12):575-580.
26. Cidre-Aranaz F, Alonso J. EWS/FLI1 target genes and therapeutic opportunities in Ewing sarcoma. Front Oncol. 2015;5:162.
27. Savoia C, Volpe M, Grassi G, Borghi C, Agabiti Rosei E, Touyz RM. Personalized medicine-a modern approach for the diagnosis and management of hypertension. Clin Sci (Lond). 2017;131(22):2671-2685.
28. Biswas B, Bakhshi S. Management of Ewing sarcoma family of tumors: Current scenario and unmet need. World J Orthop. 2016;7(9):527-538.
29. van Maldegem AM, Bovée JVMG, Peterse EFP, Hogendoorn PCW, Gelderblom H. Ewing sarcoma: the clinical relevance of the insulin-like growth factor 1 and the poly-ADP-ribose-polymerase pathway. Eur J Cancer. 2016;53:171-180.
30. Subbiah V, Hess KR, Khawaja MR, et al. Evaluation of novel targeted therapies in aggressive biology sarcoma patients after progression from US FDA approved therapies. Sci Rep. 2016;6:35448.
31. Jessen K, Moseley E, Chung EYL, et al. TK216, a novel, small molecule inhibitor of the ETS-family of transcription factors, displays anti-tumor activity in AML and DLBCL. Blood. 2016;128(22):4035-4035.
32. Sankhala K, Potts S, Christiansen J, et al. Immunohistochemistry screening to increase the efficacy of next-generation sequencing for detection of NTRK, ROS1, and ALK gene rearrangements (fusions) in sarcoma patients. Paper presented at: Connective Tissue Oncology Society Annual Meeting; November 9-12, 2016, 2016; Lisbon, Portugal.
33. Renfro LA, An MW, Mandrekar SJ. Precision oncology: a new era of cancer clinical trials. Cancer Lett. 2017;387:121-126.
34. DuBois S, Laetsch T, Federman N, et al. The use of larotrectinib in the management of locally advanced pediatric NTRK-fusion sarcoma. Paper presented at: Connective Tissue Oncology Society Annual Meeting; November 8-11, 2017; Maui, Hawaii.
35. Multani P, Manavel E, Hornby Z. Preliminary evidence of clinical response to entrectinib in three sarcome patients. Paper presented at: Connective Tissue Oncology Society Annual Meeting; November 8-11, 2017; Maui, Hawaii.
36. Barretina J, Taylor BS, Banerji S, et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat Genet. 2010;42(8):715-721.
37. Dickson MA, Schwartz GK, Keohan ML, et al. Progression-free survival among patients with well-differentiated or dedifferentiated liposarcoma treated with CDK4 inhibitor palbociclib: a phase 2 clinical trial. JAMA Oncol. 2016;2(7):937-940.
38. Barretina J, Caponigro G, Stransky N, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483(7391):603-607.
39. Kenichi K, Yoshinao O. Oncogenic roles of SMARCB1/INI1 and its deficient tumors. Cancer Science. 2017;108(4):547-552.
40. US Food and Drug Administration. Orphan drug designations and approvals. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=544416. Designated date September 28, 2017. Accessed July 4, 2018.
41. Press release. Epizyme provides update regarding tazemetostat clinical program. https://globenewswire.com/news-release/2018/04/23/1485765/0/en/Epizyme-Provides-Update-Regarding-Tazemetostat-Clinical-Program.html. Released April 23, 2018. Accessed July 4, 2018.
42. Bean GR, Kremer JC, Prudner BC, et al. A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas. Cell Death &Amp; Disease. 2016;7:e2406.
43. Bourcier K, Italiano A. Newer therapeutic strategies for soft-tissue sarcomas. Pharmacol Ther. 2018;188:118-123.
44. Somaiah N, Chawla SP, Block MS, et al. Immune response, safety, and survival impact from CMB305 in NY-ESO-1+ recurrent soft tissue sarcomas (STS). J Clin Oncol. 2017;35(15_suppl):11006-11006.
The rarity and complexities of bone and soft tissue sarcomas pose a major challenge to effective treatment. Historically, there has been a blanket approach to treatment, but more recently that has begun to change thanks to genome profiling studies and novel clinical trial strategies. Here, we discuss the resulting enrichment of the therapeutic armamentarium with molecularly targeted and immune therapies.
A challenging tumor type
Sarcomas are a large group of histologically diverse cancers that arise in the mesenchymal cells. They can be broadly divided into bone and soft tissue sarcomas (STS) but are further subdivided according to the type of cell from which they derive; osteosarcomas in the bone, rhabdomyosarcomas in the skeletal muscle, liposarcomas in the fat tissues, leiomyosarcomas in the smooth muscle, and chondrosarcomas in the cartilaginous tissue, for example.
Each sarcoma subtype itself encompasses a range of different cancers with unique biology. Under the umbrella of liposarcoma, for example, are well/dedifferentiated liposarcomas and myxoid liposarcomas, which have very different pathologies and clinical courses.
As a whole, sarcomas are extremely rare tumors, accounting for less than 1% of all adult cancers, although they disproportionately affect children and young adults, with a prevalence closer to 15%.1,2 Certain sarcoma subtypes are exceptionally rare, with only a few cases diagnosed worldwide each year, whereas liposarcomas are at the other end of the spectrum, comprising the most common form of STS (Figure 1).3
In the early stages, sarcomas are generally highly treatable with a combination of surgical resection, chemotherapy, and radiation therapy. However, many patients develop advanced, metastatic disease, which presents much more of a challenge.4,5
Magic bullet for GIST
Despite their clear heterogeneity and complexity, sarcomas have tended to be treated as a single entity. Chemotherapy has played a central role in the treatment of advanced sarcomas and continues to do so, with 2 newer drugs approved by the United States Food and Drug Administration (FDA) in the past several years.6,7
The development of targeted therapy, on the other hand, for the most part proved unsuccessful. In general, studies examining the somatic mutation landscape in sarcomas found very few that were highly recurrent. The exception was gastrointestinal stromal tumors (GIST), which represent around 8% of STS.8 Frequent mutations in several highly targetable tyrosine kinases, notably KIT, which is mutated in around 85% of cases,9 and platelet-derived growth factor receptor alpha (PDGFRα) were identified in these tumors.10This prompted the development of tyrosine kinase inhibitors (TKIs), targeting these and other kinases, for the treatment of patients with GIST, and culminated in the approval of imatinib for this indication in 2002. This revolutionized the treatment of GIST, which had a poor prognosis and were resistant to chemotherapy, extending median overall survival in patients with metastatic disease almost to 5 years.11-13
Imatinib was also shown to benefit patients with surgically resectable disease and was subsequently approved in the adjuvant setting in 2008. A recent trial demonstrated that 3-year continuation of adjuvant imatinib resulted in a significantly longer progression-free survival (PFS) compared with 1 year of adjuvant imatinib, and even longer time periods are now being evaluated.14,15 The TKIs sunitinib and regorafenib have also been approved for the treatment of patients who become resistant to imatinib.16,17 Avapritinib, a newer, more specific inhibitor of KIT is also being evaluated in patients with GIST (Table).
Long-sought success for STS
Sunitinib and regorafenib include PDGFRα and the vascular endothelial growth factor receptors (VEGFRs) among their targets, receptors that play crucial roles in the formation of new blood vessels (angiogenesis). Many types of non-GIST sarcomas have been shown to be highly vascularized and express high levels of both of those receptors and other angiogenic proteins, which sparked interest in the development of multitargeted TKIs and other anti-angiogenic drugs in patients with STS.18
In 2012, pazopanib became the first FDA-approved molecularly targeted therapy for the treatment of non-GIST sarcomas. Approval in the second-line setting was based on the demonstration of a 3-month improvement in PFS compared with placebo.19 Four years later, the monoclonal antibody olaratumab, a more specific inhibitor of PDGFRα, was approved in combination with doxorubicin, marking the first front-line approval for more than 4 decades.20Numerous other anti-angiogenic drugs continue to be evaluated for the treatment of advanced STS. Among them, anlotinib is being tested in phase 3 clinical trials, and results from the ALTER0203 trial were presented at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO).21 After failure of chemotherapy, 223 patients were randomly assigned to receive either anlotinib or placebo. Anlotinib significantly improved median PFS across all patients, compared with placebo (6.27 vs 1.4 months, respectively; hazard ratio [HR], 0.33; P < .0001), but was especially effective in patients with alveolar soft part sarcoma (ASPS; mPFS: 18.2 vs 3 months) and was well tolerated.21
Sarcoma secrets revealed
Advancements in genome sequencing technologies have made it possible to interrogate the molecular underpinnings of sarcomas in greater detail. However, their rarity presents a significant technical challenge, with a dearth of samples available for genomic testing. Large-scale worldwide collaborative efforts have facilitated the collection of sufficiently large patient populations to provide statistically robust data in many cases. The Cancer Genome Atlas has established a rare tumor characterization project to facilitate the genomic sequencing of rare cancer types like sarcomas.
Genome sequencing studies have revealed 2 types of sarcomas: those with relatively stable genomes and few molecular alterations, exemplified by Ewing sarcoma, which has a mutational load of 0.15 mutations/Megabase (Mb); and those that are much more complex with frequent somatic mutations, the prime example being leiomyosarcoma. The latter are characterized by mutations in the TP53 gene, dubbed the “guardian of the genome” for its essential role in genome stability.
The 2 types are likely to require very different therapeutic strategies. Although genomically complex tumors offer up lots of potential targets for therapy, they also display significant heterogeneity and it can be challenging to find a shared target across different tumor samples. The p53 protein would make a logical target but, to date, tumor suppressor proteins are not readily druggable.
The most common type of molecular alterations in sarcomas are chromosomal translocations, where part of a chromosome breaks off and becomes reattached to another chromosome. This can result in the formation of a gene fusion when parts of 2 different genes are brought together in a way in which the genetic code can still be read, leading to the formation of a fusion protein with altered activity.22-25
In sarcomas, these chromosomal translocations predominantly involve genes encoding transcription factors and the gene fusion results in their aberrant expression and activation of the transcriptional programs that they regulate.
Ewing sarcoma is a prime example of a sarcoma that is defined by chromosomal translocations. Most often, the resulting gene fusions occur between members of theten-eleven translocation (TET) family of RNA-binding proteins and the E26 transformation-specific (ETS) family of transcription factors. The most common fusion is between the EWSR1 and FLI1 genes, observed in between 85% and 90% of cases.
Significant efforts have been made to target EWSR1-FLI1. Since direct targeting of transcription factors is challenging, those efforts focused on targeting the aberrant transcriptional programs that they initiate. A major downstream target is the insulin-like growth factor receptor 1 (IGF1R) and numerous IGF1R inhibitors were developed and tested in patients with Ewing sarcoma, but unfortunately success was limited. Attention turned to the mammalian target of rapamycin (mTOR) as a potential mechanism of resistance to IGF1R inhibitors and explanation for the limited responses. Clinical trials combining mTOR and IGF1R inhibitors also proved unsuccessful.26
Although overall these trials were deemed failures, they were notable for the dramatic responses that were seen in 1 or 2 patients. Researchers are probing these “exceptional responses” using novel N-of-1 clinical trial designs that focus on a single patient (Figure 2).27-30 More recently, the first drug to specifically target the EWSR1-FLI1 fusion protein was developed. TK216 binds to the fusion protein and prevents it from binding to RNA helicase A, thereby blocking its function.31
Another type of gene fusion, involving the neurotrophic tropomyosin receptor kinase (NTRK) genes, has recently come into the spotlight for the treatment of lung cancer. According to a recent study, NTRK fusions may also be common in sarcomas. They were observed in 8% of patients with breast sarcomas, 5% with fibrosarcomas, and 5% with stomach or small intestine sarcomas.32
The NTRK genes encode TRK proteins and several small molecule inhibitors of TRK have been developed to treat patients with NTRK fusion-positive cancers. Another novel clinical trial design – the basket trial – is being used to test these inhibitors. This type of trial uses a tumor-agnostic approach, recruiting patients with all different histological subtypes of cancer that are unified by the shared presence of a specific molecular alteration.33
Repurposing gynecologic cancer drugs
More recently, a third group of sarcomas was categorized, with intermediate genomic complexity. These tumors, including well/dedifferentiated liposarcomas, were characterized by amplifications of chromosome 12, involving genes such as cyclin-dependent kinase 4 (CDK4). In fact, more than 90% of patients with well/dedifferentiated sarcomas display CDK4 amplification, making it a logical therapeutic target.36
CDK4 encodes CDK4 protein, a cell cycle-associated protein that regulates the transition from G1-S phase, known as the restriction point, beyond which the cell commits to undergoing mitosis. Aberrant expression of CDK4 in cancer drives the hallmark process of unchecked cellular proliferation.
Some small molecule CDK4/6 inhibitors have been developed and have shown significant promise in the treatment of breast cancer. They are also being evaluatedin patients with sarcoma whose tumors display CDK4 overexpression. In a recently published phase 2 trial of palbociclib in 60 patients with well/dedifferentiated liposarcomas, there was 1 CR.37
Another group of drugs that has advanced the treatment of gynecologic cancers comprises the poly (ADP-ribose) polymerase (PARP) inhibitors. In this context, PARP inhibitors are used in patients with mutations in the breast cancer susceptibility genes, BRCA1/2. The BRCA and PARP proteins are both involved in DNA repair pathways and the inhibition of PARP in patients who already have a defective BRCA pathway renders a lethal double blow to the cancer cell. According to the Broad Institute Cancer Cell Line Encyclopedia, Ewing sarcomas express high levels of the PARP1 enzyme, which could render them sensitive to PARP inhibition. Preclinical studies seemed to confirm that sensitivity, however, so far this has yet to translate into success in clinical trials, with no objective responses observed as yet.38
Expanding the field
Other treatment strategies being tested in patients with sarcoma are moving the field beyond conventional targeted therapies. There has been substantial focus in recent years on epigenetic alterations and their potential role in the development of cancer. Epigenetics is the secondary layer of regulation that acts on the genome and directs the spatial and temporal expression of genes.
Both DNA and the histone proteins they are packaged up with to form chromatin in nondividing cells can be modified by the attachment of chemical groups, such as acetyl and methyl groups, which can alter access to the DNA for transcription.
EZH2 is an enzyme that participates in histone methylation and thereby regulates transcriptional repression. Some types of sarcoma are characterized by a loss of expression of the INI1 gene, also known as SMARCB1. The INI1 protein is part of a chromatin remodeling complex that relieves transcriptional repression and when INI1 is lost, cells become dependent upon EZH2.39Clinical trials of the EZH2 inhibitor tazemetostat are ongoing in several types of sarcoma. Results from a phase 2 study in adults with INI1-negative tumors were presented at ASCO in 2017. Among 31 patients treated with 800 mg tazemetostat in continuous 28-day cycles, mPFS was 5.7 months, disease control rate was 10%, and confirmed overall response rate was 13%. The FDA has granted tazemetostat orphan drug designation in this indication.40A pediatric basket trial of tazemetostat is also ongoing, but the FDA recently placed it under a clinical hold as a result of a safety update from the trial in which a pediatric patient with advanced poorly differentiated chordoma developed a secondary T-cell lymphoma.41
Targeting the unique metabolism of sarcomas may offer a promising therapeutic strategy, although this is in the preliminary stages of evaluation. A recent study showed that the expression of the argininosuccinate synthase 1 enzyme, which is involved in the generation of arginine through the urea cycle, was lost in up to 90% of STS. A pegylated arginine deaminase (ADI-PEG20), is being evaluated in a phase 2 clinical trial.42
Finally, the concept of using immunotherapy to boost the anti-tumor immune response is also being examined in sarcomas. A significant number of cases of STS, osteosarcoma and GIST have been shown to express programmed cell death protein-ligand 1, therefore the use of immune checkpoint inhibitors that block this ligand or its receptor and help to reactive tumor-infiltrating T cells, could be a beneficial strategy.
Limited activity has been observed in studies conducted to date, however combination therapies, especially with inhibitors of the indoleamine 2,3-dioxygenase (IDO) enzyme, which plays a key role in immunosuppression, could help to harness the power of these drugs. Studies have suggested that sarcomas may be infiltrated by immunosuppressive macrophages that express IDO.43
It is generally believed that immunotherapy is most effective in tumors that are highly mutated because that allows a large number of cancer antigens to provoke an anti-tumor immune response. However, a single highly expressed antigen can also be strongly immunogenic. Synovial sarcomas have a relatively low mutational burden but they do express high levels of the cancer testis antigen NY-ESO-1.
NY-ESO-1 has provided a useful target for the development of adoptive cell therapies and vaccines for the treatment of sarcomas. CMB305 is an NY-ESO-1 vaccine that also incorporates a toll-like receptor 4 agonist. It is being evaluated in the phase 3 Synovate study as maintenance monotherapy in patients with locally advanced, unresectable or metastatic synovial sarcoma. In a phase 1 study, at a median follow-up of just under 18 months, the median OS for all 25 patients was 23.7 months.44
The rarity and complexities of bone and soft tissue sarcomas pose a major challenge to effective treatment. Historically, there has been a blanket approach to treatment, but more recently that has begun to change thanks to genome profiling studies and novel clinical trial strategies. Here, we discuss the resulting enrichment of the therapeutic armamentarium with molecularly targeted and immune therapies.
A challenging tumor type
Sarcomas are a large group of histologically diverse cancers that arise in the mesenchymal cells. They can be broadly divided into bone and soft tissue sarcomas (STS) but are further subdivided according to the type of cell from which they derive; osteosarcomas in the bone, rhabdomyosarcomas in the skeletal muscle, liposarcomas in the fat tissues, leiomyosarcomas in the smooth muscle, and chondrosarcomas in the cartilaginous tissue, for example.
Each sarcoma subtype itself encompasses a range of different cancers with unique biology. Under the umbrella of liposarcoma, for example, are well/dedifferentiated liposarcomas and myxoid liposarcomas, which have very different pathologies and clinical courses.
As a whole, sarcomas are extremely rare tumors, accounting for less than 1% of all adult cancers, although they disproportionately affect children and young adults, with a prevalence closer to 15%.1,2 Certain sarcoma subtypes are exceptionally rare, with only a few cases diagnosed worldwide each year, whereas liposarcomas are at the other end of the spectrum, comprising the most common form of STS (Figure 1).3
In the early stages, sarcomas are generally highly treatable with a combination of surgical resection, chemotherapy, and radiation therapy. However, many patients develop advanced, metastatic disease, which presents much more of a challenge.4,5
Magic bullet for GIST
Despite their clear heterogeneity and complexity, sarcomas have tended to be treated as a single entity. Chemotherapy has played a central role in the treatment of advanced sarcomas and continues to do so, with 2 newer drugs approved by the United States Food and Drug Administration (FDA) in the past several years.6,7
The development of targeted therapy, on the other hand, for the most part proved unsuccessful. In general, studies examining the somatic mutation landscape in sarcomas found very few that were highly recurrent. The exception was gastrointestinal stromal tumors (GIST), which represent around 8% of STS.8 Frequent mutations in several highly targetable tyrosine kinases, notably KIT, which is mutated in around 85% of cases,9 and platelet-derived growth factor receptor alpha (PDGFRα) were identified in these tumors.10This prompted the development of tyrosine kinase inhibitors (TKIs), targeting these and other kinases, for the treatment of patients with GIST, and culminated in the approval of imatinib for this indication in 2002. This revolutionized the treatment of GIST, which had a poor prognosis and were resistant to chemotherapy, extending median overall survival in patients with metastatic disease almost to 5 years.11-13
Imatinib was also shown to benefit patients with surgically resectable disease and was subsequently approved in the adjuvant setting in 2008. A recent trial demonstrated that 3-year continuation of adjuvant imatinib resulted in a significantly longer progression-free survival (PFS) compared with 1 year of adjuvant imatinib, and even longer time periods are now being evaluated.14,15 The TKIs sunitinib and regorafenib have also been approved for the treatment of patients who become resistant to imatinib.16,17 Avapritinib, a newer, more specific inhibitor of KIT is also being evaluated in patients with GIST (Table).
Long-sought success for STS
Sunitinib and regorafenib include PDGFRα and the vascular endothelial growth factor receptors (VEGFRs) among their targets, receptors that play crucial roles in the formation of new blood vessels (angiogenesis). Many types of non-GIST sarcomas have been shown to be highly vascularized and express high levels of both of those receptors and other angiogenic proteins, which sparked interest in the development of multitargeted TKIs and other anti-angiogenic drugs in patients with STS.18
In 2012, pazopanib became the first FDA-approved molecularly targeted therapy for the treatment of non-GIST sarcomas. Approval in the second-line setting was based on the demonstration of a 3-month improvement in PFS compared with placebo.19 Four years later, the monoclonal antibody olaratumab, a more specific inhibitor of PDGFRα, was approved in combination with doxorubicin, marking the first front-line approval for more than 4 decades.20Numerous other anti-angiogenic drugs continue to be evaluated for the treatment of advanced STS. Among them, anlotinib is being tested in phase 3 clinical trials, and results from the ALTER0203 trial were presented at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO).21 After failure of chemotherapy, 223 patients were randomly assigned to receive either anlotinib or placebo. Anlotinib significantly improved median PFS across all patients, compared with placebo (6.27 vs 1.4 months, respectively; hazard ratio [HR], 0.33; P < .0001), but was especially effective in patients with alveolar soft part sarcoma (ASPS; mPFS: 18.2 vs 3 months) and was well tolerated.21
Sarcoma secrets revealed
Advancements in genome sequencing technologies have made it possible to interrogate the molecular underpinnings of sarcomas in greater detail. However, their rarity presents a significant technical challenge, with a dearth of samples available for genomic testing. Large-scale worldwide collaborative efforts have facilitated the collection of sufficiently large patient populations to provide statistically robust data in many cases. The Cancer Genome Atlas has established a rare tumor characterization project to facilitate the genomic sequencing of rare cancer types like sarcomas.
Genome sequencing studies have revealed 2 types of sarcomas: those with relatively stable genomes and few molecular alterations, exemplified by Ewing sarcoma, which has a mutational load of 0.15 mutations/Megabase (Mb); and those that are much more complex with frequent somatic mutations, the prime example being leiomyosarcoma. The latter are characterized by mutations in the TP53 gene, dubbed the “guardian of the genome” for its essential role in genome stability.
The 2 types are likely to require very different therapeutic strategies. Although genomically complex tumors offer up lots of potential targets for therapy, they also display significant heterogeneity and it can be challenging to find a shared target across different tumor samples. The p53 protein would make a logical target but, to date, tumor suppressor proteins are not readily druggable.
The most common type of molecular alterations in sarcomas are chromosomal translocations, where part of a chromosome breaks off and becomes reattached to another chromosome. This can result in the formation of a gene fusion when parts of 2 different genes are brought together in a way in which the genetic code can still be read, leading to the formation of a fusion protein with altered activity.22-25
In sarcomas, these chromosomal translocations predominantly involve genes encoding transcription factors and the gene fusion results in their aberrant expression and activation of the transcriptional programs that they regulate.
Ewing sarcoma is a prime example of a sarcoma that is defined by chromosomal translocations. Most often, the resulting gene fusions occur between members of theten-eleven translocation (TET) family of RNA-binding proteins and the E26 transformation-specific (ETS) family of transcription factors. The most common fusion is between the EWSR1 and FLI1 genes, observed in between 85% and 90% of cases.
Significant efforts have been made to target EWSR1-FLI1. Since direct targeting of transcription factors is challenging, those efforts focused on targeting the aberrant transcriptional programs that they initiate. A major downstream target is the insulin-like growth factor receptor 1 (IGF1R) and numerous IGF1R inhibitors were developed and tested in patients with Ewing sarcoma, but unfortunately success was limited. Attention turned to the mammalian target of rapamycin (mTOR) as a potential mechanism of resistance to IGF1R inhibitors and explanation for the limited responses. Clinical trials combining mTOR and IGF1R inhibitors also proved unsuccessful.26
Although overall these trials were deemed failures, they were notable for the dramatic responses that were seen in 1 or 2 patients. Researchers are probing these “exceptional responses” using novel N-of-1 clinical trial designs that focus on a single patient (Figure 2).27-30 More recently, the first drug to specifically target the EWSR1-FLI1 fusion protein was developed. TK216 binds to the fusion protein and prevents it from binding to RNA helicase A, thereby blocking its function.31
Another type of gene fusion, involving the neurotrophic tropomyosin receptor kinase (NTRK) genes, has recently come into the spotlight for the treatment of lung cancer. According to a recent study, NTRK fusions may also be common in sarcomas. They were observed in 8% of patients with breast sarcomas, 5% with fibrosarcomas, and 5% with stomach or small intestine sarcomas.32
The NTRK genes encode TRK proteins and several small molecule inhibitors of TRK have been developed to treat patients with NTRK fusion-positive cancers. Another novel clinical trial design – the basket trial – is being used to test these inhibitors. This type of trial uses a tumor-agnostic approach, recruiting patients with all different histological subtypes of cancer that are unified by the shared presence of a specific molecular alteration.33
Repurposing gynecologic cancer drugs
More recently, a third group of sarcomas was categorized, with intermediate genomic complexity. These tumors, including well/dedifferentiated liposarcomas, were characterized by amplifications of chromosome 12, involving genes such as cyclin-dependent kinase 4 (CDK4). In fact, more than 90% of patients with well/dedifferentiated sarcomas display CDK4 amplification, making it a logical therapeutic target.36
CDK4 encodes CDK4 protein, a cell cycle-associated protein that regulates the transition from G1-S phase, known as the restriction point, beyond which the cell commits to undergoing mitosis. Aberrant expression of CDK4 in cancer drives the hallmark process of unchecked cellular proliferation.
Some small molecule CDK4/6 inhibitors have been developed and have shown significant promise in the treatment of breast cancer. They are also being evaluatedin patients with sarcoma whose tumors display CDK4 overexpression. In a recently published phase 2 trial of palbociclib in 60 patients with well/dedifferentiated liposarcomas, there was 1 CR.37
Another group of drugs that has advanced the treatment of gynecologic cancers comprises the poly (ADP-ribose) polymerase (PARP) inhibitors. In this context, PARP inhibitors are used in patients with mutations in the breast cancer susceptibility genes, BRCA1/2. The BRCA and PARP proteins are both involved in DNA repair pathways and the inhibition of PARP in patients who already have a defective BRCA pathway renders a lethal double blow to the cancer cell. According to the Broad Institute Cancer Cell Line Encyclopedia, Ewing sarcomas express high levels of the PARP1 enzyme, which could render them sensitive to PARP inhibition. Preclinical studies seemed to confirm that sensitivity, however, so far this has yet to translate into success in clinical trials, with no objective responses observed as yet.38
Expanding the field
Other treatment strategies being tested in patients with sarcoma are moving the field beyond conventional targeted therapies. There has been substantial focus in recent years on epigenetic alterations and their potential role in the development of cancer. Epigenetics is the secondary layer of regulation that acts on the genome and directs the spatial and temporal expression of genes.
Both DNA and the histone proteins they are packaged up with to form chromatin in nondividing cells can be modified by the attachment of chemical groups, such as acetyl and methyl groups, which can alter access to the DNA for transcription.
EZH2 is an enzyme that participates in histone methylation and thereby regulates transcriptional repression. Some types of sarcoma are characterized by a loss of expression of the INI1 gene, also known as SMARCB1. The INI1 protein is part of a chromatin remodeling complex that relieves transcriptional repression and when INI1 is lost, cells become dependent upon EZH2.39Clinical trials of the EZH2 inhibitor tazemetostat are ongoing in several types of sarcoma. Results from a phase 2 study in adults with INI1-negative tumors were presented at ASCO in 2017. Among 31 patients treated with 800 mg tazemetostat in continuous 28-day cycles, mPFS was 5.7 months, disease control rate was 10%, and confirmed overall response rate was 13%. The FDA has granted tazemetostat orphan drug designation in this indication.40A pediatric basket trial of tazemetostat is also ongoing, but the FDA recently placed it under a clinical hold as a result of a safety update from the trial in which a pediatric patient with advanced poorly differentiated chordoma developed a secondary T-cell lymphoma.41
Targeting the unique metabolism of sarcomas may offer a promising therapeutic strategy, although this is in the preliminary stages of evaluation. A recent study showed that the expression of the argininosuccinate synthase 1 enzyme, which is involved in the generation of arginine through the urea cycle, was lost in up to 90% of STS. A pegylated arginine deaminase (ADI-PEG20), is being evaluated in a phase 2 clinical trial.42
Finally, the concept of using immunotherapy to boost the anti-tumor immune response is also being examined in sarcomas. A significant number of cases of STS, osteosarcoma and GIST have been shown to express programmed cell death protein-ligand 1, therefore the use of immune checkpoint inhibitors that block this ligand or its receptor and help to reactive tumor-infiltrating T cells, could be a beneficial strategy.
Limited activity has been observed in studies conducted to date, however combination therapies, especially with inhibitors of the indoleamine 2,3-dioxygenase (IDO) enzyme, which plays a key role in immunosuppression, could help to harness the power of these drugs. Studies have suggested that sarcomas may be infiltrated by immunosuppressive macrophages that express IDO.43
It is generally believed that immunotherapy is most effective in tumors that are highly mutated because that allows a large number of cancer antigens to provoke an anti-tumor immune response. However, a single highly expressed antigen can also be strongly immunogenic. Synovial sarcomas have a relatively low mutational burden but they do express high levels of the cancer testis antigen NY-ESO-1.
NY-ESO-1 has provided a useful target for the development of adoptive cell therapies and vaccines for the treatment of sarcomas. CMB305 is an NY-ESO-1 vaccine that also incorporates a toll-like receptor 4 agonist. It is being evaluated in the phase 3 Synovate study as maintenance monotherapy in patients with locally advanced, unresectable or metastatic synovial sarcoma. In a phase 1 study, at a median follow-up of just under 18 months, the median OS for all 25 patients was 23.7 months.44
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29.
2. Toro JR, Travis LB, Wu HJ, Zhu K, Fletcher CD, Devesa SS. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978-2001: An analysis of 26,758 cases. Int J Cancer. 2006;119(12):2922-2930.
3. Burningham Z, Hashibe M, Spector L, Schiffman JD. The epidemiology of sarcoma. Clin Sarcoma Res. 2012;2(1):14.
4. Italiano A, Mathoulin-Pelissier S, Cesne AL, et al. Trends in survival for patients with metastatic soft-tissue sarcoma. Cancer. 2011;117(5):1049-1054.
5. Savina M, Le Cesne A, Blay JY, et al. Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study. BMC Med. 2017;15(1):78.
6. Demetri GD, von Mehren M, Jones RL, et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol. 2016;34(8):786-793.
7. Schöffski P, Chawla S, Maki RG, et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet. 2016;387(10028):1629-1637.
8. Brennan MF, Antonescu CR, Moraco N, Singer S. Lessons learned from the study of 10,000 patients with soft tissue sarcoma. Ann Surg. 2014;260(3):416-421; discussion 421-412.
9. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21(23):4342-4349.
10. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299(5607):708-710.
11. Dagher R, Cohen M, Williams G, et al. Approval summary. Imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res. 2002;8(10):3034-3038.
12. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26(4):626-632.
13. Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364(9440):1127-1134.
14. Zhao R, Wang Y, Huang Y, et al. Adjuvant imatinib for patients with high-risk gastrointestinal stromal tumors: a retrospective cohort study. Scientific Reports. 2017;7:16834.
15. Raut C, Espat N, Maki R, Araujo D, Williams T, Wolff J. Extended treatment with adjuvant imatinib (IM) for patients (pts) with high-risk primary gastrointestinal stromal tumor (GIST): The PERSIST-5 study. J Clin Oncol. 2017;35(15_suppl):11009.
16. Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295-302.
17. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329-1338.
18. Versleijen-Jonkers YM, Vlenterie M, van de Luijtgaarden AC, van der Graaf WT. Anti-angiogenic therapy, a new player in the field of sarcoma treatment. Crit Rev Oncol Hematol. 2014;91(2):172-185.
19. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879-1886.
20. Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016;388(10043):488-497.
21. Chi Y, Yao Y, Wang S, et al. Anlotinib for metastatic soft tissue sarcoma: A randomized, double-blind, placebo-controlled and multi-centered clinical trial. J Clin Oncol. 2018;36(suppl):abstr 11503.
22. Brohl AS, Shah HR, Wang Y-C, Kasarskis A, Maki RG. The somatic mutational landscape in soft tissue sarcoma: Early results from TCGA data. J Clin Oncol. 2015;33(15_suppl):10508-10508.
23. Crompton BD, Stewart C, Taylor-Weiner A, et al. The genomic landscape of pediatric Ewing sarcoma. Cancer Discov. 2014;4(11):1326-1341.
24. Jour G, Scarborough JD, Jones RL, et al. Molecular profiling of soft tissue sarcomas using next-generation sequencing: a pilot study toward precision therapeutics. Hum Pathol. 2014;45(8):1563-1571.
25. Yang J-L. Investigation of osteosarcoma genomics and its impact on targeted therapy: an international collaboration to conquer human osteosarcoma. Chin J Cancer. 2014;33(12):575-580.
26. Cidre-Aranaz F, Alonso J. EWS/FLI1 target genes and therapeutic opportunities in Ewing sarcoma. Front Oncol. 2015;5:162.
27. Savoia C, Volpe M, Grassi G, Borghi C, Agabiti Rosei E, Touyz RM. Personalized medicine-a modern approach for the diagnosis and management of hypertension. Clin Sci (Lond). 2017;131(22):2671-2685.
28. Biswas B, Bakhshi S. Management of Ewing sarcoma family of tumors: Current scenario and unmet need. World J Orthop. 2016;7(9):527-538.
29. van Maldegem AM, Bovée JVMG, Peterse EFP, Hogendoorn PCW, Gelderblom H. Ewing sarcoma: the clinical relevance of the insulin-like growth factor 1 and the poly-ADP-ribose-polymerase pathway. Eur J Cancer. 2016;53:171-180.
30. Subbiah V, Hess KR, Khawaja MR, et al. Evaluation of novel targeted therapies in aggressive biology sarcoma patients after progression from US FDA approved therapies. Sci Rep. 2016;6:35448.
31. Jessen K, Moseley E, Chung EYL, et al. TK216, a novel, small molecule inhibitor of the ETS-family of transcription factors, displays anti-tumor activity in AML and DLBCL. Blood. 2016;128(22):4035-4035.
32. Sankhala K, Potts S, Christiansen J, et al. Immunohistochemistry screening to increase the efficacy of next-generation sequencing for detection of NTRK, ROS1, and ALK gene rearrangements (fusions) in sarcoma patients. Paper presented at: Connective Tissue Oncology Society Annual Meeting; November 9-12, 2016, 2016; Lisbon, Portugal.
33. Renfro LA, An MW, Mandrekar SJ. Precision oncology: a new era of cancer clinical trials. Cancer Lett. 2017;387:121-126.
34. DuBois S, Laetsch T, Federman N, et al. The use of larotrectinib in the management of locally advanced pediatric NTRK-fusion sarcoma. Paper presented at: Connective Tissue Oncology Society Annual Meeting; November 8-11, 2017; Maui, Hawaii.
35. Multani P, Manavel E, Hornby Z. Preliminary evidence of clinical response to entrectinib in three sarcome patients. Paper presented at: Connective Tissue Oncology Society Annual Meeting; November 8-11, 2017; Maui, Hawaii.
36. Barretina J, Taylor BS, Banerji S, et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat Genet. 2010;42(8):715-721.
37. Dickson MA, Schwartz GK, Keohan ML, et al. Progression-free survival among patients with well-differentiated or dedifferentiated liposarcoma treated with CDK4 inhibitor palbociclib: a phase 2 clinical trial. JAMA Oncol. 2016;2(7):937-940.
38. Barretina J, Caponigro G, Stransky N, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483(7391):603-607.
39. Kenichi K, Yoshinao O. Oncogenic roles of SMARCB1/INI1 and its deficient tumors. Cancer Science. 2017;108(4):547-552.
40. US Food and Drug Administration. Orphan drug designations and approvals. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=544416. Designated date September 28, 2017. Accessed July 4, 2018.
41. Press release. Epizyme provides update regarding tazemetostat clinical program. https://globenewswire.com/news-release/2018/04/23/1485765/0/en/Epizyme-Provides-Update-Regarding-Tazemetostat-Clinical-Program.html. Released April 23, 2018. Accessed July 4, 2018.
42. Bean GR, Kremer JC, Prudner BC, et al. A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas. Cell Death &Amp; Disease. 2016;7:e2406.
43. Bourcier K, Italiano A. Newer therapeutic strategies for soft-tissue sarcomas. Pharmacol Ther. 2018;188:118-123.
44. Somaiah N, Chawla SP, Block MS, et al. Immune response, safety, and survival impact from CMB305 in NY-ESO-1+ recurrent soft tissue sarcomas (STS). J Clin Oncol. 2017;35(15_suppl):11006-11006.
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29.
2. Toro JR, Travis LB, Wu HJ, Zhu K, Fletcher CD, Devesa SS. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978-2001: An analysis of 26,758 cases. Int J Cancer. 2006;119(12):2922-2930.
3. Burningham Z, Hashibe M, Spector L, Schiffman JD. The epidemiology of sarcoma. Clin Sarcoma Res. 2012;2(1):14.
4. Italiano A, Mathoulin-Pelissier S, Cesne AL, et al. Trends in survival for patients with metastatic soft-tissue sarcoma. Cancer. 2011;117(5):1049-1054.
5. Savina M, Le Cesne A, Blay JY, et al. Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study. BMC Med. 2017;15(1):78.
6. Demetri GD, von Mehren M, Jones RL, et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol. 2016;34(8):786-793.
7. Schöffski P, Chawla S, Maki RG, et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet. 2016;387(10028):1629-1637.
8. Brennan MF, Antonescu CR, Moraco N, Singer S. Lessons learned from the study of 10,000 patients with soft tissue sarcoma. Ann Surg. 2014;260(3):416-421; discussion 421-412.
9. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21(23):4342-4349.
10. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299(5607):708-710.
11. Dagher R, Cohen M, Williams G, et al. Approval summary. Imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res. 2002;8(10):3034-3038.
12. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26(4):626-632.
13. Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364(9440):1127-1134.
14. Zhao R, Wang Y, Huang Y, et al. Adjuvant imatinib for patients with high-risk gastrointestinal stromal tumors: a retrospective cohort study. Scientific Reports. 2017;7:16834.
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16. Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295-302.
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18. Versleijen-Jonkers YM, Vlenterie M, van de Luijtgaarden AC, van der Graaf WT. Anti-angiogenic therapy, a new player in the field of sarcoma treatment. Crit Rev Oncol Hematol. 2014;91(2):172-185.
19. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879-1886.
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23. Crompton BD, Stewart C, Taylor-Weiner A, et al. The genomic landscape of pediatric Ewing sarcoma. Cancer Discov. 2014;4(11):1326-1341.
24. Jour G, Scarborough JD, Jones RL, et al. Molecular profiling of soft tissue sarcomas using next-generation sequencing: a pilot study toward precision therapeutics. Hum Pathol. 2014;45(8):1563-1571.
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28. Biswas B, Bakhshi S. Management of Ewing sarcoma family of tumors: Current scenario and unmet need. World J Orthop. 2016;7(9):527-538.
29. van Maldegem AM, Bovée JVMG, Peterse EFP, Hogendoorn PCW, Gelderblom H. Ewing sarcoma: the clinical relevance of the insulin-like growth factor 1 and the poly-ADP-ribose-polymerase pathway. Eur J Cancer. 2016;53:171-180.
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32. Sankhala K, Potts S, Christiansen J, et al. Immunohistochemistry screening to increase the efficacy of next-generation sequencing for detection of NTRK, ROS1, and ALK gene rearrangements (fusions) in sarcoma patients. Paper presented at: Connective Tissue Oncology Society Annual Meeting; November 9-12, 2016, 2016; Lisbon, Portugal.
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35. Multani P, Manavel E, Hornby Z. Preliminary evidence of clinical response to entrectinib in three sarcome patients. Paper presented at: Connective Tissue Oncology Society Annual Meeting; November 8-11, 2017; Maui, Hawaii.
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37. Dickson MA, Schwartz GK, Keohan ML, et al. Progression-free survival among patients with well-differentiated or dedifferentiated liposarcoma treated with CDK4 inhibitor palbociclib: a phase 2 clinical trial. JAMA Oncol. 2016;2(7):937-940.
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44. Somaiah N, Chawla SP, Block MS, et al. Immune response, safety, and survival impact from CMB305 in NY-ESO-1+ recurrent soft tissue sarcomas (STS). J Clin Oncol. 2017;35(15_suppl):11006-11006.
Adjuvant chemotherapy benefits high-risk sarcoma patients
CHICAGO – Patients with high-risk soft-tissue sarcomas identified by patient data and a risk calculator had significantly better overall and disease-free survival when they were treated with adjuvant doxorubicin and ifosfamide, a retrospective analysis from a randomized clinical trial showed.
The findings suggest that future clinical trials for sarcoma therapies may need to focus on specific risk categories, investigators said.
Among 290 patients with soft tissues sarcomas (STS) of the trunk wall or extremities, adjuvant chemotherapy with doxorubicin, ifosfamide, mesna, and lenograstim more than halved the risk of death for patients determined by the nomogram to have a low probability of 10-year overall survival, reported Sandro Pasquali, MD, from the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, and his colleagues.
“These findings interpret conflicting results of randomized controlled trials on perioperative chemotherapy in STS showing that inclusion of low-risk tumors have diluted the effect of chemotherapy leading to negative results and small study effect in meta-analysis,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.
The clinical trial in question, EORTC-STBSG 62931, results of which were published in 2012 in The Lancet Oncology, was technically a failure, because it did not show a significant benefit of adjuvant chemotherapy vs. observation in patients with STS.
To see whether adjuvant chemotherapy may have benefited select patients, the investigators calculated 10-year probabilities of overall survival (P-OS) for 290 patients with STS of the trunk wall or extremities out of the total trial cohort of 351 patients. The P-OS for each of three categories – low (51% or less), intermediate (52%-66%), and high (67% or greater) – was calculated using individual patient data and the freely available smartphone-based nomogram Sarculator (available in the Apple App Store and Google Play).
They calculated disease-free survival at the study median follow-up of 8 years.
The tumor histologies included malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, and others.
A total of 52 patients were in the low P-OS group, including 24 treated with observation, and 28 with adjuvant chemotherapy. Respective numbers for the intermediate and high P-OS categories were 34/34, and 90/80.
The investigators found that for patients in the low P-OS group, adjuvant chemotherapy cut the risk of death by slightly more than half, with a hazard ratio of 0.46 (P = .033). In contrast, there were no significant differences in the risk of death for patients at either intermediate or high probability of 10 year OS (HR, 1.00 and 1.08, respectively; P values not significant).
Similarly, adjuvant chemotherapy cut the risk of disease progression by the same amount, with an HR of 0.46 (P = .021), whereas there was no additional benefit among patients at either intermediate or high probability of 10-year OS (HR 0.74 and 0.90; P values were not significant).
The absolute risk reduction for adjuvant chemotherapy was 21% (8-yr disease-free survival of 34% for adjuvant chemotherapy vs. 13% for observation), with a number needed to treated of 4.76.
The study was supported by the European Organization for Research and Treatment of Cancer. Dr. Pasquali reported having no conflicts of interest.
SOURCE: Pasquali S et al. ASCO 2018, Abstract 115118.
CHICAGO – Patients with high-risk soft-tissue sarcomas identified by patient data and a risk calculator had significantly better overall and disease-free survival when they were treated with adjuvant doxorubicin and ifosfamide, a retrospective analysis from a randomized clinical trial showed.
The findings suggest that future clinical trials for sarcoma therapies may need to focus on specific risk categories, investigators said.
Among 290 patients with soft tissues sarcomas (STS) of the trunk wall or extremities, adjuvant chemotherapy with doxorubicin, ifosfamide, mesna, and lenograstim more than halved the risk of death for patients determined by the nomogram to have a low probability of 10-year overall survival, reported Sandro Pasquali, MD, from the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, and his colleagues.
“These findings interpret conflicting results of randomized controlled trials on perioperative chemotherapy in STS showing that inclusion of low-risk tumors have diluted the effect of chemotherapy leading to negative results and small study effect in meta-analysis,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.
The clinical trial in question, EORTC-STBSG 62931, results of which were published in 2012 in The Lancet Oncology, was technically a failure, because it did not show a significant benefit of adjuvant chemotherapy vs. observation in patients with STS.
To see whether adjuvant chemotherapy may have benefited select patients, the investigators calculated 10-year probabilities of overall survival (P-OS) for 290 patients with STS of the trunk wall or extremities out of the total trial cohort of 351 patients. The P-OS for each of three categories – low (51% or less), intermediate (52%-66%), and high (67% or greater) – was calculated using individual patient data and the freely available smartphone-based nomogram Sarculator (available in the Apple App Store and Google Play).
They calculated disease-free survival at the study median follow-up of 8 years.
The tumor histologies included malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, and others.
A total of 52 patients were in the low P-OS group, including 24 treated with observation, and 28 with adjuvant chemotherapy. Respective numbers for the intermediate and high P-OS categories were 34/34, and 90/80.
The investigators found that for patients in the low P-OS group, adjuvant chemotherapy cut the risk of death by slightly more than half, with a hazard ratio of 0.46 (P = .033). In contrast, there were no significant differences in the risk of death for patients at either intermediate or high probability of 10 year OS (HR, 1.00 and 1.08, respectively; P values not significant).
Similarly, adjuvant chemotherapy cut the risk of disease progression by the same amount, with an HR of 0.46 (P = .021), whereas there was no additional benefit among patients at either intermediate or high probability of 10-year OS (HR 0.74 and 0.90; P values were not significant).
The absolute risk reduction for adjuvant chemotherapy was 21% (8-yr disease-free survival of 34% for adjuvant chemotherapy vs. 13% for observation), with a number needed to treated of 4.76.
The study was supported by the European Organization for Research and Treatment of Cancer. Dr. Pasquali reported having no conflicts of interest.
SOURCE: Pasquali S et al. ASCO 2018, Abstract 115118.
CHICAGO – Patients with high-risk soft-tissue sarcomas identified by patient data and a risk calculator had significantly better overall and disease-free survival when they were treated with adjuvant doxorubicin and ifosfamide, a retrospective analysis from a randomized clinical trial showed.
The findings suggest that future clinical trials for sarcoma therapies may need to focus on specific risk categories, investigators said.
Among 290 patients with soft tissues sarcomas (STS) of the trunk wall or extremities, adjuvant chemotherapy with doxorubicin, ifosfamide, mesna, and lenograstim more than halved the risk of death for patients determined by the nomogram to have a low probability of 10-year overall survival, reported Sandro Pasquali, MD, from the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, and his colleagues.
“These findings interpret conflicting results of randomized controlled trials on perioperative chemotherapy in STS showing that inclusion of low-risk tumors have diluted the effect of chemotherapy leading to negative results and small study effect in meta-analysis,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.
The clinical trial in question, EORTC-STBSG 62931, results of which were published in 2012 in The Lancet Oncology, was technically a failure, because it did not show a significant benefit of adjuvant chemotherapy vs. observation in patients with STS.
To see whether adjuvant chemotherapy may have benefited select patients, the investigators calculated 10-year probabilities of overall survival (P-OS) for 290 patients with STS of the trunk wall or extremities out of the total trial cohort of 351 patients. The P-OS for each of three categories – low (51% or less), intermediate (52%-66%), and high (67% or greater) – was calculated using individual patient data and the freely available smartphone-based nomogram Sarculator (available in the Apple App Store and Google Play).
They calculated disease-free survival at the study median follow-up of 8 years.
The tumor histologies included malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, and others.
A total of 52 patients were in the low P-OS group, including 24 treated with observation, and 28 with adjuvant chemotherapy. Respective numbers for the intermediate and high P-OS categories were 34/34, and 90/80.
The investigators found that for patients in the low P-OS group, adjuvant chemotherapy cut the risk of death by slightly more than half, with a hazard ratio of 0.46 (P = .033). In contrast, there were no significant differences in the risk of death for patients at either intermediate or high probability of 10 year OS (HR, 1.00 and 1.08, respectively; P values not significant).
Similarly, adjuvant chemotherapy cut the risk of disease progression by the same amount, with an HR of 0.46 (P = .021), whereas there was no additional benefit among patients at either intermediate or high probability of 10-year OS (HR 0.74 and 0.90; P values were not significant).
The absolute risk reduction for adjuvant chemotherapy was 21% (8-yr disease-free survival of 34% for adjuvant chemotherapy vs. 13% for observation), with a number needed to treated of 4.76.
The study was supported by the European Organization for Research and Treatment of Cancer. Dr. Pasquali reported having no conflicts of interest.
SOURCE: Pasquali S et al. ASCO 2018, Abstract 115118.
REPORTING FROM ASCO 2018
Key clinical point: Patients with high-risk soft-tissue sarcomas benefit from adjuvant chemotherapy.
Major finding: Hazard ratios for death and disease progression in patients with a low probability of 10-year overall survival were 0.46 for each.
Study details: Retrospective analysis of a randomized phase 3 trial comparing adjuvant chemotherapy with observation in 290 patients with soft tissue sarcomas of the trunk wall or extremities.
Disclosures: The study was supported by the European Organisation for Research and Treatment of Cancer. Dr. Pasquali reported having no conflicts of interest.
Source: Pasquali S et al. ASCO 2018, Abstract 115118.
Rapid drug alteration a bust in metastatic GIST
CHICAGO – For patients with gastrointestinal stromal tumor (GIST) with KIT mutations conferring resistance to imatinib, a strategy of rapid alteration of drugs with complementary activity against KIT mutations is feasible but has thus far failed to yield significant clinical benefits, investigators said.
There were no objective responses among 12 patients treated continuously with 3 days of sunitinib (Sutent) followed by 4 days of regorafenib (Stivarga), and although 4 patients had stable disease in the short term, in each case the disease progressed within 16 weeks, reported Cesar Serrano-Garcia, MD, from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, and his colleagues.
“Drug exposure is critical to effectively target specific resistant subpopulations and low exposure may have contributed to the lack of efficacy in this cohort,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.
The investigators noted that the main mechanism of resistance to imatinib (Gleevec) in GIST is polyclonal emergence of KIT secondary mutations. They then theorized that rapid alteration of sunitinib with regorafenib, which both have complementary activity against different KIT resistance mutations, could be a novel therapeutic strategy for controlling imatinib-resistant disease.
Both agents are active against KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha). Sunitinib has stronger activity against ATP-binding pocket mutations, and regorafenib is more effective against activation loop oncoproteins, the investigators explained.
They conducted a phase Ib trial to evaluate the safety and preliminary efficacy of the strategy in patients with metastatic GIST that had advanced on therapy with all established protocols. The trial had a standard 3+3 design to determine the recommended phase 2 dose; a total of 14 patients were enrolled, but only 12 received one or more complete cycles.
The median patient age was 63.5%. Nine patients had Eastern Cooperative Oncology Group performance status of 0, and five had an ECOG status of 1. The patients had received a median of four prior lines of therapy, and all had received at least three lines.
The primary mutations were at KIT exon 11 in eight patients, exon 9 in five patients, and a KIT/PDGFR-alpha wild type in one patient.
Of the 12 patients who received one or more complete cycles, 7 were treated with sunitinib 37.5 mg daily for 3 days, followed by regorafenib 120 mg daily for 4 days. There were no dose-limiting toxicities in this group. The median number of cycles delivered was 2 (range 1-4).
The other five patients were treated with sunitinib at the same 37.5 mg daily dose for 3 days, followed immediately by regorafenib 160 mg daily for 4 days. There were two dose-limiting toxicities in this group, both grade 3 hypophosphatemia, one of which was refractory to phosphorous replacement.
Antitumor activity according to Response Evaluation Criteria in Solid Tumors version 1.1 included four cases of stable disease at the time of the efficacy analysis, and eight cases of disease progression. The median progression-free survival was 1.9 months. As noted before, there were no complete or partial responses among the 12 patients.
A pharmacokinetic profile at cycle 1 showed that neither drug reached its reported active blood drug levels.
The patients appeared to tolerate the treatment well, with grade 1 or 2 fatigue in all patients being the most common adverse events. Grade 3 or 4 events included hand-foot syndrome, hypertension, and hypophosphatemia in two patients each.
As noted, the authors acknowledged that low drug exposure levels may explain the lack of any responses in this cohort.
“Therapeutic strategies based on KIT inhibition remain crucial in GIST patients progressing to multiple lines,” they wrote.
The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.
SOURCE: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.
CHICAGO – For patients with gastrointestinal stromal tumor (GIST) with KIT mutations conferring resistance to imatinib, a strategy of rapid alteration of drugs with complementary activity against KIT mutations is feasible but has thus far failed to yield significant clinical benefits, investigators said.
There were no objective responses among 12 patients treated continuously with 3 days of sunitinib (Sutent) followed by 4 days of regorafenib (Stivarga), and although 4 patients had stable disease in the short term, in each case the disease progressed within 16 weeks, reported Cesar Serrano-Garcia, MD, from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, and his colleagues.
“Drug exposure is critical to effectively target specific resistant subpopulations and low exposure may have contributed to the lack of efficacy in this cohort,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.
The investigators noted that the main mechanism of resistance to imatinib (Gleevec) in GIST is polyclonal emergence of KIT secondary mutations. They then theorized that rapid alteration of sunitinib with regorafenib, which both have complementary activity against different KIT resistance mutations, could be a novel therapeutic strategy for controlling imatinib-resistant disease.
Both agents are active against KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha). Sunitinib has stronger activity against ATP-binding pocket mutations, and regorafenib is more effective against activation loop oncoproteins, the investigators explained.
They conducted a phase Ib trial to evaluate the safety and preliminary efficacy of the strategy in patients with metastatic GIST that had advanced on therapy with all established protocols. The trial had a standard 3+3 design to determine the recommended phase 2 dose; a total of 14 patients were enrolled, but only 12 received one or more complete cycles.
The median patient age was 63.5%. Nine patients had Eastern Cooperative Oncology Group performance status of 0, and five had an ECOG status of 1. The patients had received a median of four prior lines of therapy, and all had received at least three lines.
The primary mutations were at KIT exon 11 in eight patients, exon 9 in five patients, and a KIT/PDGFR-alpha wild type in one patient.
Of the 12 patients who received one or more complete cycles, 7 were treated with sunitinib 37.5 mg daily for 3 days, followed by regorafenib 120 mg daily for 4 days. There were no dose-limiting toxicities in this group. The median number of cycles delivered was 2 (range 1-4).
The other five patients were treated with sunitinib at the same 37.5 mg daily dose for 3 days, followed immediately by regorafenib 160 mg daily for 4 days. There were two dose-limiting toxicities in this group, both grade 3 hypophosphatemia, one of which was refractory to phosphorous replacement.
Antitumor activity according to Response Evaluation Criteria in Solid Tumors version 1.1 included four cases of stable disease at the time of the efficacy analysis, and eight cases of disease progression. The median progression-free survival was 1.9 months. As noted before, there were no complete or partial responses among the 12 patients.
A pharmacokinetic profile at cycle 1 showed that neither drug reached its reported active blood drug levels.
The patients appeared to tolerate the treatment well, with grade 1 or 2 fatigue in all patients being the most common adverse events. Grade 3 or 4 events included hand-foot syndrome, hypertension, and hypophosphatemia in two patients each.
As noted, the authors acknowledged that low drug exposure levels may explain the lack of any responses in this cohort.
“Therapeutic strategies based on KIT inhibition remain crucial in GIST patients progressing to multiple lines,” they wrote.
The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.
SOURCE: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.
CHICAGO – For patients with gastrointestinal stromal tumor (GIST) with KIT mutations conferring resistance to imatinib, a strategy of rapid alteration of drugs with complementary activity against KIT mutations is feasible but has thus far failed to yield significant clinical benefits, investigators said.
There were no objective responses among 12 patients treated continuously with 3 days of sunitinib (Sutent) followed by 4 days of regorafenib (Stivarga), and although 4 patients had stable disease in the short term, in each case the disease progressed within 16 weeks, reported Cesar Serrano-Garcia, MD, from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, and his colleagues.
“Drug exposure is critical to effectively target specific resistant subpopulations and low exposure may have contributed to the lack of efficacy in this cohort,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.
The investigators noted that the main mechanism of resistance to imatinib (Gleevec) in GIST is polyclonal emergence of KIT secondary mutations. They then theorized that rapid alteration of sunitinib with regorafenib, which both have complementary activity against different KIT resistance mutations, could be a novel therapeutic strategy for controlling imatinib-resistant disease.
Both agents are active against KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha). Sunitinib has stronger activity against ATP-binding pocket mutations, and regorafenib is more effective against activation loop oncoproteins, the investigators explained.
They conducted a phase Ib trial to evaluate the safety and preliminary efficacy of the strategy in patients with metastatic GIST that had advanced on therapy with all established protocols. The trial had a standard 3+3 design to determine the recommended phase 2 dose; a total of 14 patients were enrolled, but only 12 received one or more complete cycles.
The median patient age was 63.5%. Nine patients had Eastern Cooperative Oncology Group performance status of 0, and five had an ECOG status of 1. The patients had received a median of four prior lines of therapy, and all had received at least three lines.
The primary mutations were at KIT exon 11 in eight patients, exon 9 in five patients, and a KIT/PDGFR-alpha wild type in one patient.
Of the 12 patients who received one or more complete cycles, 7 were treated with sunitinib 37.5 mg daily for 3 days, followed by regorafenib 120 mg daily for 4 days. There were no dose-limiting toxicities in this group. The median number of cycles delivered was 2 (range 1-4).
The other five patients were treated with sunitinib at the same 37.5 mg daily dose for 3 days, followed immediately by regorafenib 160 mg daily for 4 days. There were two dose-limiting toxicities in this group, both grade 3 hypophosphatemia, one of which was refractory to phosphorous replacement.
Antitumor activity according to Response Evaluation Criteria in Solid Tumors version 1.1 included four cases of stable disease at the time of the efficacy analysis, and eight cases of disease progression. The median progression-free survival was 1.9 months. As noted before, there were no complete or partial responses among the 12 patients.
A pharmacokinetic profile at cycle 1 showed that neither drug reached its reported active blood drug levels.
The patients appeared to tolerate the treatment well, with grade 1 or 2 fatigue in all patients being the most common adverse events. Grade 3 or 4 events included hand-foot syndrome, hypertension, and hypophosphatemia in two patients each.
As noted, the authors acknowledged that low drug exposure levels may explain the lack of any responses in this cohort.
“Therapeutic strategies based on KIT inhibition remain crucial in GIST patients progressing to multiple lines,” they wrote.
The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.
SOURCE: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.
REPORTING FROM ASCO 2018
Key clinical point: The strategy of rapid alteration of drugs to overcome mutations conferring imatinib resistance in gastrointestinal stromal tumor (GIST) was feasible but ineffective.
Major finding: There were no objective responses among 12 patients treated with the strategy.
Study details: A phase Ib clinical trial in 12 patients with heavily pretreated metastatic GIST.
Disclosures: The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.
Source: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.
Low response rate with trofosfamide for advanced STS in elderly
CHICAGO – In elderly patients with previously untreated metastatic soft-tissue sarcomas (STSs), the oral alkylating agent trofosfamide was associated with a lower overall response rate but long-lasting remissions among patients who had complete responses, investigators reported.
In a randomized phase 2 trial that compared trofosfamide with doxorubicin (Adriamycin), the 6-month progression-free survival (PFS) rate with trofosfamide, the primary endpoint, was 27. 6% versus 35.9% in the doxorubicin arm, said Joerg Thomas Hartmann, MD, from Franziskus Hospital in Bielefeld, Germany.
“Median age was 70 years, which means that the population included [patients] 10-15 years older as compared to other trials in metastatic adult sarcoma. The trial met its predefined endpoint, demonstrating that patients treated with trofosfamide attained a 6-month progression-free rate of more than 20%,” he said at the annual meeting of the American Society of Clinical Oncology.
Trofosfamide is an oral alkylating agent chemically related to cyclophosphamide and ifosfamide. It has been evaluated in a variety of hematologic and solid malignancies and has shown particular activity in patients with chemotherapy-naive and treatment-refractory adult STSs.
Dr. Hartmann and his colleagues conducted the phase 2 study to determine whether oral continuous or “metronomic” therapy with trofosfamide could produce a 6-month PFS rate of at least 20% in patients older than 60 years with previously untreated STSs. They selected this rate of 20% or higher based on the European Organisation for Research and Treatment of Cancer (EORTC) target criterion for doxorubicin of 25%.
They also compared grade 3 or greater toxicities of the two regimens, as well as overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) 1,0, and overall survival.
A total of 120 patients with histologically confirmed STSs with no prior first-line chemotherapy and with adequate bone marrow, renal, and liver function were enrolled. The histologies included pleomorphic sarcoma not otherwise specified, leiomyosarcoma, liposarcoma, and others not specified by Dr. Hartmann.
The patients were randomly assigned on a 1:2 basis to receive either intravenous doxorubicin 60 mg/m2 on day 1 of each 21-day cycle for a total of 6 cycles (40 patients) or oral trofosfamide 300 mg/day for days 1 through 7 followed by 150 mg/day until disease progression or unacceptable toxicities (80 patients).
The median patient age in each arm was 70 years.
After a median follow-up of 18.4 months, the trial met its primary endpoint of a 6-months PFS with trofosfamide exceeding 20% (27.6%).
Overall response rates were 7.7% in the doxorubicin arm and 6.6% in the trofosfamide arm.
All three responses in the doxorubicin arm were partial. In the trofosfamide arm there were five responses, including two complete responses and three PR.
The duration of responses in the patients treated with trofosfamide who achieved a complete response were 8.8 and 46.6 months (median, 27.7 months). The median duration of response for trofosfamide-treated patients with a partial response was 8.2 months (range, 1.4-14.9 months).
In contrast, the median duration of response in the patients treated with doxorubicin who achieved a partial response was 4.3 months (range, 2.2-5.6 months).
Grade 3 or 4 adverse events occurred in significantly more patients treated with doxorubicin than they did in patients treated with trofosfamide (61.5% vs. 38.2%, respectively; P = .01). However, deaths within 30 or 60 days of starting on the assigned study drug were higher in the trofosfamide arm (zero vs. two and three vs. six, respectively).
Rates of anemia, leukocytopenia, nausea, and asthenia were similar between the groups, but trofosfamide was significantly associated with higher rates of dyspnea (P = .0148) and fatigue (P = .0264) and with lower rates of neutropenia (P less than .0001) and mucositis (P = .0008).
The trial was supported by Baxter Oncology of Germany. Dr. Hartmann reported having no conflicts of interest to disclose.
SOURCE: Hartman JT et al. ASCO 2018, Abstract 11507.
CHICAGO – In elderly patients with previously untreated metastatic soft-tissue sarcomas (STSs), the oral alkylating agent trofosfamide was associated with a lower overall response rate but long-lasting remissions among patients who had complete responses, investigators reported.
In a randomized phase 2 trial that compared trofosfamide with doxorubicin (Adriamycin), the 6-month progression-free survival (PFS) rate with trofosfamide, the primary endpoint, was 27. 6% versus 35.9% in the doxorubicin arm, said Joerg Thomas Hartmann, MD, from Franziskus Hospital in Bielefeld, Germany.
“Median age was 70 years, which means that the population included [patients] 10-15 years older as compared to other trials in metastatic adult sarcoma. The trial met its predefined endpoint, demonstrating that patients treated with trofosfamide attained a 6-month progression-free rate of more than 20%,” he said at the annual meeting of the American Society of Clinical Oncology.
Trofosfamide is an oral alkylating agent chemically related to cyclophosphamide and ifosfamide. It has been evaluated in a variety of hematologic and solid malignancies and has shown particular activity in patients with chemotherapy-naive and treatment-refractory adult STSs.
Dr. Hartmann and his colleagues conducted the phase 2 study to determine whether oral continuous or “metronomic” therapy with trofosfamide could produce a 6-month PFS rate of at least 20% in patients older than 60 years with previously untreated STSs. They selected this rate of 20% or higher based on the European Organisation for Research and Treatment of Cancer (EORTC) target criterion for doxorubicin of 25%.
They also compared grade 3 or greater toxicities of the two regimens, as well as overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) 1,0, and overall survival.
A total of 120 patients with histologically confirmed STSs with no prior first-line chemotherapy and with adequate bone marrow, renal, and liver function were enrolled. The histologies included pleomorphic sarcoma not otherwise specified, leiomyosarcoma, liposarcoma, and others not specified by Dr. Hartmann.
The patients were randomly assigned on a 1:2 basis to receive either intravenous doxorubicin 60 mg/m2 on day 1 of each 21-day cycle for a total of 6 cycles (40 patients) or oral trofosfamide 300 mg/day for days 1 through 7 followed by 150 mg/day until disease progression or unacceptable toxicities (80 patients).
The median patient age in each arm was 70 years.
After a median follow-up of 18.4 months, the trial met its primary endpoint of a 6-months PFS with trofosfamide exceeding 20% (27.6%).
Overall response rates were 7.7% in the doxorubicin arm and 6.6% in the trofosfamide arm.
All three responses in the doxorubicin arm were partial. In the trofosfamide arm there were five responses, including two complete responses and three PR.
The duration of responses in the patients treated with trofosfamide who achieved a complete response were 8.8 and 46.6 months (median, 27.7 months). The median duration of response for trofosfamide-treated patients with a partial response was 8.2 months (range, 1.4-14.9 months).
In contrast, the median duration of response in the patients treated with doxorubicin who achieved a partial response was 4.3 months (range, 2.2-5.6 months).
Grade 3 or 4 adverse events occurred in significantly more patients treated with doxorubicin than they did in patients treated with trofosfamide (61.5% vs. 38.2%, respectively; P = .01). However, deaths within 30 or 60 days of starting on the assigned study drug were higher in the trofosfamide arm (zero vs. two and three vs. six, respectively).
Rates of anemia, leukocytopenia, nausea, and asthenia were similar between the groups, but trofosfamide was significantly associated with higher rates of dyspnea (P = .0148) and fatigue (P = .0264) and with lower rates of neutropenia (P less than .0001) and mucositis (P = .0008).
The trial was supported by Baxter Oncology of Germany. Dr. Hartmann reported having no conflicts of interest to disclose.
SOURCE: Hartman JT et al. ASCO 2018, Abstract 11507.
CHICAGO – In elderly patients with previously untreated metastatic soft-tissue sarcomas (STSs), the oral alkylating agent trofosfamide was associated with a lower overall response rate but long-lasting remissions among patients who had complete responses, investigators reported.
In a randomized phase 2 trial that compared trofosfamide with doxorubicin (Adriamycin), the 6-month progression-free survival (PFS) rate with trofosfamide, the primary endpoint, was 27. 6% versus 35.9% in the doxorubicin arm, said Joerg Thomas Hartmann, MD, from Franziskus Hospital in Bielefeld, Germany.
“Median age was 70 years, which means that the population included [patients] 10-15 years older as compared to other trials in metastatic adult sarcoma. The trial met its predefined endpoint, demonstrating that patients treated with trofosfamide attained a 6-month progression-free rate of more than 20%,” he said at the annual meeting of the American Society of Clinical Oncology.
Trofosfamide is an oral alkylating agent chemically related to cyclophosphamide and ifosfamide. It has been evaluated in a variety of hematologic and solid malignancies and has shown particular activity in patients with chemotherapy-naive and treatment-refractory adult STSs.
Dr. Hartmann and his colleagues conducted the phase 2 study to determine whether oral continuous or “metronomic” therapy with trofosfamide could produce a 6-month PFS rate of at least 20% in patients older than 60 years with previously untreated STSs. They selected this rate of 20% or higher based on the European Organisation for Research and Treatment of Cancer (EORTC) target criterion for doxorubicin of 25%.
They also compared grade 3 or greater toxicities of the two regimens, as well as overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) 1,0, and overall survival.
A total of 120 patients with histologically confirmed STSs with no prior first-line chemotherapy and with adequate bone marrow, renal, and liver function were enrolled. The histologies included pleomorphic sarcoma not otherwise specified, leiomyosarcoma, liposarcoma, and others not specified by Dr. Hartmann.
The patients were randomly assigned on a 1:2 basis to receive either intravenous doxorubicin 60 mg/m2 on day 1 of each 21-day cycle for a total of 6 cycles (40 patients) or oral trofosfamide 300 mg/day for days 1 through 7 followed by 150 mg/day until disease progression or unacceptable toxicities (80 patients).
The median patient age in each arm was 70 years.
After a median follow-up of 18.4 months, the trial met its primary endpoint of a 6-months PFS with trofosfamide exceeding 20% (27.6%).
Overall response rates were 7.7% in the doxorubicin arm and 6.6% in the trofosfamide arm.
All three responses in the doxorubicin arm were partial. In the trofosfamide arm there were five responses, including two complete responses and three PR.
The duration of responses in the patients treated with trofosfamide who achieved a complete response were 8.8 and 46.6 months (median, 27.7 months). The median duration of response for trofosfamide-treated patients with a partial response was 8.2 months (range, 1.4-14.9 months).
In contrast, the median duration of response in the patients treated with doxorubicin who achieved a partial response was 4.3 months (range, 2.2-5.6 months).
Grade 3 or 4 adverse events occurred in significantly more patients treated with doxorubicin than they did in patients treated with trofosfamide (61.5% vs. 38.2%, respectively; P = .01). However, deaths within 30 or 60 days of starting on the assigned study drug were higher in the trofosfamide arm (zero vs. two and three vs. six, respectively).
Rates of anemia, leukocytopenia, nausea, and asthenia were similar between the groups, but trofosfamide was significantly associated with higher rates of dyspnea (P = .0148) and fatigue (P = .0264) and with lower rates of neutropenia (P less than .0001) and mucositis (P = .0008).
The trial was supported by Baxter Oncology of Germany. Dr. Hartmann reported having no conflicts of interest to disclose.
SOURCE: Hartman JT et al. ASCO 2018, Abstract 11507.
PRESENTED AT ASCO 2018
Key clinical point: The oral alkylating agent trofosfamide showed efficacy in a small number of elderly patients with untreated metastatic soft-tissue sarcomas (STS).
Major finding: The trial met its primary endpoint with a 6-month progression-free survival with trofosfamide of 27.6%
Study details: Randomized phase 2 trial comparing trofosfamide with doxorubicin in elderly patients with previously untreated metastatic STS.
Disclosures: The trial was supported by Baxter Oncology of Germany. Dr. Hartmann reported having no conflicts of interest to disclose.
Source: Hartman JT et al. ASCO 2018, Abstract 11507.
Trabectedin bests supportive care in advanced soft-tissue sarcomas
CHICAGO – Trabectedin (Yondelis) was superior to best supportive care at prolonging progression-free survival in patients with heavily pretreated advanced leiomyosarcomas and liposarcomas, investigators in the randomized phase 3 T-SAR trial reported.
Among 103 patients with soft-tissue sarcomas that had progressed after two to four lines of standard chemotherapy, median progression-free survival (PFS) for patients randomized to trabectedin was 3.12 months, compared with 1.51 for patients randomized to best supportive care.
This difference translated into a hazard ratio (HR) favoring trabectedin of 0.39 (P less than .0001), Axel Le Cesne, MD, of Gustave Roussy Cancer Institute in Villejuif, France, reported on behalf of colleagues in the French Sarcoma Group.
All of the benefit was apparently among patients with what he termed “L-sarcomas” – leiomyosarcoma and liposarcoma – compared with other sarcoma histologies.
“The tumor control rate after six courses of trabectedin is similar to previous studies. As already reported, trabectedin is well-tolerated,” he said at the annual meeting of the American Society of Clinical Oncology.
Trabectedin was shown to be superior to best supportive care at delaying disease progression among patients with advanced translocation-related sarcomas in a randomized phase 2 trial in Japan, but had not been studied in this setting against other sarcoma histologies, Dr. Le Cesne said.
The investigators enrolled 103 patients and randomly assigned them to receive either best supportive care or trabectedin in a 1.5 mg/m2 infusion over 24 hours every 3 weeks. Patients in the best supportive care arm could be crossed over to the trabectedin arm at the time of progression.
Sarcoma histologies included liposarcoma, leiomyosarcoma, undifferentiated sarcomas, myxofibrosarcoma, synovial sarcoma, and others. The L-sarcomas accounted for 60.2% of the patient population.
Fifty-two patients were randomized to trabectedin and 51 to best supportive care, but 2 patients assigned to best supportive care dropped out soon after randomization, leaving 52 and 49 patients, respectively, for the as-treated analysis. All 103 patients were assessable for efficacy.
After a median follow-up of 26 months, median PFS for all patients, as noted before, was 3.12 months in the trabectedin arm and 1.51 months in the best supportive care arm.
The overall response rate in the trabectedin arm was 13.7%, composed of seven partial responses. There were no responses in the best supportive care arm. In all, 66.7% of patients in the trabectedin arm and 61.2% of patients in the best supportive care arm had stable disease, and 19.6% and 38.8%, respectively, had disease progression.
An analysis of PFS by sarcoma histology showed that all of the benefit appeared to be in patients with L-sarcomas, with a median PFS for trabectedin-treated patients of 5.13 months compared with 1.41 months for controls (HR 0.29, P less than .0001).
In contrast, there was no significant difference between the groups among patients with non–L sarcomas, with respective median PFS of 1.81 and 1.51 months (HR 0.60, P = .16). There were no treatment responses among patients in either treatment arm in this subgroup.
Not surprisingly, there were more grade 3 or 4 adverse events among patients in the trabectedin arm. Neutropenia was seen in 23 patients given trabectedin and 1 given best supportive care; leukopenia in 18 patients vs. 0, thrombocytopenia in 13 vs. 0, and elevated liver transaminases in 17 vs. 1, respectively.
In all, 45 of the 49 patients who were treated in the best supportive care arm were crossed over to trabectedin.
Median overall survival was 13.6 months in the trabectedin arm and 10.8 months in the best supportive care arm. This difference was not statistically significant.
Dr Le Cesne noted that the tumor control rate of 30% with trabectedin was similar to that seen in an earlier French trial (Lancet Oncol. 2015 Mar 1;16[3]:312-19).
Pharmamar supplied trabectedin for the study. Dr. Le Cesne disclosed honoraria from the company and from Amgen, Bayer, Lilly, Novartis, and Pfizer.
SOURCE: Le Cesne A et al. ASCO 2018. Abstract 11508.
CHICAGO – Trabectedin (Yondelis) was superior to best supportive care at prolonging progression-free survival in patients with heavily pretreated advanced leiomyosarcomas and liposarcomas, investigators in the randomized phase 3 T-SAR trial reported.
Among 103 patients with soft-tissue sarcomas that had progressed after two to four lines of standard chemotherapy, median progression-free survival (PFS) for patients randomized to trabectedin was 3.12 months, compared with 1.51 for patients randomized to best supportive care.
This difference translated into a hazard ratio (HR) favoring trabectedin of 0.39 (P less than .0001), Axel Le Cesne, MD, of Gustave Roussy Cancer Institute in Villejuif, France, reported on behalf of colleagues in the French Sarcoma Group.
All of the benefit was apparently among patients with what he termed “L-sarcomas” – leiomyosarcoma and liposarcoma – compared with other sarcoma histologies.
“The tumor control rate after six courses of trabectedin is similar to previous studies. As already reported, trabectedin is well-tolerated,” he said at the annual meeting of the American Society of Clinical Oncology.
Trabectedin was shown to be superior to best supportive care at delaying disease progression among patients with advanced translocation-related sarcomas in a randomized phase 2 trial in Japan, but had not been studied in this setting against other sarcoma histologies, Dr. Le Cesne said.
The investigators enrolled 103 patients and randomly assigned them to receive either best supportive care or trabectedin in a 1.5 mg/m2 infusion over 24 hours every 3 weeks. Patients in the best supportive care arm could be crossed over to the trabectedin arm at the time of progression.
Sarcoma histologies included liposarcoma, leiomyosarcoma, undifferentiated sarcomas, myxofibrosarcoma, synovial sarcoma, and others. The L-sarcomas accounted for 60.2% of the patient population.
Fifty-two patients were randomized to trabectedin and 51 to best supportive care, but 2 patients assigned to best supportive care dropped out soon after randomization, leaving 52 and 49 patients, respectively, for the as-treated analysis. All 103 patients were assessable for efficacy.
After a median follow-up of 26 months, median PFS for all patients, as noted before, was 3.12 months in the trabectedin arm and 1.51 months in the best supportive care arm.
The overall response rate in the trabectedin arm was 13.7%, composed of seven partial responses. There were no responses in the best supportive care arm. In all, 66.7% of patients in the trabectedin arm and 61.2% of patients in the best supportive care arm had stable disease, and 19.6% and 38.8%, respectively, had disease progression.
An analysis of PFS by sarcoma histology showed that all of the benefit appeared to be in patients with L-sarcomas, with a median PFS for trabectedin-treated patients of 5.13 months compared with 1.41 months for controls (HR 0.29, P less than .0001).
In contrast, there was no significant difference between the groups among patients with non–L sarcomas, with respective median PFS of 1.81 and 1.51 months (HR 0.60, P = .16). There were no treatment responses among patients in either treatment arm in this subgroup.
Not surprisingly, there were more grade 3 or 4 adverse events among patients in the trabectedin arm. Neutropenia was seen in 23 patients given trabectedin and 1 given best supportive care; leukopenia in 18 patients vs. 0, thrombocytopenia in 13 vs. 0, and elevated liver transaminases in 17 vs. 1, respectively.
In all, 45 of the 49 patients who were treated in the best supportive care arm were crossed over to trabectedin.
Median overall survival was 13.6 months in the trabectedin arm and 10.8 months in the best supportive care arm. This difference was not statistically significant.
Dr Le Cesne noted that the tumor control rate of 30% with trabectedin was similar to that seen in an earlier French trial (Lancet Oncol. 2015 Mar 1;16[3]:312-19).
Pharmamar supplied trabectedin for the study. Dr. Le Cesne disclosed honoraria from the company and from Amgen, Bayer, Lilly, Novartis, and Pfizer.
SOURCE: Le Cesne A et al. ASCO 2018. Abstract 11508.
CHICAGO – Trabectedin (Yondelis) was superior to best supportive care at prolonging progression-free survival in patients with heavily pretreated advanced leiomyosarcomas and liposarcomas, investigators in the randomized phase 3 T-SAR trial reported.
Among 103 patients with soft-tissue sarcomas that had progressed after two to four lines of standard chemotherapy, median progression-free survival (PFS) for patients randomized to trabectedin was 3.12 months, compared with 1.51 for patients randomized to best supportive care.
This difference translated into a hazard ratio (HR) favoring trabectedin of 0.39 (P less than .0001), Axel Le Cesne, MD, of Gustave Roussy Cancer Institute in Villejuif, France, reported on behalf of colleagues in the French Sarcoma Group.
All of the benefit was apparently among patients with what he termed “L-sarcomas” – leiomyosarcoma and liposarcoma – compared with other sarcoma histologies.
“The tumor control rate after six courses of trabectedin is similar to previous studies. As already reported, trabectedin is well-tolerated,” he said at the annual meeting of the American Society of Clinical Oncology.
Trabectedin was shown to be superior to best supportive care at delaying disease progression among patients with advanced translocation-related sarcomas in a randomized phase 2 trial in Japan, but had not been studied in this setting against other sarcoma histologies, Dr. Le Cesne said.
The investigators enrolled 103 patients and randomly assigned them to receive either best supportive care or trabectedin in a 1.5 mg/m2 infusion over 24 hours every 3 weeks. Patients in the best supportive care arm could be crossed over to the trabectedin arm at the time of progression.
Sarcoma histologies included liposarcoma, leiomyosarcoma, undifferentiated sarcomas, myxofibrosarcoma, synovial sarcoma, and others. The L-sarcomas accounted for 60.2% of the patient population.
Fifty-two patients were randomized to trabectedin and 51 to best supportive care, but 2 patients assigned to best supportive care dropped out soon after randomization, leaving 52 and 49 patients, respectively, for the as-treated analysis. All 103 patients were assessable for efficacy.
After a median follow-up of 26 months, median PFS for all patients, as noted before, was 3.12 months in the trabectedin arm and 1.51 months in the best supportive care arm.
The overall response rate in the trabectedin arm was 13.7%, composed of seven partial responses. There were no responses in the best supportive care arm. In all, 66.7% of patients in the trabectedin arm and 61.2% of patients in the best supportive care arm had stable disease, and 19.6% and 38.8%, respectively, had disease progression.
An analysis of PFS by sarcoma histology showed that all of the benefit appeared to be in patients with L-sarcomas, with a median PFS for trabectedin-treated patients of 5.13 months compared with 1.41 months for controls (HR 0.29, P less than .0001).
In contrast, there was no significant difference between the groups among patients with non–L sarcomas, with respective median PFS of 1.81 and 1.51 months (HR 0.60, P = .16). There were no treatment responses among patients in either treatment arm in this subgroup.
Not surprisingly, there were more grade 3 or 4 adverse events among patients in the trabectedin arm. Neutropenia was seen in 23 patients given trabectedin and 1 given best supportive care; leukopenia in 18 patients vs. 0, thrombocytopenia in 13 vs. 0, and elevated liver transaminases in 17 vs. 1, respectively.
In all, 45 of the 49 patients who were treated in the best supportive care arm were crossed over to trabectedin.
Median overall survival was 13.6 months in the trabectedin arm and 10.8 months in the best supportive care arm. This difference was not statistically significant.
Dr Le Cesne noted that the tumor control rate of 30% with trabectedin was similar to that seen in an earlier French trial (Lancet Oncol. 2015 Mar 1;16[3]:312-19).
Pharmamar supplied trabectedin for the study. Dr. Le Cesne disclosed honoraria from the company and from Amgen, Bayer, Lilly, Novartis, and Pfizer.
SOURCE: Le Cesne A et al. ASCO 2018. Abstract 11508.
REPORTING FROM ASCO 2018
Key clinical point: Trabectedin was superior to best supportive care in delaying disease progression among patients with advanced soft tissue sarcomas.
Major finding: Median progression-free survival for patients with leiomyosarcoma or liposarcoma treated with trabectedin was 5.13 months vs. 1.41 months for patients treated with best supportive care.
Study details: Randomized open-label trial of 103 patients with histologically proven advanced soft-tissue sarcoma who progressed after at least 1 anthracycline-containing regimen.
Disclosures: Pharmamar supplied trabectedin for the study. Dr. Le Cesne disclosed receiving honoraria from the company and from Amgen, Bayer, Lilly, Novartis, and Pfizer.
Source: Le Cesne A et al. ASCO 2018. Abstract 11508.
DESMOPAZ: Pazopanib slows disease progression of desmoid tumors
Pazopanib elicited clinically meaningful responses in adults with progressive desmoid tumors according to RECIST 1.1 criteria, based on two imaging studies within a 6-month interval in the phase 2 DESMOPAZ trial.
“Pazopanib has meaningful clinical activity in patients with progressive desmoid tumors,” Maud Toulmonde, MD, of the Institut Bergonié, Bordeaux, France, reported at the annual meeting of the American Society of Clinical Oncology.
Patients were accrued for the study at 12 centers of the French Sarcoma Group and were randomly assigned to receive either oral pazopanib 800 mg/day or methotrexate (30 mg/m²) plus vinblastine (5 mg/m²) given intravenously once a week for 6 months and then every 15 days for 6 months. Treatment was administered until disease progressed (these patients were allowed to cross over to pazopanib) or patients had unacceptable toxicity. Maximum treatment time was one year.
Based on central pathological and radiological review, tumors shrank in 38 of 46 assessable patients (82.6%) given pazopanib. A partial response was seen in 17 patients (37%) and stable disease was observed in 21 patients (45.7%).
In the patients given methotrexate plus vinblastine, tumors shrank in 11 of 20 assessable patients (55%), resulting in partial responses in 5 (25%) and stable disease in 6 (30%).
The 6-month non-progressive disease rate was 86% (95% CI = 72.1-94.7) in the pazopanib-treated patients (37/43) and 50% (95% CI = 27.2-72.8) in the methotrexate plus vinblastine-treated patients (10/20).
Dr. Toulmonde and most of her co-authors had no relevant financial disclosures. Some authors disclosed funding from a wide range of drug companies including Novartis, the maker of pazopanib (Votrient). Clinical trial information: NCT01876082
SOURCE: Toulmonde M et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11501.
Pazopanib elicited clinically meaningful responses in adults with progressive desmoid tumors according to RECIST 1.1 criteria, based on two imaging studies within a 6-month interval in the phase 2 DESMOPAZ trial.
“Pazopanib has meaningful clinical activity in patients with progressive desmoid tumors,” Maud Toulmonde, MD, of the Institut Bergonié, Bordeaux, France, reported at the annual meeting of the American Society of Clinical Oncology.
Patients were accrued for the study at 12 centers of the French Sarcoma Group and were randomly assigned to receive either oral pazopanib 800 mg/day or methotrexate (30 mg/m²) plus vinblastine (5 mg/m²) given intravenously once a week for 6 months and then every 15 days for 6 months. Treatment was administered until disease progressed (these patients were allowed to cross over to pazopanib) or patients had unacceptable toxicity. Maximum treatment time was one year.
Based on central pathological and radiological review, tumors shrank in 38 of 46 assessable patients (82.6%) given pazopanib. A partial response was seen in 17 patients (37%) and stable disease was observed in 21 patients (45.7%).
In the patients given methotrexate plus vinblastine, tumors shrank in 11 of 20 assessable patients (55%), resulting in partial responses in 5 (25%) and stable disease in 6 (30%).
The 6-month non-progressive disease rate was 86% (95% CI = 72.1-94.7) in the pazopanib-treated patients (37/43) and 50% (95% CI = 27.2-72.8) in the methotrexate plus vinblastine-treated patients (10/20).
Dr. Toulmonde and most of her co-authors had no relevant financial disclosures. Some authors disclosed funding from a wide range of drug companies including Novartis, the maker of pazopanib (Votrient). Clinical trial information: NCT01876082
SOURCE: Toulmonde M et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11501.
Pazopanib elicited clinically meaningful responses in adults with progressive desmoid tumors according to RECIST 1.1 criteria, based on two imaging studies within a 6-month interval in the phase 2 DESMOPAZ trial.
“Pazopanib has meaningful clinical activity in patients with progressive desmoid tumors,” Maud Toulmonde, MD, of the Institut Bergonié, Bordeaux, France, reported at the annual meeting of the American Society of Clinical Oncology.
Patients were accrued for the study at 12 centers of the French Sarcoma Group and were randomly assigned to receive either oral pazopanib 800 mg/day or methotrexate (30 mg/m²) plus vinblastine (5 mg/m²) given intravenously once a week for 6 months and then every 15 days for 6 months. Treatment was administered until disease progressed (these patients were allowed to cross over to pazopanib) or patients had unacceptable toxicity. Maximum treatment time was one year.
Based on central pathological and radiological review, tumors shrank in 38 of 46 assessable patients (82.6%) given pazopanib. A partial response was seen in 17 patients (37%) and stable disease was observed in 21 patients (45.7%).
In the patients given methotrexate plus vinblastine, tumors shrank in 11 of 20 assessable patients (55%), resulting in partial responses in 5 (25%) and stable disease in 6 (30%).
The 6-month non-progressive disease rate was 86% (95% CI = 72.1-94.7) in the pazopanib-treated patients (37/43) and 50% (95% CI = 27.2-72.8) in the methotrexate plus vinblastine-treated patients (10/20).
Dr. Toulmonde and most of her co-authors had no relevant financial disclosures. Some authors disclosed funding from a wide range of drug companies including Novartis, the maker of pazopanib (Votrient). Clinical trial information: NCT01876082
SOURCE: Toulmonde M et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11501.
FROM ASCO 2018
Metastatic soft tissue sarcomas respond to anlotinib
Anlotinib was confirmed to be safe and effective for soft tissue sarcoma patients who have progressed after first-line chemotherapy, based on results of a randomized, placebo-controlled, multicenter trial of patients in China.
“Anlotinib is a new treatment option for patients with advanced STS after failure of standard chemotherapy,” Yihebali Chi, MD, of the National Cancer Center/Cancer Hospital in Beijing, China, reported at the annual meeting of the American Society of Clinical Oncology.
In a study of patients with disease progression after first-line therapy, the median progression-free survival (PFS) was 6.3 months (95% CI: 4.3-8.4) with anlotinib and 1.5 months (95% CI: 1.43-1.57) with placebo (HR=0.33, P less than 0.0001). The objective response rate was 10.13% for anlotinib and 1.33% for placebo (P = 0.0145); disease control rate was 55.7% versus 22.67% (P less than 0.0001).
For 57 patients with synovial sarcomas, the median PFS was 5.73 months versus 1.43 months (HR = 0.2, P less than 0.0001). For 56 patients with alveolar soft part sarcomas, the median PFS was 18.23 months versus 3 months (HR = 0.14, P less than 0.0001). For 41 patients with leiomyosarcomas, the median PFS was 5.83 months versus 1.43 months (HR = 0.19, P less than 0.0001).
The most common grade 3 or higher adverse events were hypertension (19% with anlotinib versus 0 with placebo), gamma glutamyl transferase elevation (4.4% versus 1.3%), triglyceride increase (4.4% versus 0), low density lipoprotein elevation (3.2% versus 2.7%), hyponatremia (3.2% versus 1.3%) and neutrophil count reduction (3.2% versus 0).
The study included 233 patients aged 18 years and older with angiogenesis inhibitor naive, histologically proven advanced soft tissue sarcomas, intolerance or failure to respond to anthracycline-based chemotherapy, and at least one measurable lesion according to RECIST 1.1. Subjects were randomly assigned (2:1) to receive anlotinib (12 mg per day, 2 weeks on and 1 week off) or to placebo. Anlotinib was given to 158 patients and placebo to 75.
The authors disclosed having no relevant financial relationships. Clinical trial information: NCT02449343
SOURCE: Chi Y et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology, Abstract 11503.
Anlotinib was confirmed to be safe and effective for soft tissue sarcoma patients who have progressed after first-line chemotherapy, based on results of a randomized, placebo-controlled, multicenter trial of patients in China.
“Anlotinib is a new treatment option for patients with advanced STS after failure of standard chemotherapy,” Yihebali Chi, MD, of the National Cancer Center/Cancer Hospital in Beijing, China, reported at the annual meeting of the American Society of Clinical Oncology.
In a study of patients with disease progression after first-line therapy, the median progression-free survival (PFS) was 6.3 months (95% CI: 4.3-8.4) with anlotinib and 1.5 months (95% CI: 1.43-1.57) with placebo (HR=0.33, P less than 0.0001). The objective response rate was 10.13% for anlotinib and 1.33% for placebo (P = 0.0145); disease control rate was 55.7% versus 22.67% (P less than 0.0001).
For 57 patients with synovial sarcomas, the median PFS was 5.73 months versus 1.43 months (HR = 0.2, P less than 0.0001). For 56 patients with alveolar soft part sarcomas, the median PFS was 18.23 months versus 3 months (HR = 0.14, P less than 0.0001). For 41 patients with leiomyosarcomas, the median PFS was 5.83 months versus 1.43 months (HR = 0.19, P less than 0.0001).
The most common grade 3 or higher adverse events were hypertension (19% with anlotinib versus 0 with placebo), gamma glutamyl transferase elevation (4.4% versus 1.3%), triglyceride increase (4.4% versus 0), low density lipoprotein elevation (3.2% versus 2.7%), hyponatremia (3.2% versus 1.3%) and neutrophil count reduction (3.2% versus 0).
The study included 233 patients aged 18 years and older with angiogenesis inhibitor naive, histologically proven advanced soft tissue sarcomas, intolerance or failure to respond to anthracycline-based chemotherapy, and at least one measurable lesion according to RECIST 1.1. Subjects were randomly assigned (2:1) to receive anlotinib (12 mg per day, 2 weeks on and 1 week off) or to placebo. Anlotinib was given to 158 patients and placebo to 75.
The authors disclosed having no relevant financial relationships. Clinical trial information: NCT02449343
SOURCE: Chi Y et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology, Abstract 11503.
Anlotinib was confirmed to be safe and effective for soft tissue sarcoma patients who have progressed after first-line chemotherapy, based on results of a randomized, placebo-controlled, multicenter trial of patients in China.
“Anlotinib is a new treatment option for patients with advanced STS after failure of standard chemotherapy,” Yihebali Chi, MD, of the National Cancer Center/Cancer Hospital in Beijing, China, reported at the annual meeting of the American Society of Clinical Oncology.
In a study of patients with disease progression after first-line therapy, the median progression-free survival (PFS) was 6.3 months (95% CI: 4.3-8.4) with anlotinib and 1.5 months (95% CI: 1.43-1.57) with placebo (HR=0.33, P less than 0.0001). The objective response rate was 10.13% for anlotinib and 1.33% for placebo (P = 0.0145); disease control rate was 55.7% versus 22.67% (P less than 0.0001).
For 57 patients with synovial sarcomas, the median PFS was 5.73 months versus 1.43 months (HR = 0.2, P less than 0.0001). For 56 patients with alveolar soft part sarcomas, the median PFS was 18.23 months versus 3 months (HR = 0.14, P less than 0.0001). For 41 patients with leiomyosarcomas, the median PFS was 5.83 months versus 1.43 months (HR = 0.19, P less than 0.0001).
The most common grade 3 or higher adverse events were hypertension (19% with anlotinib versus 0 with placebo), gamma glutamyl transferase elevation (4.4% versus 1.3%), triglyceride increase (4.4% versus 0), low density lipoprotein elevation (3.2% versus 2.7%), hyponatremia (3.2% versus 1.3%) and neutrophil count reduction (3.2% versus 0).
The study included 233 patients aged 18 years and older with angiogenesis inhibitor naive, histologically proven advanced soft tissue sarcomas, intolerance or failure to respond to anthracycline-based chemotherapy, and at least one measurable lesion according to RECIST 1.1. Subjects were randomly assigned (2:1) to receive anlotinib (12 mg per day, 2 weeks on and 1 week off) or to placebo. Anlotinib was given to 158 patients and placebo to 75.
The authors disclosed having no relevant financial relationships. Clinical trial information: NCT02449343
SOURCE: Chi Y et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology, Abstract 11503.
FROM ASCO 2018