2017 ASCO Annual Meeting

CHICAGO – William J. Gradishar, MD, outlines key research on breast cancer treatment presented at the annual meeting of the American Society of Clinical Oncology.

In a video interview, Dr. Gradishar, the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago, discusses the take-home messages on pertuzumab for HER2+ breast cancer, PARP inhibitors for BRCA-mutated breast cancer, and CDK4/6 inhibitors for ER+ breast cancers.

In another video interview, Katherine O’Brien of the Metastatic Breast Cancer Network provides the patient advocate view on this years’ meeting.

lnikolaides@frontlinemedcom.com

On Twitter @NikolaidesLaura

CHICAGO – William J. Gradishar, MD, outlines key research on breast cancer treatment presented at the annual meeting of the American Society of Clinical Oncology.

In a video interview, Dr. Gradishar, the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago, discusses the take-home messages on pertuzumab for HER2+ breast cancer, PARP inhibitors for BRCA-mutated breast cancer, and CDK4/6 inhibitors for ER+ breast cancers.

In another video interview, Katherine O’Brien of the Metastatic Breast Cancer Network provides the patient advocate view on this years’ meeting.

lnikolaides@frontlinemedcom.com

On Twitter @NikolaidesLaura

CHICAGO – William J. Gradishar, MD, outlines key research on breast cancer treatment presented at the annual meeting of the American Society of Clinical Oncology.

In a video interview, Dr. Gradishar, the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago, discusses the take-home messages on pertuzumab for HER2+ breast cancer, PARP inhibitors for BRCA-mutated breast cancer, and CDK4/6 inhibitors for ER+ breast cancers.

In another video interview, Katherine O’Brien of the Metastatic Breast Cancer Network provides the patient advocate view on this years’ meeting.

lnikolaides@frontlinemedcom.com

On Twitter @NikolaidesLaura

CHICAGO – The antiangiogenic agent pazopanib is not efficacious when used as adjuvant therapy for resected renal cell carcinoma (RCC) with features that confer a high risk of recurrence, the PROTECT investigators reported at the annual meeting of the American Society of Clinical Oncology.

Pazopanib (Votrient) is an oral multitargeted tyrosine kinase inhibitor active against the vascular endothelial growth factor receptor (VEGFR). Adjuvant use of other agents in this class has yielded mixed results, noted lead investigator Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center in New York.

Expert perspective

“The current landscape of RCC adjuvant therapy is really controversial,” commented invited discussant Daniel Y. C. Heng, MD, MPH, of the University of Calgary (Alta.) Tom Baker Cancer Centre.

Susan London/Frontline Medical News

Study details

The PROTECT trial was funded by Novartis Oncology and randomized 1,538 patients with resected pT2 (high grade), pT3, or greater nonmetastatic clear cell RCC, a highly vascular tumor typically reliant on aberrant signaling in the VEGF pathway.

The patients were assigned evenly to receive pazopanib or placebo for 1 year. The starting dose was lowered from 800 mg daily to 600 mg daily (with escalation permitted) after 403 patients had been treated.

In intention-to-treat analysis among patients started on the 600-mg dose and having a median follow-up of about 31 months, disease-free survival was better with pazopanib but not significantly so (hazard ratio, 0.86; P = .16), Dr. Motzer reported.

In secondary analyses, pazopanib did have a significant disease-free survival benefit among patients started on the 800-mg dose (hazard ratio, 0.69; P = .02) and among the entire trial population started on either dose (hazard ratio, 0.80; P = .01).

One possible explanation for the differing results seen with the two doses was the difference in follow-up, as the 800-mg group was treated earlier in the trial, he proposed. But with an additional year of blinded follow-up, the benefit in the 600-mg group actually diminished, whereas that in the 800-mg group did not.

Another possibility was the somewhat better performance of the placebo group used for comparison with the lower dose: the 3-year disease-free survival rate with placebo was 64% for the 600-mg comparison but 56% for the 800-mg comparison. “One factor that could explain differences in the outcomes of the placebo groups includes unidentified patient demographic characteristics,” Dr. Motzer noted.

Overall survival was statistically indistinguishable between the pazopanib and placebo groups, regardless of dose. However, “the results are inconclusive as the data are not yet mature,” he said, with a definitive analysis planned for 2019.

Compared with counterparts given placebo, patients started on the 600-mg dose of pazopanib had a higher rate of grade 3 or 4 adverse events overall (60% vs. 21%), driven in large part by higher rates of hypertension and increased alanine aminotransferase levels.

“Although the intent of modifying the protocol dose of pazopanib from 800 mg to 600 mg was to reduce the rate of discontinuation and improve the safety profile ... both cohorts had similar discontinuation rates and safety profiles,” Dr. Motzer noted.

A quality of life analysis for the 600-mg group using the 19-item Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index (FKSI-19) showed values were consistently lower with the drug than with placebo during treatment, with a crossing of the threshold for a minimally important difference at week 8.

Pharmacokinetic analyses from the trial, reported in a poster at the meeting (Abstract 4564), showed that in the group starting pazopanib at 600 mg, disease-free survival was longer in patients who achieved higher drug trough concentrations at week 3 or 5.

op@frontlinemedcom.com

CHICAGO – The antiangiogenic agent pazopanib is not efficacious when used as adjuvant therapy for resected renal cell carcinoma (RCC) with features that confer a high risk of recurrence, the PROTECT investigators reported at the annual meeting of the American Society of Clinical Oncology.

Pazopanib (Votrient) is an oral multitargeted tyrosine kinase inhibitor active against the vascular endothelial growth factor receptor (VEGFR). Adjuvant use of other agents in this class has yielded mixed results, noted lead investigator Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center in New York.

Expert perspective

“The current landscape of RCC adjuvant therapy is really controversial,” commented invited discussant Daniel Y. C. Heng, MD, MPH, of the University of Calgary (Alta.) Tom Baker Cancer Centre.

Susan London/Frontline Medical News

Study details

The PROTECT trial was funded by Novartis Oncology and randomized 1,538 patients with resected pT2 (high grade), pT3, or greater nonmetastatic clear cell RCC, a highly vascular tumor typically reliant on aberrant signaling in the VEGF pathway.

The patients were assigned evenly to receive pazopanib or placebo for 1 year. The starting dose was lowered from 800 mg daily to 600 mg daily (with escalation permitted) after 403 patients had been treated.

In intention-to-treat analysis among patients started on the 600-mg dose and having a median follow-up of about 31 months, disease-free survival was better with pazopanib but not significantly so (hazard ratio, 0.86; P = .16), Dr. Motzer reported.

In secondary analyses, pazopanib did have a significant disease-free survival benefit among patients started on the 800-mg dose (hazard ratio, 0.69; P = .02) and among the entire trial population started on either dose (hazard ratio, 0.80; P = .01).

One possible explanation for the differing results seen with the two doses was the difference in follow-up, as the 800-mg group was treated earlier in the trial, he proposed. But with an additional year of blinded follow-up, the benefit in the 600-mg group actually diminished, whereas that in the 800-mg group did not.

Another possibility was the somewhat better performance of the placebo group used for comparison with the lower dose: the 3-year disease-free survival rate with placebo was 64% for the 600-mg comparison but 56% for the 800-mg comparison. “One factor that could explain differences in the outcomes of the placebo groups includes unidentified patient demographic characteristics,” Dr. Motzer noted.

Overall survival was statistically indistinguishable between the pazopanib and placebo groups, regardless of dose. However, “the results are inconclusive as the data are not yet mature,” he said, with a definitive analysis planned for 2019.

Compared with counterparts given placebo, patients started on the 600-mg dose of pazopanib had a higher rate of grade 3 or 4 adverse events overall (60% vs. 21%), driven in large part by higher rates of hypertension and increased alanine aminotransferase levels.

“Although the intent of modifying the protocol dose of pazopanib from 800 mg to 600 mg was to reduce the rate of discontinuation and improve the safety profile ... both cohorts had similar discontinuation rates and safety profiles,” Dr. Motzer noted.

A quality of life analysis for the 600-mg group using the 19-item Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index (FKSI-19) showed values were consistently lower with the drug than with placebo during treatment, with a crossing of the threshold for a minimally important difference at week 8.

Pharmacokinetic analyses from the trial, reported in a poster at the meeting (Abstract 4564), showed that in the group starting pazopanib at 600 mg, disease-free survival was longer in patients who achieved higher drug trough concentrations at week 3 or 5.

op@frontlinemedcom.com

CHICAGO – The antiangiogenic agent pazopanib is not efficacious when used as adjuvant therapy for resected renal cell carcinoma (RCC) with features that confer a high risk of recurrence, the PROTECT investigators reported at the annual meeting of the American Society of Clinical Oncology.

Pazopanib (Votrient) is an oral multitargeted tyrosine kinase inhibitor active against the vascular endothelial growth factor receptor (VEGFR). Adjuvant use of other agents in this class has yielded mixed results, noted lead investigator Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center in New York.

Expert perspective

“The current landscape of RCC adjuvant therapy is really controversial,” commented invited discussant Daniel Y. C. Heng, MD, MPH, of the University of Calgary (Alta.) Tom Baker Cancer Centre.

Susan London/Frontline Medical News

Study details

The PROTECT trial was funded by Novartis Oncology and randomized 1,538 patients with resected pT2 (high grade), pT3, or greater nonmetastatic clear cell RCC, a highly vascular tumor typically reliant on aberrant signaling in the VEGF pathway.

The patients were assigned evenly to receive pazopanib or placebo for 1 year. The starting dose was lowered from 800 mg daily to 600 mg daily (with escalation permitted) after 403 patients had been treated.

In intention-to-treat analysis among patients started on the 600-mg dose and having a median follow-up of about 31 months, disease-free survival was better with pazopanib but not significantly so (hazard ratio, 0.86; P = .16), Dr. Motzer reported.

In secondary analyses, pazopanib did have a significant disease-free survival benefit among patients started on the 800-mg dose (hazard ratio, 0.69; P = .02) and among the entire trial population started on either dose (hazard ratio, 0.80; P = .01).

One possible explanation for the differing results seen with the two doses was the difference in follow-up, as the 800-mg group was treated earlier in the trial, he proposed. But with an additional year of blinded follow-up, the benefit in the 600-mg group actually diminished, whereas that in the 800-mg group did not.

Another possibility was the somewhat better performance of the placebo group used for comparison with the lower dose: the 3-year disease-free survival rate with placebo was 64% for the 600-mg comparison but 56% for the 800-mg comparison. “One factor that could explain differences in the outcomes of the placebo groups includes unidentified patient demographic characteristics,” Dr. Motzer noted.

Overall survival was statistically indistinguishable between the pazopanib and placebo groups, regardless of dose. However, “the results are inconclusive as the data are not yet mature,” he said, with a definitive analysis planned for 2019.

Compared with counterparts given placebo, patients started on the 600-mg dose of pazopanib had a higher rate of grade 3 or 4 adverse events overall (60% vs. 21%), driven in large part by higher rates of hypertension and increased alanine aminotransferase levels.

“Although the intent of modifying the protocol dose of pazopanib from 800 mg to 600 mg was to reduce the rate of discontinuation and improve the safety profile ... both cohorts had similar discontinuation rates and safety profiles,” Dr. Motzer noted.

A quality of life analysis for the 600-mg group using the 19-item Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index (FKSI-19) showed values were consistently lower with the drug than with placebo during treatment, with a crossing of the threshold for a minimally important difference at week 8.

Pharmacokinetic analyses from the trial, reported in a poster at the meeting (Abstract 4564), showed that in the group starting pazopanib at 600 mg, disease-free survival was longer in patients who achieved higher drug trough concentrations at week 3 or 5.

op@frontlinemedcom.com

Photo © ASCO/Scott Morgan 2017

CHICAGO—The largest international multiple myeloma (MM) trial ever conducted, according to the trial sponsor, met its primary endpoint, demonstrating that denosumab is non-inferior to zoledronic acid (ZA) in delaying the time to first on-study skeletal-related event (SRE) in patients with MM.

In addition to bone-specific benefits, denosumab-treated patients had significantly fewer renal adverse events and possible prolongation of progression-free survival.

Denosumab “may in fact be a new standard of care for multiple myeloma-related bone disease,” according to one of the investigators.

“The other important thing to note,” Noopur S. Raje, MD, said during her presentation at the ASCO 2017 Annual Meeting, “is denosumab can be administered despite renal function in patients with myeloma.” It does not need to be dose-adjusted, unlike bisphosphonates.

Dr Raje, of the Massachusetts General Hospital Cancer Center in Boston, Massachusetts, presented the study results as abstract 8005.

Study design

The international, phase 3, randomized, double-blind study is evaluating the safety of denosumab compared with ZA in newly diagnosed MM patients.

Investigators enrolled 1718 patients from 259 sites and 29 countries.

They randomized 859 patients to receive denosumab 120 mg subcutaneously every 4 weeks plus intravenous placebo every 4 weeks, and 859 patients to the standard ZA dose of 4 mg intravenously plus subcutaneous placebo every 4 weeks.

Patients were stratified by whether they were on novel-based anti-myeloma therapy, whether they planned to have an autologous peripheral blood stem cell (PBSC) transplant, disease stage, and previous SRE.

“We were looking for 676 on-study SREs, and if we saw a benefit, patients would be offered open-label denosumab for up to 2 years after this,” Dr Raje said.

“Patients had to have radiographic evidence of bone disease, and this is different from some of the other bone disease studies that you’ve seen in the recent past,” she added.

In addition to documented evidence of MM, patients had to be 18 years or older, be ECOG status of 2 or better, have adequate organ function, and plan to receive or be receiving primary frontline anti-myeloma therapy.

Patients were excluded if they had nonsecretory MM, more than 30 days of previous treatment with anti-myeloma therapy prior to screening, prior use of denosumab, use of oral bisphosphonates with a cumulative dose of more than 1 year, more than 1 previous dose of intravenous bisphosphonate, or prior history or current evidence of osteonecrosis/osteomyelitis of the jaw.

The primary endpoint was time to first on-study SRE, “and the idea here was to look for non-inferiority,” Dr Raje explained.

Secondary endpoints included time to the first on-study SRE (superiority), time to the first-and-subsequent on-study SRE (superiority), and overall survival.

Investigators also included the exploratory objective of progression-free survival (PFS).

Patient demographics

Patients were well balanced across the 2 arms, Dr Raje noted, and the breakdown of myeloma disease stage at diagnosis was comparable between the ZA and denosumab arms.

About 32% of patients were stage I, 37% stage II, and 29% stage III. Stage was not available for 49 patients.

A little more than half (54%) were male, mean age was 63 years, and 82% were white.

Two thirds had prior SRE history, and 54% of patients intended to undergo autologous PBSC transplant.

Enrollment began May 2012 and continued through the end of March 2016. The primary analysis cutoff was July 19, 2016.

Results

The primary endpoint for non-inferiority for time to first on-study SRE was met by denosumab (HR=0.98, 95%CI: 0.85, 1.14; P=0.01).

“When we looked at the secondary endpoints for superiority, we were not able to confirm superiority in this analysis, either for time to first SRE or time to first-and subsequent SRE on this study,” Dr Raje said.

The investigators also did not observe a survival difference between denosumab and ZA, with a hazard ratio (HR) (95% CI) of 0.90 (0.70, 1.16), P=0.41.

“Importantly, we had an exploratory endpoint where we looked at progression-free survival in this newly diagnosed patient population,” she added, “and we saw an interestingly increased or prolonged progression-free survival in patients getting denosumab.”

“And that survival difference was more than 10 months between denosumab and zoledronic acid, favoring the denosumab arm,” she affirmed. The HR was 0.82, 95% CI: 0.68, 0.99, P=0.036 (descriptive).

Safety

“[I]f you look at all treatment-emergent adverse events between denosumab and zoledronic acid, we really could not find a big difference in either of these 2 groups of patients,” Dr Raje said.

“We saw that in general both denosumab and zoledronic acid were extremely well tolerated between the 2 groups of patients.”

The investigators “drilled down” on certain toxicity issues of interest and examined events such as atypical stress fractures, hypersensitivity reactions, musculoskeletal pain, infections and infestations, new primary malignancies, and acute phase reactions.

They observed no atypical femur fractures on the study, nor did they see any big differences with respect to hypersensitivity or acute phase reactions.

The investigators examined closely any renal issues because dosing of ZA specifically is impacted by renal function.

The data showed that treatment-emergent adverse event (TEAE) renal toxicity was significantly higher in the ZA group compared to the denosumab group, 17% and 10%, respectively (P<0.001).

“When you look at patients who had a creatinine clearance less than 60 mL per minute,” Dr Raje emphasized, “we saw an almost doubling of renal toxicity in the zoledronic acid arm (26.4%) compared to the denosumab arm (12.9%).”

Patients with a creatinine level greater than 2 mg/dL had a significant increase in creatinine in the ZA arm (P=0.010), which was also significantly increased if their creatinine clearance was less than 60 mL/minute (P=0.054).

“There was a doubling of creatinine from baseline, more so in the zoledronic acid arm compared to the patients with denosumab,” Dr Raje said. “And this was again more pronounced if you had a creatinine clearance of less than 60.”

Hypocalcemia was “not surprisingly” more common in the denosumab arm than the ZA arm (P=0.009) for all patients, and osteonecrosis of the jaw was equal in both arms (P=0.147), although numerically slightly higher with denosumab treatment.

Dr Raje summarized that there was no difference in overall survival at the time of this analysis, “but I will say that the follow-up for a newly diagnosed patient population is fairly short right now.”

“Progression-free survival, which we saw [cut] off 10.7 months, was actually quite striking when denosumab was compared to zoledronic acid, and this was statistically highly significant.”

“The bone-specific benefits in combination with significantly fewer renal adverse events and possible prolongation of PFS with denosumab therapy we do think is very promising,” she said, “and may in fact be a new standard of care for multiple myeloma-related bone disease.”

The study was funded by Amgen Inc.

Denosumab (XGEVA^®) is indicated by the US Food and Drug Administration for the prevention of fractures and other SREs in patients with bone metastases from solid tumors. It is currently not indicated for the prevention of SREs in patients with MM. 

Photo © ASCO/Scott Morgan 2017

CHICAGO—The largest international multiple myeloma (MM) trial ever conducted, according to the trial sponsor, met its primary endpoint, demonstrating that denosumab is non-inferior to zoledronic acid (ZA) in delaying the time to first on-study skeletal-related event (SRE) in patients with MM.

In addition to bone-specific benefits, denosumab-treated patients had significantly fewer renal adverse events and possible prolongation of progression-free survival.

Denosumab “may in fact be a new standard of care for multiple myeloma-related bone disease,” according to one of the investigators.

“The other important thing to note,” Noopur S. Raje, MD, said during her presentation at the ASCO 2017 Annual Meeting, “is denosumab can be administered despite renal function in patients with myeloma.” It does not need to be dose-adjusted, unlike bisphosphonates.

Dr Raje, of the Massachusetts General Hospital Cancer Center in Boston, Massachusetts, presented the study results as abstract 8005.

Study design

The international, phase 3, randomized, double-blind study is evaluating the safety of denosumab compared with ZA in newly diagnosed MM patients.

Investigators enrolled 1718 patients from 259 sites and 29 countries.

They randomized 859 patients to receive denosumab 120 mg subcutaneously every 4 weeks plus intravenous placebo every 4 weeks, and 859 patients to the standard ZA dose of 4 mg intravenously plus subcutaneous placebo every 4 weeks.

Patients were stratified by whether they were on novel-based anti-myeloma therapy, whether they planned to have an autologous peripheral blood stem cell (PBSC) transplant, disease stage, and previous SRE.

“We were looking for 676 on-study SREs, and if we saw a benefit, patients would be offered open-label denosumab for up to 2 years after this,” Dr Raje said.

“Patients had to have radiographic evidence of bone disease, and this is different from some of the other bone disease studies that you’ve seen in the recent past,” she added.

In addition to documented evidence of MM, patients had to be 18 years or older, be ECOG status of 2 or better, have adequate organ function, and plan to receive or be receiving primary frontline anti-myeloma therapy.

Patients were excluded if they had nonsecretory MM, more than 30 days of previous treatment with anti-myeloma therapy prior to screening, prior use of denosumab, use of oral bisphosphonates with a cumulative dose of more than 1 year, more than 1 previous dose of intravenous bisphosphonate, or prior history or current evidence of osteonecrosis/osteomyelitis of the jaw.

The primary endpoint was time to first on-study SRE, “and the idea here was to look for non-inferiority,” Dr Raje explained.

Secondary endpoints included time to the first on-study SRE (superiority), time to the first-and-subsequent on-study SRE (superiority), and overall survival.

Investigators also included the exploratory objective of progression-free survival (PFS).

Patient demographics

Patients were well balanced across the 2 arms, Dr Raje noted, and the breakdown of myeloma disease stage at diagnosis was comparable between the ZA and denosumab arms.

About 32% of patients were stage I, 37% stage II, and 29% stage III. Stage was not available for 49 patients.

A little more than half (54%) were male, mean age was 63 years, and 82% were white.

Two thirds had prior SRE history, and 54% of patients intended to undergo autologous PBSC transplant.

Enrollment began May 2012 and continued through the end of March 2016. The primary analysis cutoff was July 19, 2016.

Results

The primary endpoint for non-inferiority for time to first on-study SRE was met by denosumab (HR=0.98, 95%CI: 0.85, 1.14; P=0.01).

“When we looked at the secondary endpoints for superiority, we were not able to confirm superiority in this analysis, either for time to first SRE or time to first-and subsequent SRE on this study,” Dr Raje said.

The investigators also did not observe a survival difference between denosumab and ZA, with a hazard ratio (HR) (95% CI) of 0.90 (0.70, 1.16), P=0.41.

“Importantly, we had an exploratory endpoint where we looked at progression-free survival in this newly diagnosed patient population,” she added, “and we saw an interestingly increased or prolonged progression-free survival in patients getting denosumab.”

“And that survival difference was more than 10 months between denosumab and zoledronic acid, favoring the denosumab arm,” she affirmed. The HR was 0.82, 95% CI: 0.68, 0.99, P=0.036 (descriptive).

Safety

“[I]f you look at all treatment-emergent adverse events between denosumab and zoledronic acid, we really could not find a big difference in either of these 2 groups of patients,” Dr Raje said.

“We saw that in general both denosumab and zoledronic acid were extremely well tolerated between the 2 groups of patients.”

The investigators “drilled down” on certain toxicity issues of interest and examined events such as atypical stress fractures, hypersensitivity reactions, musculoskeletal pain, infections and infestations, new primary malignancies, and acute phase reactions.

They observed no atypical femur fractures on the study, nor did they see any big differences with respect to hypersensitivity or acute phase reactions.

The investigators examined closely any renal issues because dosing of ZA specifically is impacted by renal function.

The data showed that treatment-emergent adverse event (TEAE) renal toxicity was significantly higher in the ZA group compared to the denosumab group, 17% and 10%, respectively (P<0.001).

“When you look at patients who had a creatinine clearance less than 60 mL per minute,” Dr Raje emphasized, “we saw an almost doubling of renal toxicity in the zoledronic acid arm (26.4%) compared to the denosumab arm (12.9%).”

Patients with a creatinine level greater than 2 mg/dL had a significant increase in creatinine in the ZA arm (P=0.010), which was also significantly increased if their creatinine clearance was less than 60 mL/minute (P=0.054).

“There was a doubling of creatinine from baseline, more so in the zoledronic acid arm compared to the patients with denosumab,” Dr Raje said. “And this was again more pronounced if you had a creatinine clearance of less than 60.”

Hypocalcemia was “not surprisingly” more common in the denosumab arm than the ZA arm (P=0.009) for all patients, and osteonecrosis of the jaw was equal in both arms (P=0.147), although numerically slightly higher with denosumab treatment.

Dr Raje summarized that there was no difference in overall survival at the time of this analysis, “but I will say that the follow-up for a newly diagnosed patient population is fairly short right now.”

“Progression-free survival, which we saw [cut] off 10.7 months, was actually quite striking when denosumab was compared to zoledronic acid, and this was statistically highly significant.”

“The bone-specific benefits in combination with significantly fewer renal adverse events and possible prolongation of PFS with denosumab therapy we do think is very promising,” she said, “and may in fact be a new standard of care for multiple myeloma-related bone disease.”

The study was funded by Amgen Inc.

Denosumab (XGEVA^®) is indicated by the US Food and Drug Administration for the prevention of fractures and other SREs in patients with bone metastases from solid tumors. It is currently not indicated for the prevention of SREs in patients with MM. 

Photo © ASCO/Scott Morgan 2017

CHICAGO—The largest international multiple myeloma (MM) trial ever conducted, according to the trial sponsor, met its primary endpoint, demonstrating that denosumab is non-inferior to zoledronic acid (ZA) in delaying the time to first on-study skeletal-related event (SRE) in patients with MM.

In addition to bone-specific benefits, denosumab-treated patients had significantly fewer renal adverse events and possible prolongation of progression-free survival.

Denosumab “may in fact be a new standard of care for multiple myeloma-related bone disease,” according to one of the investigators.

“The other important thing to note,” Noopur S. Raje, MD, said during her presentation at the ASCO 2017 Annual Meeting, “is denosumab can be administered despite renal function in patients with myeloma.” It does not need to be dose-adjusted, unlike bisphosphonates.

Dr Raje, of the Massachusetts General Hospital Cancer Center in Boston, Massachusetts, presented the study results as abstract 8005.

Study design

The international, phase 3, randomized, double-blind study is evaluating the safety of denosumab compared with ZA in newly diagnosed MM patients.

Investigators enrolled 1718 patients from 259 sites and 29 countries.

They randomized 859 patients to receive denosumab 120 mg subcutaneously every 4 weeks plus intravenous placebo every 4 weeks, and 859 patients to the standard ZA dose of 4 mg intravenously plus subcutaneous placebo every 4 weeks.

Patients were stratified by whether they were on novel-based anti-myeloma therapy, whether they planned to have an autologous peripheral blood stem cell (PBSC) transplant, disease stage, and previous SRE.

“We were looking for 676 on-study SREs, and if we saw a benefit, patients would be offered open-label denosumab for up to 2 years after this,” Dr Raje said.

“Patients had to have radiographic evidence of bone disease, and this is different from some of the other bone disease studies that you’ve seen in the recent past,” she added.

In addition to documented evidence of MM, patients had to be 18 years or older, be ECOG status of 2 or better, have adequate organ function, and plan to receive or be receiving primary frontline anti-myeloma therapy.

Patients were excluded if they had nonsecretory MM, more than 30 days of previous treatment with anti-myeloma therapy prior to screening, prior use of denosumab, use of oral bisphosphonates with a cumulative dose of more than 1 year, more than 1 previous dose of intravenous bisphosphonate, or prior history or current evidence of osteonecrosis/osteomyelitis of the jaw.

The primary endpoint was time to first on-study SRE, “and the idea here was to look for non-inferiority,” Dr Raje explained.

Secondary endpoints included time to the first on-study SRE (superiority), time to the first-and-subsequent on-study SRE (superiority), and overall survival.

Investigators also included the exploratory objective of progression-free survival (PFS).

Patient demographics

Patients were well balanced across the 2 arms, Dr Raje noted, and the breakdown of myeloma disease stage at diagnosis was comparable between the ZA and denosumab arms.

About 32% of patients were stage I, 37% stage II, and 29% stage III. Stage was not available for 49 patients.

A little more than half (54%) were male, mean age was 63 years, and 82% were white.

Two thirds had prior SRE history, and 54% of patients intended to undergo autologous PBSC transplant.

Enrollment began May 2012 and continued through the end of March 2016. The primary analysis cutoff was July 19, 2016.

Results

The primary endpoint for non-inferiority for time to first on-study SRE was met by denosumab (HR=0.98, 95%CI: 0.85, 1.14; P=0.01).

“When we looked at the secondary endpoints for superiority, we were not able to confirm superiority in this analysis, either for time to first SRE or time to first-and subsequent SRE on this study,” Dr Raje said.

The investigators also did not observe a survival difference between denosumab and ZA, with a hazard ratio (HR) (95% CI) of 0.90 (0.70, 1.16), P=0.41.

“Importantly, we had an exploratory endpoint where we looked at progression-free survival in this newly diagnosed patient population,” she added, “and we saw an interestingly increased or prolonged progression-free survival in patients getting denosumab.”

“And that survival difference was more than 10 months between denosumab and zoledronic acid, favoring the denosumab arm,” she affirmed. The HR was 0.82, 95% CI: 0.68, 0.99, P=0.036 (descriptive).

Safety

“[I]f you look at all treatment-emergent adverse events between denosumab and zoledronic acid, we really could not find a big difference in either of these 2 groups of patients,” Dr Raje said.

“We saw that in general both denosumab and zoledronic acid were extremely well tolerated between the 2 groups of patients.”

The investigators “drilled down” on certain toxicity issues of interest and examined events such as atypical stress fractures, hypersensitivity reactions, musculoskeletal pain, infections and infestations, new primary malignancies, and acute phase reactions.

They observed no atypical femur fractures on the study, nor did they see any big differences with respect to hypersensitivity or acute phase reactions.

The investigators examined closely any renal issues because dosing of ZA specifically is impacted by renal function.

The data showed that treatment-emergent adverse event (TEAE) renal toxicity was significantly higher in the ZA group compared to the denosumab group, 17% and 10%, respectively (P<0.001).

“When you look at patients who had a creatinine clearance less than 60 mL per minute,” Dr Raje emphasized, “we saw an almost doubling of renal toxicity in the zoledronic acid arm (26.4%) compared to the denosumab arm (12.9%).”

Patients with a creatinine level greater than 2 mg/dL had a significant increase in creatinine in the ZA arm (P=0.010), which was also significantly increased if their creatinine clearance was less than 60 mL/minute (P=0.054).

“There was a doubling of creatinine from baseline, more so in the zoledronic acid arm compared to the patients with denosumab,” Dr Raje said. “And this was again more pronounced if you had a creatinine clearance of less than 60.”

Hypocalcemia was “not surprisingly” more common in the denosumab arm than the ZA arm (P=0.009) for all patients, and osteonecrosis of the jaw was equal in both arms (P=0.147), although numerically slightly higher with denosumab treatment.

Dr Raje summarized that there was no difference in overall survival at the time of this analysis, “but I will say that the follow-up for a newly diagnosed patient population is fairly short right now.”

“Progression-free survival, which we saw [cut] off 10.7 months, was actually quite striking when denosumab was compared to zoledronic acid, and this was statistically highly significant.”

“The bone-specific benefits in combination with significantly fewer renal adverse events and possible prolongation of PFS with denosumab therapy we do think is very promising,” she said, “and may in fact be a new standard of care for multiple myeloma-related bone disease.”

The study was funded by Amgen Inc.

Denosumab (XGEVA^®) is indicated by the US Food and Drug Administration for the prevention of fractures and other SREs in patients with bone metastases from solid tumors. It is currently not indicated for the prevention of SREs in patients with MM. 

Photo © ASCO/Todd Buchanan 2017

CHICAGO – The neurotoxicity in adult patients with relapsed or refractory B-cell acute lymphocytic leukemia (B-ALL) treated with CD19 CAR T cells is a separate process from cytokine release syndrome (CRS) and needs to be treated separately, according to a new study presented at the American Society of Clinical Oncology annual meeting (abstract 3019).

CD19-specific CAR-modified T cells produce high, durable anti-tumor activity, but can be associated with treatment-related toxicities, including CRS and neurotoxicity.

Neurotoxicity is poorly understood and it hasn't been clear where to focus further research, said Bianca Santomasso, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

Dr Santomasso and colleagues had conducted a phase 1 study using autologous 19-CAR T cells in adult patients with relapsing/refractory B-ALL, with high response rates.

To gain a better understanding of CD19 CAR T-cell-associated neurotoxicity, they analyzed clinical and research parameters after stratifying patients by neurotoxicity grade.

At ASCO, she reported neurologic symptom presentation in 51 adult patients with relapsed/refractory B-ALL who were treated with CAR T cells following conditioning chemotherapy, along with cerebrospinal fluid (CSF) data and neuroimaging findings associated with neurotoxicity.

Of the 51 patients treated, 10 patients (20%) developed mild neurologic symptoms (grade 1 or 2) and 21 patients (41%) developed severe neurotoxicity (grade 3 or 4).

No grade 5 neurotoxicity or diffuse cerebral edema occurred and, in all but one case, neurologic symptoms fully resolved.

Fourteen patients (27.4%) developed severe CRS; 6 patients received tocilizumab alone, 13 patients tocilizumab plus steroids, 4 patients steroids alone, and 29 patients supportive care.

The cytokines IL-6, IL-8, IL-10, interferon gamma, and granulocyte-colony stimulating factor were elevated in CSF over serum at the time of neurotoxicity and correlated with CSF protein levels.

“We found no significant correlation between neurotoxicity grade and the CAR T-cell concentration in the CSF during neurotoxicity,” Dr Santomasso said. “Instead, CSF protein level was correlated with neurotoxicity grade.”

Neurotoxicity was associated with peak CAR T-cell expansion in the blood and peak serum levels of several cytokines associated with T-cell activation or proliferation, she said.

“CAR T cells traffic to the CSF of patients with all grades of neurotoxicity, including grade 0, and there is no significant correlation between CAR T cells in CSF at the time of acute neurotoxicity and grade of neurotoxicity,” Dr Santomasso reported. “This suggests that neurotoxicity is not directly mediated by CAR T cells, which cross into the spinal fluid.”

Some chemokines/cytokines are elevated in CSF relative to serum, suggesting CNS-specific production of these factors, she said.

“Clinicians treating these patients tend to lump CRS and neurotoxicity together. Now we have an increasing understanding that these adverse events are separated in time and possibly in underlying pathology,” said Dr Santomasso.

“Even when patients recover from CRS, they could still be at risk for neurotoxicity.”

She noted that the neurotoxicity symptoms that B-ALL patients develop in the setting of CAR T cells are manageable.

In a subset of patients with severe neurotoxicity, T2/FLAIR changes were observed, which resolved with steroids and neurologic symptom resolution. 

Photo © ASCO/Todd Buchanan 2017

CHICAGO – The neurotoxicity in adult patients with relapsed or refractory B-cell acute lymphocytic leukemia (B-ALL) treated with CD19 CAR T cells is a separate process from cytokine release syndrome (CRS) and needs to be treated separately, according to a new study presented at the American Society of Clinical Oncology annual meeting (abstract 3019).

CD19-specific CAR-modified T cells produce high, durable anti-tumor activity, but can be associated with treatment-related toxicities, including CRS and neurotoxicity.

Neurotoxicity is poorly understood and it hasn't been clear where to focus further research, said Bianca Santomasso, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

Dr Santomasso and colleagues had conducted a phase 1 study using autologous 19-CAR T cells in adult patients with relapsing/refractory B-ALL, with high response rates.

To gain a better understanding of CD19 CAR T-cell-associated neurotoxicity, they analyzed clinical and research parameters after stratifying patients by neurotoxicity grade.

At ASCO, she reported neurologic symptom presentation in 51 adult patients with relapsed/refractory B-ALL who were treated with CAR T cells following conditioning chemotherapy, along with cerebrospinal fluid (CSF) data and neuroimaging findings associated with neurotoxicity.

Of the 51 patients treated, 10 patients (20%) developed mild neurologic symptoms (grade 1 or 2) and 21 patients (41%) developed severe neurotoxicity (grade 3 or 4).

No grade 5 neurotoxicity or diffuse cerebral edema occurred and, in all but one case, neurologic symptoms fully resolved.

Fourteen patients (27.4%) developed severe CRS; 6 patients received tocilizumab alone, 13 patients tocilizumab plus steroids, 4 patients steroids alone, and 29 patients supportive care.

The cytokines IL-6, IL-8, IL-10, interferon gamma, and granulocyte-colony stimulating factor were elevated in CSF over serum at the time of neurotoxicity and correlated with CSF protein levels.

“We found no significant correlation between neurotoxicity grade and the CAR T-cell concentration in the CSF during neurotoxicity,” Dr Santomasso said. “Instead, CSF protein level was correlated with neurotoxicity grade.”

Neurotoxicity was associated with peak CAR T-cell expansion in the blood and peak serum levels of several cytokines associated with T-cell activation or proliferation, she said.

“CAR T cells traffic to the CSF of patients with all grades of neurotoxicity, including grade 0, and there is no significant correlation between CAR T cells in CSF at the time of acute neurotoxicity and grade of neurotoxicity,” Dr Santomasso reported. “This suggests that neurotoxicity is not directly mediated by CAR T cells, which cross into the spinal fluid.”

Some chemokines/cytokines are elevated in CSF relative to serum, suggesting CNS-specific production of these factors, she said.

“Clinicians treating these patients tend to lump CRS and neurotoxicity together. Now we have an increasing understanding that these adverse events are separated in time and possibly in underlying pathology,” said Dr Santomasso.

“Even when patients recover from CRS, they could still be at risk for neurotoxicity.”

She noted that the neurotoxicity symptoms that B-ALL patients develop in the setting of CAR T cells are manageable.

In a subset of patients with severe neurotoxicity, T2/FLAIR changes were observed, which resolved with steroids and neurologic symptom resolution. 

Photo © ASCO/Todd Buchanan 2017

CHICAGO – The neurotoxicity in adult patients with relapsed or refractory B-cell acute lymphocytic leukemia (B-ALL) treated with CD19 CAR T cells is a separate process from cytokine release syndrome (CRS) and needs to be treated separately, according to a new study presented at the American Society of Clinical Oncology annual meeting (abstract 3019).

CD19-specific CAR-modified T cells produce high, durable anti-tumor activity, but can be associated with treatment-related toxicities, including CRS and neurotoxicity.

Neurotoxicity is poorly understood and it hasn't been clear where to focus further research, said Bianca Santomasso, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

Dr Santomasso and colleagues had conducted a phase 1 study using autologous 19-CAR T cells in adult patients with relapsing/refractory B-ALL, with high response rates.

To gain a better understanding of CD19 CAR T-cell-associated neurotoxicity, they analyzed clinical and research parameters after stratifying patients by neurotoxicity grade.

At ASCO, she reported neurologic symptom presentation in 51 adult patients with relapsed/refractory B-ALL who were treated with CAR T cells following conditioning chemotherapy, along with cerebrospinal fluid (CSF) data and neuroimaging findings associated with neurotoxicity.

Of the 51 patients treated, 10 patients (20%) developed mild neurologic symptoms (grade 1 or 2) and 21 patients (41%) developed severe neurotoxicity (grade 3 or 4).

No grade 5 neurotoxicity or diffuse cerebral edema occurred and, in all but one case, neurologic symptoms fully resolved.

Fourteen patients (27.4%) developed severe CRS; 6 patients received tocilizumab alone, 13 patients tocilizumab plus steroids, 4 patients steroids alone, and 29 patients supportive care.

The cytokines IL-6, IL-8, IL-10, interferon gamma, and granulocyte-colony stimulating factor were elevated in CSF over serum at the time of neurotoxicity and correlated with CSF protein levels.

“We found no significant correlation between neurotoxicity grade and the CAR T-cell concentration in the CSF during neurotoxicity,” Dr Santomasso said. “Instead, CSF protein level was correlated with neurotoxicity grade.”

Neurotoxicity was associated with peak CAR T-cell expansion in the blood and peak serum levels of several cytokines associated with T-cell activation or proliferation, she said.

“CAR T cells traffic to the CSF of patients with all grades of neurotoxicity, including grade 0, and there is no significant correlation between CAR T cells in CSF at the time of acute neurotoxicity and grade of neurotoxicity,” Dr Santomasso reported. “This suggests that neurotoxicity is not directly mediated by CAR T cells, which cross into the spinal fluid.”

Some chemokines/cytokines are elevated in CSF relative to serum, suggesting CNS-specific production of these factors, she said.

“Clinicians treating these patients tend to lump CRS and neurotoxicity together. Now we have an increasing understanding that these adverse events are separated in time and possibly in underlying pathology,” said Dr Santomasso.

“Even when patients recover from CRS, they could still be at risk for neurotoxicity.”

She noted that the neurotoxicity symptoms that B-ALL patients develop in the setting of CAR T cells are manageable.

In a subset of patients with severe neurotoxicity, T2/FLAIR changes were observed, which resolved with steroids and neurologic symptom resolution. 

Photo © ASCO/David Eulitt 2017

CHICAGO—Chimeric antigen receptor (CAR) T cells combined with ibrutinib enhance T-cell function and can induce complete remission (CR) in patients with chronic lymphocytic leukemia (CLL), researchers report.

Many CLL patients receive ibrutinib treatment, which is well tolerated, but few patients achieve CR.

Immunotherapy with anti-CD19 CAR T cells has induced CR in 25% - 45% of patients with CLL, Saar Gill, MD, of the University of Pennsylvania in Philadelphia, told Hematology Times, and these CRs tend to be durable.

So investigators conducted a pilot trial in 10 patients to test whether combining anti-CD19 CAR T cells with ibrutinib would enhance the CR rate.

Dr Gill reported the findings of the pilot trial at the ASCO 2017 Annual Meeting (abstract 7509).

The patients must have failed at least 1 regimen before ibrutinib, unless they had del(17)(p13.1) or a TP53 mutation.

T cells were lentivirally transduced to express a CAR that included humanized anti-CD19.

Patients were lymphodepleted 1 week before infusion, and ibrutinib was continued throughout the trial.

After a median follow-up of 6 months, 8 of the 9 evaluable patients show absence of CLL in the bone marrow by flow cytometry or minimal residual disease (MRD) negative, and all remain in marrow CR at last follow-up, Dr Gill said.

Radiologic responses are less clear-cut and may require longer follow-up.

“All but 1 patient achieved MRD with deep sequencing. We have deep response in the bone marrow,” Dr Gill said. He also noted that the treatment was well tolerated.

Cytokine release syndrome (CRS) developed in 9 patients: grade 1 in 2 patients, grade 2 in 6 patients, and grade 3 in 1 patient. One patient developed grade 4 tumor lysis syndrome. Treatment of CRS with the IL-6 receptor antagonist tocilizumab was not required.

There was modest residual splenomegaly in 3 of 5 patients, and adenopathy resolved in 4 of 6 patients, with progression in 1 patient.

Ibrutinib reduced CRS apparently by blocking cytokine production by T cells, said Dr Gill, adding, “The combination led to improved efficacy without increased toxicity.”

Ibrutinib may make CAR T-cell therapy more feasible.

Patients who receive ibrutinib for 6 months have a better T-cell response.

“This opens up future discussions of bringing CAR T-cell therapy earlier into CLL treatment,” said Dr Gill.

He envisions patients receiving ibrutinib for 6 months, which would allow time to manufacture T cells, and then have a T-cell infusion.

“Once patients achieve MRD, then we can discuss the possibility of stopping ibrutinib therapy,” he said.

“Most patients remain on ibrutinib, but longer follow-up may show whether remissions are sustained off ibrutinib.”

The researchers have ongoing plans to treat 25 patients with CTL19 plus ibrutinib in a continuation of this trial.

Dr Gill said longer follow-up will reveal the durability of these results “and could support evaluation of a first-line combination approach in an attempt to obviate the need for chronic therapy.” 

Photo © ASCO/David Eulitt 2017

CHICAGO—Chimeric antigen receptor (CAR) T cells combined with ibrutinib enhance T-cell function and can induce complete remission (CR) in patients with chronic lymphocytic leukemia (CLL), researchers report.

Many CLL patients receive ibrutinib treatment, which is well tolerated, but few patients achieve CR.

Immunotherapy with anti-CD19 CAR T cells has induced CR in 25% - 45% of patients with CLL, Saar Gill, MD, of the University of Pennsylvania in Philadelphia, told Hematology Times, and these CRs tend to be durable.

So investigators conducted a pilot trial in 10 patients to test whether combining anti-CD19 CAR T cells with ibrutinib would enhance the CR rate.

Dr Gill reported the findings of the pilot trial at the ASCO 2017 Annual Meeting (abstract 7509).

The patients must have failed at least 1 regimen before ibrutinib, unless they had del(17)(p13.1) or a TP53 mutation.

T cells were lentivirally transduced to express a CAR that included humanized anti-CD19.

Patients were lymphodepleted 1 week before infusion, and ibrutinib was continued throughout the trial.

After a median follow-up of 6 months, 8 of the 9 evaluable patients show absence of CLL in the bone marrow by flow cytometry or minimal residual disease (MRD) negative, and all remain in marrow CR at last follow-up, Dr Gill said.

Radiologic responses are less clear-cut and may require longer follow-up.

“All but 1 patient achieved MRD with deep sequencing. We have deep response in the bone marrow,” Dr Gill said. He also noted that the treatment was well tolerated.

Cytokine release syndrome (CRS) developed in 9 patients: grade 1 in 2 patients, grade 2 in 6 patients, and grade 3 in 1 patient. One patient developed grade 4 tumor lysis syndrome. Treatment of CRS with the IL-6 receptor antagonist tocilizumab was not required.

There was modest residual splenomegaly in 3 of 5 patients, and adenopathy resolved in 4 of 6 patients, with progression in 1 patient.

Ibrutinib reduced CRS apparently by blocking cytokine production by T cells, said Dr Gill, adding, “The combination led to improved efficacy without increased toxicity.”

Ibrutinib may make CAR T-cell therapy more feasible.

Patients who receive ibrutinib for 6 months have a better T-cell response.

“This opens up future discussions of bringing CAR T-cell therapy earlier into CLL treatment,” said Dr Gill.

He envisions patients receiving ibrutinib for 6 months, which would allow time to manufacture T cells, and then have a T-cell infusion.

“Once patients achieve MRD, then we can discuss the possibility of stopping ibrutinib therapy,” he said.

“Most patients remain on ibrutinib, but longer follow-up may show whether remissions are sustained off ibrutinib.”

The researchers have ongoing plans to treat 25 patients with CTL19 plus ibrutinib in a continuation of this trial.

Dr Gill said longer follow-up will reveal the durability of these results “and could support evaluation of a first-line combination approach in an attempt to obviate the need for chronic therapy.” 

Photo © ASCO/David Eulitt 2017

CHICAGO—Chimeric antigen receptor (CAR) T cells combined with ibrutinib enhance T-cell function and can induce complete remission (CR) in patients with chronic lymphocytic leukemia (CLL), researchers report.

Many CLL patients receive ibrutinib treatment, which is well tolerated, but few patients achieve CR.

Immunotherapy with anti-CD19 CAR T cells has induced CR in 25% - 45% of patients with CLL, Saar Gill, MD, of the University of Pennsylvania in Philadelphia, told Hematology Times, and these CRs tend to be durable.

So investigators conducted a pilot trial in 10 patients to test whether combining anti-CD19 CAR T cells with ibrutinib would enhance the CR rate.

Dr Gill reported the findings of the pilot trial at the ASCO 2017 Annual Meeting (abstract 7509).

The patients must have failed at least 1 regimen before ibrutinib, unless they had del(17)(p13.1) or a TP53 mutation.

T cells were lentivirally transduced to express a CAR that included humanized anti-CD19.

Patients were lymphodepleted 1 week before infusion, and ibrutinib was continued throughout the trial.

After a median follow-up of 6 months, 8 of the 9 evaluable patients show absence of CLL in the bone marrow by flow cytometry or minimal residual disease (MRD) negative, and all remain in marrow CR at last follow-up, Dr Gill said.

Radiologic responses are less clear-cut and may require longer follow-up.

“All but 1 patient achieved MRD with deep sequencing. We have deep response in the bone marrow,” Dr Gill said. He also noted that the treatment was well tolerated.

Cytokine release syndrome (CRS) developed in 9 patients: grade 1 in 2 patients, grade 2 in 6 patients, and grade 3 in 1 patient. One patient developed grade 4 tumor lysis syndrome. Treatment of CRS with the IL-6 receptor antagonist tocilizumab was not required.

There was modest residual splenomegaly in 3 of 5 patients, and adenopathy resolved in 4 of 6 patients, with progression in 1 patient.

Ibrutinib reduced CRS apparently by blocking cytokine production by T cells, said Dr Gill, adding, “The combination led to improved efficacy without increased toxicity.”

Ibrutinib may make CAR T-cell therapy more feasible.

Patients who receive ibrutinib for 6 months have a better T-cell response.

“This opens up future discussions of bringing CAR T-cell therapy earlier into CLL treatment,” said Dr Gill.

He envisions patients receiving ibrutinib for 6 months, which would allow time to manufacture T cells, and then have a T-cell infusion.

“Once patients achieve MRD, then we can discuss the possibility of stopping ibrutinib therapy,” he said.

“Most patients remain on ibrutinib, but longer follow-up may show whether remissions are sustained off ibrutinib.”

The researchers have ongoing plans to treat 25 patients with CTL19 plus ibrutinib in a continuation of this trial.

Dr Gill said longer follow-up will reveal the durability of these results “and could support evaluation of a first-line combination approach in an attempt to obviate the need for chronic therapy.” 

CHICAGO – Nine weeks of treatment with trastuzumab resulted in comparable disease-free and overall survival to that seen with the standard 12 months of trastuzumab – with about one-third of the rate of severe cardiac toxicity – in patients with HER2-positive early breast cancer in the Italian phase III multicenter Short-HER study.

The 5-year disease-free survival rate in 626 patients who received 9 weeks of trastuzumab was 87.5%, compared with 85.4% in 627 patients who received 1 year of trastuzumab therapy (hazard ratio, 1.15), Pier F. Conte, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The upper limit of the 90% confidence interval (0.91-1.46) crossed the noninferiority margin set at 1.29 for this frequentist analysis, Dr. Conte of the University of Padova, Italy, said, noting that a subgroup analysis showed that patients with stage III disease and those with four or more positive lymph nodes – who together represented about 15% of the study population – had a disease-free survival advantage with longer treatment (HR, 2.30 and 2.25, respectively), and an interaction test was statistically significant.

However, a preplanned Bayesian analysis showed a 78% probability that the shorter treatment is not inferior to longer treatment for disease-free survival, he said.

The secondary endpoint of overall survival was also similar in the two groups (95.1% vs. 95.0%; HR, 1.06).

As for the secondary endpoint of cardiac events, the rate was 5.1% with shorter treatment vs. 14.4% with longer treatment. Grade 2 cardiac events occurred in 11.2% vs. 3.5% of patients in the treatment arms, respectively, and the grade 3 cardiac vents occurred in 2.7% vs. 1.1%, respectively. The rate of grade 4 events was 0.5% in both groups.

The overall difference between the groups with respect to cardiac events was highly statistically significant in favor of shorter treatment (HR, 0.32), Dr. Conte said.

Multiple studies have demonstrated the superiority of combining trastuzumab and adjuvant chemotherapy for HER2+ early breast cancer, and, following the release of some of those findings at the ASCO annual meeting in 2005, the agent was granted accelerated approval for this indication, Dr. Conte said.

“It was, however, clear that there were a number of reasons to believe that further investigation was appropriate on the optimal duration of trastuzumab duration,” he said, explaining that the same magnitude of benefit was reported by the small FinHER study with 9 weeks of trastuzumab and that clinical data suggest synergism of trastuzumab with chemotherapy.

“Finally, in the real world, there are patients at lower risk of relapse (more node-negative, more small tumors) and at higher risk of cardiac toxicity because of age or comorbidities,” he said. “So, the hypotheses behind the Short-HER [study] was that a shorter duration of trastuzumab administered concomitantly with chemotherapy might produce comparable efficacy with significantly lower toxicities and, of course, costs.”

Short-HER study subjects, who had a mean age of 55 years, had either HER2-positive, node-positive, or high-risk node-negative disease and were randomized to receive either the shorter treatment, including three courses of docetaxel given three times weekly plus trastuzumab given weekly for 9 doses, followed by three courses of 5-fluorouracil/epirubicin/cyclophosphamide, or standard 12-month treatment with four courses of anthracycline-based chemotherapy followed by four courses of docetaxel in combination with trastuzumab given three times weekly, followed by 14 additional courses of trastuzumab given three times weekly (for a total of 18 3-times-weekly doses). Radiation therapy was administered when indicated after chemotherapy, and hormonal therapy was started after completion of chemotherapy in patients with hormone-receptor–positive tumors.

Based on the frequentist analysis, noninferiority of the shorter treatment approach cannot be claimed, but, according to the preplanned Bayesian analysis, noninferiority is likely, Dr. Conte said.

“One year of trastuzumab is still standard. The Short-Her trial, however, reinforces the hypothesis that treatment deescalation retains efficacy with less toxicity. A shorter treatment might be an option for patients at low risk of relapse and/or higher risk of cardiac toxicity,” he said. “Moreover, these results might facilitate trastuzumab to patients in low/middle income countries.”

Individual patient meta-analysis with other trials testing different durations of trastuzumab administration is ongoing, he noted.

The Short-HER study was funded by the Italian Drug Agency, and drugs and insurance coverage were supplied by the National Health System. The study was sponsored by the University of Modena & Regio Emilia and the University of Padova. Dr. Conte has served on the speakers’ bureau for AstraZeneca, Lilly, Novartis, and Roche/Genentech and has received research funding and/or travel or other expenses from AstraZeneca, Celgene, and Novartis.

sworcester@frontlinemedcom.com

CHICAGO – Nine weeks of treatment with trastuzumab resulted in comparable disease-free and overall survival to that seen with the standard 12 months of trastuzumab – with about one-third of the rate of severe cardiac toxicity – in patients with HER2-positive early breast cancer in the Italian phase III multicenter Short-HER study.

The 5-year disease-free survival rate in 626 patients who received 9 weeks of trastuzumab was 87.5%, compared with 85.4% in 627 patients who received 1 year of trastuzumab therapy (hazard ratio, 1.15), Pier F. Conte, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The upper limit of the 90% confidence interval (0.91-1.46) crossed the noninferiority margin set at 1.29 for this frequentist analysis, Dr. Conte of the University of Padova, Italy, said, noting that a subgroup analysis showed that patients with stage III disease and those with four or more positive lymph nodes – who together represented about 15% of the study population – had a disease-free survival advantage with longer treatment (HR, 2.30 and 2.25, respectively), and an interaction test was statistically significant.

However, a preplanned Bayesian analysis showed a 78% probability that the shorter treatment is not inferior to longer treatment for disease-free survival, he said.

The secondary endpoint of overall survival was also similar in the two groups (95.1% vs. 95.0%; HR, 1.06).

As for the secondary endpoint of cardiac events, the rate was 5.1% with shorter treatment vs. 14.4% with longer treatment. Grade 2 cardiac events occurred in 11.2% vs. 3.5% of patients in the treatment arms, respectively, and the grade 3 cardiac vents occurred in 2.7% vs. 1.1%, respectively. The rate of grade 4 events was 0.5% in both groups.

The overall difference between the groups with respect to cardiac events was highly statistically significant in favor of shorter treatment (HR, 0.32), Dr. Conte said.

Multiple studies have demonstrated the superiority of combining trastuzumab and adjuvant chemotherapy for HER2+ early breast cancer, and, following the release of some of those findings at the ASCO annual meeting in 2005, the agent was granted accelerated approval for this indication, Dr. Conte said.

“It was, however, clear that there were a number of reasons to believe that further investigation was appropriate on the optimal duration of trastuzumab duration,” he said, explaining that the same magnitude of benefit was reported by the small FinHER study with 9 weeks of trastuzumab and that clinical data suggest synergism of trastuzumab with chemotherapy.

“Finally, in the real world, there are patients at lower risk of relapse (more node-negative, more small tumors) and at higher risk of cardiac toxicity because of age or comorbidities,” he said. “So, the hypotheses behind the Short-HER [study] was that a shorter duration of trastuzumab administered concomitantly with chemotherapy might produce comparable efficacy with significantly lower toxicities and, of course, costs.”

Short-HER study subjects, who had a mean age of 55 years, had either HER2-positive, node-positive, or high-risk node-negative disease and were randomized to receive either the shorter treatment, including three courses of docetaxel given three times weekly plus trastuzumab given weekly for 9 doses, followed by three courses of 5-fluorouracil/epirubicin/cyclophosphamide, or standard 12-month treatment with four courses of anthracycline-based chemotherapy followed by four courses of docetaxel in combination with trastuzumab given three times weekly, followed by 14 additional courses of trastuzumab given three times weekly (for a total of 18 3-times-weekly doses). Radiation therapy was administered when indicated after chemotherapy, and hormonal therapy was started after completion of chemotherapy in patients with hormone-receptor–positive tumors.

Based on the frequentist analysis, noninferiority of the shorter treatment approach cannot be claimed, but, according to the preplanned Bayesian analysis, noninferiority is likely, Dr. Conte said.

“One year of trastuzumab is still standard. The Short-Her trial, however, reinforces the hypothesis that treatment deescalation retains efficacy with less toxicity. A shorter treatment might be an option for patients at low risk of relapse and/or higher risk of cardiac toxicity,” he said. “Moreover, these results might facilitate trastuzumab to patients in low/middle income countries.”

Individual patient meta-analysis with other trials testing different durations of trastuzumab administration is ongoing, he noted.

The Short-HER study was funded by the Italian Drug Agency, and drugs and insurance coverage were supplied by the National Health System. The study was sponsored by the University of Modena & Regio Emilia and the University of Padova. Dr. Conte has served on the speakers’ bureau for AstraZeneca, Lilly, Novartis, and Roche/Genentech and has received research funding and/or travel or other expenses from AstraZeneca, Celgene, and Novartis.

sworcester@frontlinemedcom.com

CHICAGO – Nine weeks of treatment with trastuzumab resulted in comparable disease-free and overall survival to that seen with the standard 12 months of trastuzumab – with about one-third of the rate of severe cardiac toxicity – in patients with HER2-positive early breast cancer in the Italian phase III multicenter Short-HER study.

The 5-year disease-free survival rate in 626 patients who received 9 weeks of trastuzumab was 87.5%, compared with 85.4% in 627 patients who received 1 year of trastuzumab therapy (hazard ratio, 1.15), Pier F. Conte, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The upper limit of the 90% confidence interval (0.91-1.46) crossed the noninferiority margin set at 1.29 for this frequentist analysis, Dr. Conte of the University of Padova, Italy, said, noting that a subgroup analysis showed that patients with stage III disease and those with four or more positive lymph nodes – who together represented about 15% of the study population – had a disease-free survival advantage with longer treatment (HR, 2.30 and 2.25, respectively), and an interaction test was statistically significant.

However, a preplanned Bayesian analysis showed a 78% probability that the shorter treatment is not inferior to longer treatment for disease-free survival, he said.

The secondary endpoint of overall survival was also similar in the two groups (95.1% vs. 95.0%; HR, 1.06).

As for the secondary endpoint of cardiac events, the rate was 5.1% with shorter treatment vs. 14.4% with longer treatment. Grade 2 cardiac events occurred in 11.2% vs. 3.5% of patients in the treatment arms, respectively, and the grade 3 cardiac vents occurred in 2.7% vs. 1.1%, respectively. The rate of grade 4 events was 0.5% in both groups.

The overall difference between the groups with respect to cardiac events was highly statistically significant in favor of shorter treatment (HR, 0.32), Dr. Conte said.

Multiple studies have demonstrated the superiority of combining trastuzumab and adjuvant chemotherapy for HER2+ early breast cancer, and, following the release of some of those findings at the ASCO annual meeting in 2005, the agent was granted accelerated approval for this indication, Dr. Conte said.

“It was, however, clear that there were a number of reasons to believe that further investigation was appropriate on the optimal duration of trastuzumab duration,” he said, explaining that the same magnitude of benefit was reported by the small FinHER study with 9 weeks of trastuzumab and that clinical data suggest synergism of trastuzumab with chemotherapy.

“Finally, in the real world, there are patients at lower risk of relapse (more node-negative, more small tumors) and at higher risk of cardiac toxicity because of age or comorbidities,” he said. “So, the hypotheses behind the Short-HER [study] was that a shorter duration of trastuzumab administered concomitantly with chemotherapy might produce comparable efficacy with significantly lower toxicities and, of course, costs.”

Short-HER study subjects, who had a mean age of 55 years, had either HER2-positive, node-positive, or high-risk node-negative disease and were randomized to receive either the shorter treatment, including three courses of docetaxel given three times weekly plus trastuzumab given weekly for 9 doses, followed by three courses of 5-fluorouracil/epirubicin/cyclophosphamide, or standard 12-month treatment with four courses of anthracycline-based chemotherapy followed by four courses of docetaxel in combination with trastuzumab given three times weekly, followed by 14 additional courses of trastuzumab given three times weekly (for a total of 18 3-times-weekly doses). Radiation therapy was administered when indicated after chemotherapy, and hormonal therapy was started after completion of chemotherapy in patients with hormone-receptor–positive tumors.

Based on the frequentist analysis, noninferiority of the shorter treatment approach cannot be claimed, but, according to the preplanned Bayesian analysis, noninferiority is likely, Dr. Conte said.

“One year of trastuzumab is still standard. The Short-Her trial, however, reinforces the hypothesis that treatment deescalation retains efficacy with less toxicity. A shorter treatment might be an option for patients at low risk of relapse and/or higher risk of cardiac toxicity,” he said. “Moreover, these results might facilitate trastuzumab to patients in low/middle income countries.”

Individual patient meta-analysis with other trials testing different durations of trastuzumab administration is ongoing, he noted.

The Short-HER study was funded by the Italian Drug Agency, and drugs and insurance coverage were supplied by the National Health System. The study was sponsored by the University of Modena & Regio Emilia and the University of Padova. Dr. Conte has served on the speakers’ bureau for AstraZeneca, Lilly, Novartis, and Roche/Genentech and has received research funding and/or travel or other expenses from AstraZeneca, Celgene, and Novartis.

sworcester@frontlinemedcom.com

CHICAGO – After Shirley A. Mertz, JD, was diagnosed with metastatic breast cancer, she was surprised to learn the government wasn’t counting people like her in data gathered on the disease. Only a minority of women with the disease – those diagnosed de novo – are included in Surveillance, Epidemiology and End Results (SEER) data, she said in a video interview at the annual meeting of the American Society of Clinical Oncology.

A recently published report by a National Cancer Institute mathematician and her associates estimates that about 155,000 women are living with metastatic breast cancer and that three-quarters of those women were initially diagnosed with lower-stage disease that progressed to stage IV. Ms. Mertz, president of the Metastatic Breast Cancer Network, says the estimate is a good start, but it’s important to go further and include those diagnosed with a metastatic recurrence in SEER data to get an accurate view.

“If we are not counted, then it appears we don’t matter, and how can we know if we are doing better if we don’t know how many of us are out there,” she said.

lnikolaides@frontlinemedcom.com

On Twitter @NikolaidesLaura

CHICAGO – After Shirley A. Mertz, JD, was diagnosed with metastatic breast cancer, she was surprised to learn the government wasn’t counting people like her in data gathered on the disease. Only a minority of women with the disease – those diagnosed de novo – are included in Surveillance, Epidemiology and End Results (SEER) data, she said in a video interview at the annual meeting of the American Society of Clinical Oncology.

A recently published report by a National Cancer Institute mathematician and her associates estimates that about 155,000 women are living with metastatic breast cancer and that three-quarters of those women were initially diagnosed with lower-stage disease that progressed to stage IV. Ms. Mertz, president of the Metastatic Breast Cancer Network, says the estimate is a good start, but it’s important to go further and include those diagnosed with a metastatic recurrence in SEER data to get an accurate view.

“If we are not counted, then it appears we don’t matter, and how can we know if we are doing better if we don’t know how many of us are out there,” she said.

lnikolaides@frontlinemedcom.com

On Twitter @NikolaidesLaura

CHICAGO – After Shirley A. Mertz, JD, was diagnosed with metastatic breast cancer, she was surprised to learn the government wasn’t counting people like her in data gathered on the disease. Only a minority of women with the disease – those diagnosed de novo – are included in Surveillance, Epidemiology and End Results (SEER) data, she said in a video interview at the annual meeting of the American Society of Clinical Oncology.

A recently published report by a National Cancer Institute mathematician and her associates estimates that about 155,000 women are living with metastatic breast cancer and that three-quarters of those women were initially diagnosed with lower-stage disease that progressed to stage IV. Ms. Mertz, president of the Metastatic Breast Cancer Network, says the estimate is a good start, but it’s important to go further and include those diagnosed with a metastatic recurrence in SEER data to get an accurate view.

“If we are not counted, then it appears we don’t matter, and how can we know if we are doing better if we don’t know how many of us are out there,” she said.

lnikolaides@frontlinemedcom.com

On Twitter @NikolaidesLaura

Photo © ASCO/Danny Morton 2017

CHICAGO—The experimental mutant IDH2 (mIDH2) inhibitor enasidenib has produced “admirable” overall survival in patients with mIDH2 relapsed or refractory acute myeloid leukemia (AML), according to Eytan M. Stein, MD, an investigator on the phase 1 dose escalation and expansion study.

Patients who achieved a complete remission (CR) had a median overall survival (OS) of 19.7 months and non-CR responders, 13.8 months.

“I really want to make the point,” Dr Stein said, “this is a group of patients that are highly refractory, either refractory to induction chemotherapy, refractory to standard of care approaches for patients who are unable to get induction chemotherapy, so refractory to hypomethylating agents or low-dose cytarabine.”

Mutations in IDH2 occur in approximately 12% of AML patients.

Dr Stein explained that the mutant protein converts alpha ketoglutarate to beta hydroxyglutarate (2-HG). And increased levels of intracellular 2-HG lead to methylation changes in the cell that cause a block in myeloid differentiation.

Enasidenib, also known as AG-221, is a selective, oral, potent inhibitor of the mIDH2 enzyyme.

Dr Stein, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the results during the ASCO 2017 Annual Meeting (abstract 7004).

The clinical and translational papers were published simultaneously in Blood.

Study design

The phase 1/2 study had a large dose-escalation component, with 113 patients enrolled. Patients had to have an advanced hematologic malignancy with an IDH2 mutation.

Patients received cumulative daily doses of 50 mg – 650 mg of enasidenib in continuous 28-day cycles.

Four expansion arms were added, with 126 patients.

Two expansion arms were in relapsed/refractory AML patients: one in patients 60 years or older or any age if they had relapsed after bone marrow transplant (BMT), and the other in patients younger than 60 excluding those relapsed after BMT.

The other 2 expansion arms were in untreated AML patients and in patients with any hematologic malignancy ineligible for the other arms.

Dr Stein presented results for the relapsed/refractory AML patients in the dose escalation and expansion phases of the study.

The key endpoints were safety, tolerability, maximum tolerated dose (MTD), and dose-limiting toxicities; response rates as assessed by the local investigator according to IWG criteria; and assessment of clinical activity.

Dr Stein noted the phase 2 study is now completely accrued (n=91) and the recommended enasidenib dose is 100 mg/day in relapsed/refractory AML.

The MTD was not reached at doses up to 650 mg/day.

Baseline characteristics

Median age of all 239 phase 1 patients was 70 years (range, 19-100), 57% were male, and almost all patients had intermediate- or poor-risk disease.

The investigators were also interested in the co-occurring mutations in patients on screening and whether there were differences between patients with mIDH2 at R172 and R140.

Seventy-five percent of the patients (n=179) had R140 and 24% had R172 (n=57).

There was a statistically significant difference in the number of co-occurring mutations in the R140 and R172 patients, with the R140 patients having a higher co-mutation burden compared with the R172 patients, (P=0.020).

The most frequent mutations co-occurring in R140 patients were SRSF2, followed by, in descending order of frequency, DNMT3A, RUNX1, ASXL1, and 24 others.

SFSR2 does not occur in R172 patients. DNMT3A was the most frequently co-occurring mutation in R172, followed by ASXL1, BCOR, NRAS, RUNX1, KMT2A, KRAS, and STAG2.

Safety

The most common treatment-emergent adverse events (TEAE) that occurred in 20% or more of all patients of any grade included nausea (46%), hyperbilirubinemia (45%), diarrhea and fatigue (40% each), decreased appetite (38%), vomiting (32%), dyspnea (31%), cough (29%), pyrexia and febrile neutropenia (28% each), thrombocytopenia, anemia, constipation, hypokalemia, and peripheral edema (27% each), pneumonia (21%), and hyperuricemia (20%).

The only 2 grade 3/4 TEAEs that rose above the level of 5% were hyperbilirubinemia (12%) and thrombocytopenia (6%).

“The hyperbilirubinemia, as I’ve mentioned in a number of meetings before this,” Dr Stein clarified, “is one that occurs because the enzyme is an off-target effect of inhibiting the UGT1A1 enzyme, which conjugates bilirubin.”

“So a patient who goes on this study who has a defect in bilirubin conjugation because they have Gilbert’s disease, they will have a higher level of bilirubin compared to a patient who doesn’t have Gilbert’s disease. This does not appear to have any clinical sequelae. You’ll also notice AST, ALT, alkaline phosphatase or any liver failure is not on this [TEAE] list.”

Response

The overall response rate for the patients who received enasidenib 100 mg/day was 38.5% (42/109) and for all doses 40.3% (71/176).

The true CR rate was 20.2% (100 mg/day) and 19.3% for all doses.

An additional 20% achieved a CR with incomplete hematologic recovery, CR with incomplete platelet recovery, partial response (PR), and morphologic leukemia-free state  with either 100 mg enasidenib daily or all doses.

“Time to first response is not immediate,” Dr Stein pointed out. “It takes a median of 1.9 months to get there, and the time to complete remission takes even longer, a median of 3.7 months in the 100-mg experience, 3.8 months in all doses, to get to that best response.”

“I think the clinical importance of this is,” he added, “for a patient that one might have who is on this drug, it is important to keep them on the drug for a prolonged period of time so that they have the opportunity to have that response.”

Hematologic parameters also improved gradually.

Increases in platelet count, absolute neutrophil count, and hemoglobin level did not rise exponentially upon administration of study drug, but rather they slowly rose, “again getting to this point, that the drug takes time to work,” Dr Stein emphasized.

Patients in CR had very high transfusion independence rates, “which is what I would expect,” Dr Stein said. “If you are in complete remission, you should be transfusion independent.”

“What’s a little bit more interesting, though,” Dr Stein added, “is those patients who are non-CR responders. [I]n those patients who have responded but have less than a complete remission, 50% of them are independent of red cell transfusions and 50% of them are independent of platelet transfusions.”

Survival

The CR data and transfusion independence data translated into a median OS in these relapsed and refractory AML patients of 9.3 months.

And about 10% - 15% of the patients had prolonged survival up to 2 years and longer on the single agent.

Analysis of OS by best response revealed that for patients with a CR, “they really have an admirable overall survival of 19.7 months, almost 20 months,” Dr Stein said.

Patients who had a non-CR response had a median OS of 13.8 months, and non-responders had a median OS of 7.0 months.

And there was a qualitative improvement in response over time: the number of patients with CRs and PRs increased, while the number with stable disease decreased.

“Again, I think getting at the point it takes time for these responses to occur,” Dr Stein iterated.

Over the course of therapy, some responders had a differentiation of myeloblasts, so that by cycle 3, the marrow looked largely normal.

The investigators did not observe any morphological evidence of cytotoxicity or cellular aplasia.

But they did observe myeloid differentiation using FISH.

Trisomy 8 that was evident at the time of screening in responders’ myeloblasts, persisted in the promyelocytes and mature granulocyte population, and was no longer evident in the lymphoid compartment.

Baseline 2-HG levels and mIDH2 variant allele frequency were similar for responding and non-responding patients.

The investigators believe that differentiation of myeloblsts, not cytotoxicity, may drive the clinical efficacy of enasidenib.

A phase 3 trial of enasidenib monotherapy versus conventional care regimens is underway in older patients with late-stage AML, and phase 1/2 studies of enasidenib combinations are ongoing in newly diagnosed AML patients.

Enasidenib, which also has efficacy in myelodysplastic syndromes, has been granted priority review for relapsed/refractory AML by the US Food and Drug Administration. 

Photo © ASCO/Danny Morton 2017

CHICAGO—The experimental mutant IDH2 (mIDH2) inhibitor enasidenib has produced “admirable” overall survival in patients with mIDH2 relapsed or refractory acute myeloid leukemia (AML), according to Eytan M. Stein, MD, an investigator on the phase 1 dose escalation and expansion study.

Patients who achieved a complete remission (CR) had a median overall survival (OS) of 19.7 months and non-CR responders, 13.8 months.

“I really want to make the point,” Dr Stein said, “this is a group of patients that are highly refractory, either refractory to induction chemotherapy, refractory to standard of care approaches for patients who are unable to get induction chemotherapy, so refractory to hypomethylating agents or low-dose cytarabine.”

Mutations in IDH2 occur in approximately 12% of AML patients.

Dr Stein explained that the mutant protein converts alpha ketoglutarate to beta hydroxyglutarate (2-HG). And increased levels of intracellular 2-HG lead to methylation changes in the cell that cause a block in myeloid differentiation.

Enasidenib, also known as AG-221, is a selective, oral, potent inhibitor of the mIDH2 enzyyme.

Dr Stein, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the results during the ASCO 2017 Annual Meeting (abstract 7004).

The clinical and translational papers were published simultaneously in Blood.

Study design

The phase 1/2 study had a large dose-escalation component, with 113 patients enrolled. Patients had to have an advanced hematologic malignancy with an IDH2 mutation.

Patients received cumulative daily doses of 50 mg – 650 mg of enasidenib in continuous 28-day cycles.

Four expansion arms were added, with 126 patients.

Two expansion arms were in relapsed/refractory AML patients: one in patients 60 years or older or any age if they had relapsed after bone marrow transplant (BMT), and the other in patients younger than 60 excluding those relapsed after BMT.

The other 2 expansion arms were in untreated AML patients and in patients with any hematologic malignancy ineligible for the other arms.

Dr Stein presented results for the relapsed/refractory AML patients in the dose escalation and expansion phases of the study.

The key endpoints were safety, tolerability, maximum tolerated dose (MTD), and dose-limiting toxicities; response rates as assessed by the local investigator according to IWG criteria; and assessment of clinical activity.

Dr Stein noted the phase 2 study is now completely accrued (n=91) and the recommended enasidenib dose is 100 mg/day in relapsed/refractory AML.

The MTD was not reached at doses up to 650 mg/day.

Baseline characteristics

Median age of all 239 phase 1 patients was 70 years (range, 19-100), 57% were male, and almost all patients had intermediate- or poor-risk disease.

The investigators were also interested in the co-occurring mutations in patients on screening and whether there were differences between patients with mIDH2 at R172 and R140.

Seventy-five percent of the patients (n=179) had R140 and 24% had R172 (n=57).

There was a statistically significant difference in the number of co-occurring mutations in the R140 and R172 patients, with the R140 patients having a higher co-mutation burden compared with the R172 patients, (P=0.020).

The most frequent mutations co-occurring in R140 patients were SRSF2, followed by, in descending order of frequency, DNMT3A, RUNX1, ASXL1, and 24 others.

SFSR2 does not occur in R172 patients. DNMT3A was the most frequently co-occurring mutation in R172, followed by ASXL1, BCOR, NRAS, RUNX1, KMT2A, KRAS, and STAG2.

Safety

The most common treatment-emergent adverse events (TEAE) that occurred in 20% or more of all patients of any grade included nausea (46%), hyperbilirubinemia (45%), diarrhea and fatigue (40% each), decreased appetite (38%), vomiting (32%), dyspnea (31%), cough (29%), pyrexia and febrile neutropenia (28% each), thrombocytopenia, anemia, constipation, hypokalemia, and peripheral edema (27% each), pneumonia (21%), and hyperuricemia (20%).

The only 2 grade 3/4 TEAEs that rose above the level of 5% were hyperbilirubinemia (12%) and thrombocytopenia (6%).

“The hyperbilirubinemia, as I’ve mentioned in a number of meetings before this,” Dr Stein clarified, “is one that occurs because the enzyme is an off-target effect of inhibiting the UGT1A1 enzyme, which conjugates bilirubin.”

“So a patient who goes on this study who has a defect in bilirubin conjugation because they have Gilbert’s disease, they will have a higher level of bilirubin compared to a patient who doesn’t have Gilbert’s disease. This does not appear to have any clinical sequelae. You’ll also notice AST, ALT, alkaline phosphatase or any liver failure is not on this [TEAE] list.”

Response

The overall response rate for the patients who received enasidenib 100 mg/day was 38.5% (42/109) and for all doses 40.3% (71/176).

The true CR rate was 20.2% (100 mg/day) and 19.3% for all doses.

An additional 20% achieved a CR with incomplete hematologic recovery, CR with incomplete platelet recovery, partial response (PR), and morphologic leukemia-free state  with either 100 mg enasidenib daily or all doses.

“Time to first response is not immediate,” Dr Stein pointed out. “It takes a median of 1.9 months to get there, and the time to complete remission takes even longer, a median of 3.7 months in the 100-mg experience, 3.8 months in all doses, to get to that best response.”

“I think the clinical importance of this is,” he added, “for a patient that one might have who is on this drug, it is important to keep them on the drug for a prolonged period of time so that they have the opportunity to have that response.”

Hematologic parameters also improved gradually.

Increases in platelet count, absolute neutrophil count, and hemoglobin level did not rise exponentially upon administration of study drug, but rather they slowly rose, “again getting to this point, that the drug takes time to work,” Dr Stein emphasized.

Patients in CR had very high transfusion independence rates, “which is what I would expect,” Dr Stein said. “If you are in complete remission, you should be transfusion independent.”

“What’s a little bit more interesting, though,” Dr Stein added, “is those patients who are non-CR responders. [I]n those patients who have responded but have less than a complete remission, 50% of them are independent of red cell transfusions and 50% of them are independent of platelet transfusions.”

Survival

The CR data and transfusion independence data translated into a median OS in these relapsed and refractory AML patients of 9.3 months.

And about 10% - 15% of the patients had prolonged survival up to 2 years and longer on the single agent.

Analysis of OS by best response revealed that for patients with a CR, “they really have an admirable overall survival of 19.7 months, almost 20 months,” Dr Stein said.

Patients who had a non-CR response had a median OS of 13.8 months, and non-responders had a median OS of 7.0 months.

And there was a qualitative improvement in response over time: the number of patients with CRs and PRs increased, while the number with stable disease decreased.

“Again, I think getting at the point it takes time for these responses to occur,” Dr Stein iterated.

Over the course of therapy, some responders had a differentiation of myeloblasts, so that by cycle 3, the marrow looked largely normal.

The investigators did not observe any morphological evidence of cytotoxicity or cellular aplasia.

But they did observe myeloid differentiation using FISH.

Trisomy 8 that was evident at the time of screening in responders’ myeloblasts, persisted in the promyelocytes and mature granulocyte population, and was no longer evident in the lymphoid compartment.

Baseline 2-HG levels and mIDH2 variant allele frequency were similar for responding and non-responding patients.

The investigators believe that differentiation of myeloblsts, not cytotoxicity, may drive the clinical efficacy of enasidenib.

A phase 3 trial of enasidenib monotherapy versus conventional care regimens is underway in older patients with late-stage AML, and phase 1/2 studies of enasidenib combinations are ongoing in newly diagnosed AML patients.

Enasidenib, which also has efficacy in myelodysplastic syndromes, has been granted priority review for relapsed/refractory AML by the US Food and Drug Administration. 

Photo © ASCO/Danny Morton 2017

CHICAGO—The experimental mutant IDH2 (mIDH2) inhibitor enasidenib has produced “admirable” overall survival in patients with mIDH2 relapsed or refractory acute myeloid leukemia (AML), according to Eytan M. Stein, MD, an investigator on the phase 1 dose escalation and expansion study.

Patients who achieved a complete remission (CR) had a median overall survival (OS) of 19.7 months and non-CR responders, 13.8 months.

“I really want to make the point,” Dr Stein said, “this is a group of patients that are highly refractory, either refractory to induction chemotherapy, refractory to standard of care approaches for patients who are unable to get induction chemotherapy, so refractory to hypomethylating agents or low-dose cytarabine.”

Mutations in IDH2 occur in approximately 12% of AML patients.

Dr Stein explained that the mutant protein converts alpha ketoglutarate to beta hydroxyglutarate (2-HG). And increased levels of intracellular 2-HG lead to methylation changes in the cell that cause a block in myeloid differentiation.

Enasidenib, also known as AG-221, is a selective, oral, potent inhibitor of the mIDH2 enzyyme.

Dr Stein, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the results during the ASCO 2017 Annual Meeting (abstract 7004).

The clinical and translational papers were published simultaneously in Blood.

Study design

The phase 1/2 study had a large dose-escalation component, with 113 patients enrolled. Patients had to have an advanced hematologic malignancy with an IDH2 mutation.

Patients received cumulative daily doses of 50 mg – 650 mg of enasidenib in continuous 28-day cycles.

Four expansion arms were added, with 126 patients.

Two expansion arms were in relapsed/refractory AML patients: one in patients 60 years or older or any age if they had relapsed after bone marrow transplant (BMT), and the other in patients younger than 60 excluding those relapsed after BMT.

The other 2 expansion arms were in untreated AML patients and in patients with any hematologic malignancy ineligible for the other arms.

Dr Stein presented results for the relapsed/refractory AML patients in the dose escalation and expansion phases of the study.

The key endpoints were safety, tolerability, maximum tolerated dose (MTD), and dose-limiting toxicities; response rates as assessed by the local investigator according to IWG criteria; and assessment of clinical activity.

Dr Stein noted the phase 2 study is now completely accrued (n=91) and the recommended enasidenib dose is 100 mg/day in relapsed/refractory AML.

The MTD was not reached at doses up to 650 mg/day.

Baseline characteristics

Median age of all 239 phase 1 patients was 70 years (range, 19-100), 57% were male, and almost all patients had intermediate- or poor-risk disease.

The investigators were also interested in the co-occurring mutations in patients on screening and whether there were differences between patients with mIDH2 at R172 and R140.

Seventy-five percent of the patients (n=179) had R140 and 24% had R172 (n=57).

There was a statistically significant difference in the number of co-occurring mutations in the R140 and R172 patients, with the R140 patients having a higher co-mutation burden compared with the R172 patients, (P=0.020).

The most frequent mutations co-occurring in R140 patients were SRSF2, followed by, in descending order of frequency, DNMT3A, RUNX1, ASXL1, and 24 others.

SFSR2 does not occur in R172 patients. DNMT3A was the most frequently co-occurring mutation in R172, followed by ASXL1, BCOR, NRAS, RUNX1, KMT2A, KRAS, and STAG2.

Safety

The most common treatment-emergent adverse events (TEAE) that occurred in 20% or more of all patients of any grade included nausea (46%), hyperbilirubinemia (45%), diarrhea and fatigue (40% each), decreased appetite (38%), vomiting (32%), dyspnea (31%), cough (29%), pyrexia and febrile neutropenia (28% each), thrombocytopenia, anemia, constipation, hypokalemia, and peripheral edema (27% each), pneumonia (21%), and hyperuricemia (20%).

The only 2 grade 3/4 TEAEs that rose above the level of 5% were hyperbilirubinemia (12%) and thrombocytopenia (6%).

“The hyperbilirubinemia, as I’ve mentioned in a number of meetings before this,” Dr Stein clarified, “is one that occurs because the enzyme is an off-target effect of inhibiting the UGT1A1 enzyme, which conjugates bilirubin.”

“So a patient who goes on this study who has a defect in bilirubin conjugation because they have Gilbert’s disease, they will have a higher level of bilirubin compared to a patient who doesn’t have Gilbert’s disease. This does not appear to have any clinical sequelae. You’ll also notice AST, ALT, alkaline phosphatase or any liver failure is not on this [TEAE] list.”

Response

The overall response rate for the patients who received enasidenib 100 mg/day was 38.5% (42/109) and for all doses 40.3% (71/176).

The true CR rate was 20.2% (100 mg/day) and 19.3% for all doses.

An additional 20% achieved a CR with incomplete hematologic recovery, CR with incomplete platelet recovery, partial response (PR), and morphologic leukemia-free state  with either 100 mg enasidenib daily or all doses.

“Time to first response is not immediate,” Dr Stein pointed out. “It takes a median of 1.9 months to get there, and the time to complete remission takes even longer, a median of 3.7 months in the 100-mg experience, 3.8 months in all doses, to get to that best response.”

“I think the clinical importance of this is,” he added, “for a patient that one might have who is on this drug, it is important to keep them on the drug for a prolonged period of time so that they have the opportunity to have that response.”

Hematologic parameters also improved gradually.

Increases in platelet count, absolute neutrophil count, and hemoglobin level did not rise exponentially upon administration of study drug, but rather they slowly rose, “again getting to this point, that the drug takes time to work,” Dr Stein emphasized.

Patients in CR had very high transfusion independence rates, “which is what I would expect,” Dr Stein said. “If you are in complete remission, you should be transfusion independent.”

“What’s a little bit more interesting, though,” Dr Stein added, “is those patients who are non-CR responders. [I]n those patients who have responded but have less than a complete remission, 50% of them are independent of red cell transfusions and 50% of them are independent of platelet transfusions.”

Survival

The CR data and transfusion independence data translated into a median OS in these relapsed and refractory AML patients of 9.3 months.

And about 10% - 15% of the patients had prolonged survival up to 2 years and longer on the single agent.

Analysis of OS by best response revealed that for patients with a CR, “they really have an admirable overall survival of 19.7 months, almost 20 months,” Dr Stein said.

Patients who had a non-CR response had a median OS of 13.8 months, and non-responders had a median OS of 7.0 months.

And there was a qualitative improvement in response over time: the number of patients with CRs and PRs increased, while the number with stable disease decreased.

“Again, I think getting at the point it takes time for these responses to occur,” Dr Stein iterated.

Over the course of therapy, some responders had a differentiation of myeloblasts, so that by cycle 3, the marrow looked largely normal.

The investigators did not observe any morphological evidence of cytotoxicity or cellular aplasia.

But they did observe myeloid differentiation using FISH.

Trisomy 8 that was evident at the time of screening in responders’ myeloblasts, persisted in the promyelocytes and mature granulocyte population, and was no longer evident in the lymphoid compartment.

Baseline 2-HG levels and mIDH2 variant allele frequency were similar for responding and non-responding patients.

The investigators believe that differentiation of myeloblsts, not cytotoxicity, may drive the clinical efficacy of enasidenib.

A phase 3 trial of enasidenib monotherapy versus conventional care regimens is underway in older patients with late-stage AML, and phase 1/2 studies of enasidenib combinations are ongoing in newly diagnosed AML patients.

Enasidenib, which also has efficacy in myelodysplastic syndromes, has been granted priority review for relapsed/refractory AML by the US Food and Drug Administration. 

CHICAGO – Adjuvant chemotherapy given during and after pelvic radiotherapy in women with high-risk endometrial cancer provided no significant 5-year failure-free or overall survival benefit, compared with pelvic radiotherapy alone, in the randomized PORTEC-3 intergroup trial. It did, however, show a trend toward improved 5-year failure-free survival (FFS).

Further, study participants with stage III endometrial cancer experienced a statistically significant 11% improvement in FFS – defined as relapse or endometrial cancer-related death – at 5 years, Stephanie M. de Boer, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The 5-year FFS rate in 330 women who received both chemotherapy and radiotherapy was 76%, vs. 69% in 330 women who received only radiotherapy (hazard ratio, 0.77). The respective 5-year overall survival rates were 82%, vs. 77% (HR, 0.79), said Dr. de Boer of Leiden University Medical Center, the Netherlands.

The differences did not reach statistical significance, but there was a “trend for better failure-free survival” beginning after 1 year and “a small suggestion for an overall survival benefit” after 3 years in patients treated with chemotherapy and radiotherapy, she said.

Among the 45% of study participants with stage III endometrial cancer, 5-year FFS and overall survival were significantly lower than in those with stage I-II disease (64% vs. 79% and 74% vs. 83%, respectively), but those with stage III disease experienced the greatest benefit with adjuvant chemotherapy.

“Five-year failure-free survival was 69% for those [with stage III disease] treated with radiotherapy and chemotherapy, vs. 58% for those treated with radiotherapy alone,” she said, noting that the hazard ratio was 0.66.

Five-year overall survival in the stage III patients was 79%, vs. 70% (HR, 0.69). Only the difference in FFS reached statistical significance, Dr. de Boer noted.

Study subjects were women with either Federation Internationale de Gynecologie et d’Obstetrique stage I grade 3 endometrial cancer with deep myometrial invasion and/or lymphovascular space invasion or with stage II or III disease or with serous/clear cell histology. They had a mean age of 62 years, good performance status, and no residual macroscopic tumor after surgery. They were randomly assigned to receive two cycles of cisplatin at 50 mg/m² in week 1 and 4 of radiotherapy (48.6 Gy in 1.8 Gy fractions), followed by four cycles of carboplatin AUC5 and paclitaxel at 175 mg/m² in 3-week intervals, or to receive radiotherapy alone.

Median follow-up was 60.2 months.

“The rationale of the PORTEC-3 trial was that 15% of endometrial cancer patients have high-risk disease features, and these patients are at increased risk of distant metastases and endometrial cancer–related death,” Dr. de Boer said.

Several trials have looked at intensified treatment in these patients and include some that have compared chemotherapy and radiation and that found no difference in progression-free survival or overall survival. A Radiation Therapy Oncology Group (RTOG) phase II trial of concurrent chemotherapy and radiotherapy, however, showed promising results and a feasible toxicity profile, she said.

A phase III Nordic Society of Gynecologic Oncology (SGO)/European Organization for Research and Treatment of Cancer (EORTC) trial suggested that sequential chemotherapy and radiotherapy was associated with improved progression-free survival.

“But, various chemotherapy schedules and sequences have been used in these trials, and no extensive quality of life analysis was done,” she noted.

In PORTEC-3, radiotherapy and two cycles of concurrent cisplatin followed by four cycles of carboplatin and paclitaxel showed some promise, and quality of life analyses showed no difference between groups at 1 and 2 years after randomization.

In fact, although the adverse events findings as reported in 2016 in Lancet Oncology showed that, during therapy and for the first 6 months after therapy, “significantly more and more severe toxicity” occurred in the chemotherapy and radiotherapy group, vs. the radiotherapy group alone, this effect was transient and not associated with long-term effects on quality of life.

“There was significant recovery without significant differences at 1 and 2 years after randomization,” Dr. de Boer said, adding that the toxicity translated to worse physical functioning and quality of life during and for 6 months after therapy but that no differences in quality of life, and only small differences in physical functioning, were seen at 1 and 2 years.

The residual effect on physical functioning may have been related to the tingling and numbness, which was the most important long-term side effect reported in the trial, she said, noting that 25% of patients in the chemotherapy and radiotherapy group reported tingling and numbness at 2 years, compared with 6% in the radiotherapy group.

Based on these findings, combined chemotherapy and radiotherapy cannot be recommended as standard for patients with stage I and II high-risk endometrial cancer, she said.

However, based on the 11% FFS benefit for stage III patients, “the combined chemotherapy and radiotherapy schedule is recommended to maximize failure-free survival,” she concluded, noting that interpretation of overall survival results may need longer follow-up.

Ritu Salani, MD, who was invited to discuss Dr. de Boer’s abstract, said the PORTEC-3 findings raise a number of questions for studies going forward, such as the role of therapy sequence.

“Radiation has always preceded chemotherapy, and I wonder if distant recurrences could actually be impacted if we do chemotherapy first, whether it’s a complete course or in a sandwich-approach style. I think these are questions that we need to continue to address,” said Dr. Salani of Ohio State University, Columbus.

Other questions posed by Dr. Salani focused on whether high risk early stage and advanced disease should be studied separately, whether maintenance therapy should be evaluated in this population, whether there was under-staging in PORTEC-3 as 42% of patients did not undergo lymphadenectomy, whether there is a role for sentinel node assessment, and whether residual disease status should be a surgical metric and if chemotherapy should be reserved for those with residual disease.

“I think we continue to have many treatment options, and I think our tumor board debates will continue. And I think PORTEC-3 will add to this discussion. But, at this point I think we’re left to individualize treatment and to continue to provide the best outcome for our patients while minimizing toxicity,” she concluded.

Dr. de Boer reported having no disclosures. Dr. Salani has received honoraria from Clovis Oncology and Lynparza and has served as a consultant or advisor for Genentech/Roche.

sworcester@frontlinemedcom.com

CHICAGO – Adjuvant chemotherapy given during and after pelvic radiotherapy in women with high-risk endometrial cancer provided no significant 5-year failure-free or overall survival benefit, compared with pelvic radiotherapy alone, in the randomized PORTEC-3 intergroup trial. It did, however, show a trend toward improved 5-year failure-free survival (FFS).

Further, study participants with stage III endometrial cancer experienced a statistically significant 11% improvement in FFS – defined as relapse or endometrial cancer-related death – at 5 years, Stephanie M. de Boer, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The 5-year FFS rate in 330 women who received both chemotherapy and radiotherapy was 76%, vs. 69% in 330 women who received only radiotherapy (hazard ratio, 0.77). The respective 5-year overall survival rates were 82%, vs. 77% (HR, 0.79), said Dr. de Boer of Leiden University Medical Center, the Netherlands.

The differences did not reach statistical significance, but there was a “trend for better failure-free survival” beginning after 1 year and “a small suggestion for an overall survival benefit” after 3 years in patients treated with chemotherapy and radiotherapy, she said.

Among the 45% of study participants with stage III endometrial cancer, 5-year FFS and overall survival were significantly lower than in those with stage I-II disease (64% vs. 79% and 74% vs. 83%, respectively), but those with stage III disease experienced the greatest benefit with adjuvant chemotherapy.

“Five-year failure-free survival was 69% for those [with stage III disease] treated with radiotherapy and chemotherapy, vs. 58% for those treated with radiotherapy alone,” she said, noting that the hazard ratio was 0.66.

Five-year overall survival in the stage III patients was 79%, vs. 70% (HR, 0.69). Only the difference in FFS reached statistical significance, Dr. de Boer noted.

Study subjects were women with either Federation Internationale de Gynecologie et d’Obstetrique stage I grade 3 endometrial cancer with deep myometrial invasion and/or lymphovascular space invasion or with stage II or III disease or with serous/clear cell histology. They had a mean age of 62 years, good performance status, and no residual macroscopic tumor after surgery. They were randomly assigned to receive two cycles of cisplatin at 50 mg/m² in week 1 and 4 of radiotherapy (48.6 Gy in 1.8 Gy fractions), followed by four cycles of carboplatin AUC5 and paclitaxel at 175 mg/m² in 3-week intervals, or to receive radiotherapy alone.

Median follow-up was 60.2 months.

“The rationale of the PORTEC-3 trial was that 15% of endometrial cancer patients have high-risk disease features, and these patients are at increased risk of distant metastases and endometrial cancer–related death,” Dr. de Boer said.

Several trials have looked at intensified treatment in these patients and include some that have compared chemotherapy and radiation and that found no difference in progression-free survival or overall survival. A Radiation Therapy Oncology Group (RTOG) phase II trial of concurrent chemotherapy and radiotherapy, however, showed promising results and a feasible toxicity profile, she said.

A phase III Nordic Society of Gynecologic Oncology (SGO)/European Organization for Research and Treatment of Cancer (EORTC) trial suggested that sequential chemotherapy and radiotherapy was associated with improved progression-free survival.

“But, various chemotherapy schedules and sequences have been used in these trials, and no extensive quality of life analysis was done,” she noted.

In PORTEC-3, radiotherapy and two cycles of concurrent cisplatin followed by four cycles of carboplatin and paclitaxel showed some promise, and quality of life analyses showed no difference between groups at 1 and 2 years after randomization.

In fact, although the adverse events findings as reported in 2016 in Lancet Oncology showed that, during therapy and for the first 6 months after therapy, “significantly more and more severe toxicity” occurred in the chemotherapy and radiotherapy group, vs. the radiotherapy group alone, this effect was transient and not associated with long-term effects on quality of life.

“There was significant recovery without significant differences at 1 and 2 years after randomization,” Dr. de Boer said, adding that the toxicity translated to worse physical functioning and quality of life during and for 6 months after therapy but that no differences in quality of life, and only small differences in physical functioning, were seen at 1 and 2 years.

The residual effect on physical functioning may have been related to the tingling and numbness, which was the most important long-term side effect reported in the trial, she said, noting that 25% of patients in the chemotherapy and radiotherapy group reported tingling and numbness at 2 years, compared with 6% in the radiotherapy group.

Based on these findings, combined chemotherapy and radiotherapy cannot be recommended as standard for patients with stage I and II high-risk endometrial cancer, she said.

However, based on the 11% FFS benefit for stage III patients, “the combined chemotherapy and radiotherapy schedule is recommended to maximize failure-free survival,” she concluded, noting that interpretation of overall survival results may need longer follow-up.

Ritu Salani, MD, who was invited to discuss Dr. de Boer’s abstract, said the PORTEC-3 findings raise a number of questions for studies going forward, such as the role of therapy sequence.

“Radiation has always preceded chemotherapy, and I wonder if distant recurrences could actually be impacted if we do chemotherapy first, whether it’s a complete course or in a sandwich-approach style. I think these are questions that we need to continue to address,” said Dr. Salani of Ohio State University, Columbus.

Other questions posed by Dr. Salani focused on whether high risk early stage and advanced disease should be studied separately, whether maintenance therapy should be evaluated in this population, whether there was under-staging in PORTEC-3 as 42% of patients did not undergo lymphadenectomy, whether there is a role for sentinel node assessment, and whether residual disease status should be a surgical metric and if chemotherapy should be reserved for those with residual disease.

“I think we continue to have many treatment options, and I think our tumor board debates will continue. And I think PORTEC-3 will add to this discussion. But, at this point I think we’re left to individualize treatment and to continue to provide the best outcome for our patients while minimizing toxicity,” she concluded.

Dr. de Boer reported having no disclosures. Dr. Salani has received honoraria from Clovis Oncology and Lynparza and has served as a consultant or advisor for Genentech/Roche.

sworcester@frontlinemedcom.com

CHICAGO – Adjuvant chemotherapy given during and after pelvic radiotherapy in women with high-risk endometrial cancer provided no significant 5-year failure-free or overall survival benefit, compared with pelvic radiotherapy alone, in the randomized PORTEC-3 intergroup trial. It did, however, show a trend toward improved 5-year failure-free survival (FFS).

Further, study participants with stage III endometrial cancer experienced a statistically significant 11% improvement in FFS – defined as relapse or endometrial cancer-related death – at 5 years, Stephanie M. de Boer, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The 5-year FFS rate in 330 women who received both chemotherapy and radiotherapy was 76%, vs. 69% in 330 women who received only radiotherapy (hazard ratio, 0.77). The respective 5-year overall survival rates were 82%, vs. 77% (HR, 0.79), said Dr. de Boer of Leiden University Medical Center, the Netherlands.

The differences did not reach statistical significance, but there was a “trend for better failure-free survival” beginning after 1 year and “a small suggestion for an overall survival benefit” after 3 years in patients treated with chemotherapy and radiotherapy, she said.

Among the 45% of study participants with stage III endometrial cancer, 5-year FFS and overall survival were significantly lower than in those with stage I-II disease (64% vs. 79% and 74% vs. 83%, respectively), but those with stage III disease experienced the greatest benefit with adjuvant chemotherapy.

“Five-year failure-free survival was 69% for those [with stage III disease] treated with radiotherapy and chemotherapy, vs. 58% for those treated with radiotherapy alone,” she said, noting that the hazard ratio was 0.66.

Five-year overall survival in the stage III patients was 79%, vs. 70% (HR, 0.69). Only the difference in FFS reached statistical significance, Dr. de Boer noted.

Study subjects were women with either Federation Internationale de Gynecologie et d’Obstetrique stage I grade 3 endometrial cancer with deep myometrial invasion and/or lymphovascular space invasion or with stage II or III disease or with serous/clear cell histology. They had a mean age of 62 years, good performance status, and no residual macroscopic tumor after surgery. They were randomly assigned to receive two cycles of cisplatin at 50 mg/m² in week 1 and 4 of radiotherapy (48.6 Gy in 1.8 Gy fractions), followed by four cycles of carboplatin AUC5 and paclitaxel at 175 mg/m² in 3-week intervals, or to receive radiotherapy alone.

Median follow-up was 60.2 months.

“The rationale of the PORTEC-3 trial was that 15% of endometrial cancer patients have high-risk disease features, and these patients are at increased risk of distant metastases and endometrial cancer–related death,” Dr. de Boer said.

Several trials have looked at intensified treatment in these patients and include some that have compared chemotherapy and radiation and that found no difference in progression-free survival or overall survival. A Radiation Therapy Oncology Group (RTOG) phase II trial of concurrent chemotherapy and radiotherapy, however, showed promising results and a feasible toxicity profile, she said.

A phase III Nordic Society of Gynecologic Oncology (SGO)/European Organization for Research and Treatment of Cancer (EORTC) trial suggested that sequential chemotherapy and radiotherapy was associated with improved progression-free survival.

“But, various chemotherapy schedules and sequences have been used in these trials, and no extensive quality of life analysis was done,” she noted.

In PORTEC-3, radiotherapy and two cycles of concurrent cisplatin followed by four cycles of carboplatin and paclitaxel showed some promise, and quality of life analyses showed no difference between groups at 1 and 2 years after randomization.

In fact, although the adverse events findings as reported in 2016 in Lancet Oncology showed that, during therapy and for the first 6 months after therapy, “significantly more and more severe toxicity” occurred in the chemotherapy and radiotherapy group, vs. the radiotherapy group alone, this effect was transient and not associated with long-term effects on quality of life.

“There was significant recovery without significant differences at 1 and 2 years after randomization,” Dr. de Boer said, adding that the toxicity translated to worse physical functioning and quality of life during and for 6 months after therapy but that no differences in quality of life, and only small differences in physical functioning, were seen at 1 and 2 years.

The residual effect on physical functioning may have been related to the tingling and numbness, which was the most important long-term side effect reported in the trial, she said, noting that 25% of patients in the chemotherapy and radiotherapy group reported tingling and numbness at 2 years, compared with 6% in the radiotherapy group.

Based on these findings, combined chemotherapy and radiotherapy cannot be recommended as standard for patients with stage I and II high-risk endometrial cancer, she said.

However, based on the 11% FFS benefit for stage III patients, “the combined chemotherapy and radiotherapy schedule is recommended to maximize failure-free survival,” she concluded, noting that interpretation of overall survival results may need longer follow-up.

Ritu Salani, MD, who was invited to discuss Dr. de Boer’s abstract, said the PORTEC-3 findings raise a number of questions for studies going forward, such as the role of therapy sequence.

“Radiation has always preceded chemotherapy, and I wonder if distant recurrences could actually be impacted if we do chemotherapy first, whether it’s a complete course or in a sandwich-approach style. I think these are questions that we need to continue to address,” said Dr. Salani of Ohio State University, Columbus.

Other questions posed by Dr. Salani focused on whether high risk early stage and advanced disease should be studied separately, whether maintenance therapy should be evaluated in this population, whether there was under-staging in PORTEC-3 as 42% of patients did not undergo lymphadenectomy, whether there is a role for sentinel node assessment, and whether residual disease status should be a surgical metric and if chemotherapy should be reserved for those with residual disease.

“I think we continue to have many treatment options, and I think our tumor board debates will continue. And I think PORTEC-3 will add to this discussion. But, at this point I think we’re left to individualize treatment and to continue to provide the best outcome for our patients while minimizing toxicity,” she concluded.

Dr. de Boer reported having no disclosures. Dr. Salani has received honoraria from Clovis Oncology and Lynparza and has served as a consultant or advisor for Genentech/Roche.

sworcester@frontlinemedcom.com

CHICAGO – Secondary cytoreductive surgery resulted in a clinically meaningful increase in progression-free survival and time to first subsequent therapy in a phase III study of carefully selected women with ovarian cancer who experienced their first relapse after a platin-free interval of 6 months.

These interim findings from the randomized international DESKTOP III trial suggest that until final overall survival data are available to more definitively define the role of secondary cytoreductive surgery in this setting, it should at least be considered as an option in patients who are good candidates based on a positive AGO Study Group score, defined as an ECOG performance status score of 0, ascites of 500 mL or less, and complete resection at initial surgery, Andreas du Bois, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The median progression-free survival (PFS) in 204 women who met this criteria and who were randomized to undergo surgery followed by chemotherapy was 19.6 months, compared with 14 months in 203 women who were randomized to receive only second-line chemotherapy (hazard ratio, 0.66), said Dr. du Bois of AGO and Kliniken Essen-Mitte, Essen, Germany.

“Even more important ... only complete resection makes a difference ... and that adds a median 7.2 months PFS with a hazard ratio of 0.56, which is highly significant. Fortunately that translates into time to first subsequent treatment, which is a more patient-oriented outcome,” he said.

The time to third-line therapy was prolonged by a highly statistically significant median of 7.1 month (hazard ratio, 0.6).

“What was the trade-off for these benefits? The patients did not pay for it with excessive mortality,” he said, explaining that no significant differences were seen between the groups in terms of mortality at 30, 60, 90, or 180 days, and that no excessive toxicity or treatment burden was seen in either group.

sworcester@frontlinemedcom.com

CHICAGO – Secondary cytoreductive surgery resulted in a clinically meaningful increase in progression-free survival and time to first subsequent therapy in a phase III study of carefully selected women with ovarian cancer who experienced their first relapse after a platin-free interval of 6 months.

These interim findings from the randomized international DESKTOP III trial suggest that until final overall survival data are available to more definitively define the role of secondary cytoreductive surgery in this setting, it should at least be considered as an option in patients who are good candidates based on a positive AGO Study Group score, defined as an ECOG performance status score of 0, ascites of 500 mL or less, and complete resection at initial surgery, Andreas du Bois, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The median progression-free survival (PFS) in 204 women who met this criteria and who were randomized to undergo surgery followed by chemotherapy was 19.6 months, compared with 14 months in 203 women who were randomized to receive only second-line chemotherapy (hazard ratio, 0.66), said Dr. du Bois of AGO and Kliniken Essen-Mitte, Essen, Germany.

“Even more important ... only complete resection makes a difference ... and that adds a median 7.2 months PFS with a hazard ratio of 0.56, which is highly significant. Fortunately that translates into time to first subsequent treatment, which is a more patient-oriented outcome,” he said.

The time to third-line therapy was prolonged by a highly statistically significant median of 7.1 month (hazard ratio, 0.6).

“What was the trade-off for these benefits? The patients did not pay for it with excessive mortality,” he said, explaining that no significant differences were seen between the groups in terms of mortality at 30, 60, 90, or 180 days, and that no excessive toxicity or treatment burden was seen in either group.

sworcester@frontlinemedcom.com

CHICAGO – Secondary cytoreductive surgery resulted in a clinically meaningful increase in progression-free survival and time to first subsequent therapy in a phase III study of carefully selected women with ovarian cancer who experienced their first relapse after a platin-free interval of 6 months.

These interim findings from the randomized international DESKTOP III trial suggest that until final overall survival data are available to more definitively define the role of secondary cytoreductive surgery in this setting, it should at least be considered as an option in patients who are good candidates based on a positive AGO Study Group score, defined as an ECOG performance status score of 0, ascites of 500 mL or less, and complete resection at initial surgery, Andreas du Bois, MD, reported at the annual meeting of the American Society of Clinical Oncology.

The median progression-free survival (PFS) in 204 women who met this criteria and who were randomized to undergo surgery followed by chemotherapy was 19.6 months, compared with 14 months in 203 women who were randomized to receive only second-line chemotherapy (hazard ratio, 0.66), said Dr. du Bois of AGO and Kliniken Essen-Mitte, Essen, Germany.

“Even more important ... only complete resection makes a difference ... and that adds a median 7.2 months PFS with a hazard ratio of 0.56, which is highly significant. Fortunately that translates into time to first subsequent treatment, which is a more patient-oriented outcome,” he said.

The time to third-line therapy was prolonged by a highly statistically significant median of 7.1 month (hazard ratio, 0.6).

“What was the trade-off for these benefits? The patients did not pay for it with excessive mortality,” he said, explaining that no significant differences were seen between the groups in terms of mortality at 30, 60, 90, or 180 days, and that no excessive toxicity or treatment burden was seen in either group.

sworcester@frontlinemedcom.com