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The overall response rate (ORR) in the 115 patients was 14.8%, according to Xiuning Le, MD, PhD, of MD Anderson Cancer Center in Houston, who reported these results at the AACR virtual meeting I.
The ORR fell short of the greater than 17% required to meet the primary endpoint, but 65% of patients experienced tumor shrinkage, Dr. Le noted.
Overall, 17 patients had a confirmed partial response, 5 had an unconfirmed partial response, and 62 had stable disease, for a disease control rate of 68.7%.
Responses occurred early and were durable, Dr. Le said. The median duration of response was 7.4 months.
Responses were also consistent across subgroups based on the number of prior lines of therapy and prior EGFR tyrosine kinase inhibitor (TKI) therapy.
The median progression-free survival was 4.2 months.
Patients, treatment, and safety
The patients, who were enrolled in the first cohort of the ZENITH20 study, had a median age of 61 years. They had received a median of two prior therapies, with most having received both chemotherapy and immunotherapy.
Poziotinib was given at a once-daily dose of 16 mg for 28-day cycles, with follow-up of 24 months. Dose reductions were allowed for adverse events (AEs).
AEs were on target and consistent with EGFR TKI class effects. The most common AEs were rash, diarrhea, stomatitis, and paronychia.
Grade 3 AEs included rash (28%) and diarrhea (25%). No grade 5 treatment-related AEs occurred.
Dose reductions were common, occurring in 68% of patients. The median relative poziotinib dose intensity was 72%, suggesting that response can be maintained at lower dose levels, Dr. Le said.
Drug interruptions were also common, occurring in 88% of patients. Ten percent of patients discontinued treatment permanently, Dr. Le said, noting that this is consistent with findings in prior large trials of second-generation TKIs.
Implications
The results of this study are of note because EGFR is a known driver of NSCLC, Dr. Le said. She explained that, while effective treatments exist for more common EGFR mutations, such as the classic sensitizing exon 21 mutation L858R and exon 19 deletion, no approved targeted therapies are available for the approximately 10% of lung cancer patients whose tumors harbor EGFR exon 20 insertions.
“Those EGFR exon 20 insertions are not sensitive to most of the approved EGFR inhibitors,” Dr. Le said. She noted that, in one study, the median progression-free survival following treatment with an approved agent was 14 months in patients with classical mutations, compared with 2 months in those with exon 20 insertions.
The difference is attributable to molecular structural differences. Exon 20 insertions create a smaller and more shallow EGFR protein interaction surface, Dr. Le explained. “So some of the approved inhibitors don’t fit well into the oncogenic molecule,” she said.
Poziotinib has a small size and shape that can fit into the binding pocket of exon 20, and that, along with its mechanism of action, made it a promising candidate for this population, Dr. Le said. She referenced a study of 44 patients at MD Anderson Cancer Center in which poziotinib produced an ORR of 43%.
In the current study, “[p]oziotinib has further demonstrated clinical activity in previously treated lung cancer patients with EGFR exon 20 insertions ... with a toxicity profile similar to that of other second-generation TKIs,” she said.
The findings underscore the promise of EGFR exon 20 insertions as targets for therapeutic intervention, said invited discussant Taofeek Owonikoko, MD, PhD, of Winship Cancer Institute of Emory University in Atlanta.
“Poziotinib showed modest but meaningful efficacy,” he said. “However, its safety remains a challenge. It is expected that ongoing modifications in the dosing schedule will make it a more tolerable agent.”
“Future studies to systematically explore differential sensitivity of various exon 20 insertion mutations by location will be informative, as will [elucidation of] mechanisms of resistance to prioritize combinatorial strategies to further enhance the efficacy of this drug,” Dr. Owonikoko added.
Next steps
Analyses of other cohorts in the ZENITH20 trial will be reported at upcoming conferences as the data mature, Dr. Le noted. Cohorts 2-4 include patients with previously treated HER2 exon 20 insertions and treatment-naive patients with EGFR and HER2 exon 20 insertions, respectively.
Additionally, three new cohorts are being added, including one with patients who have EGFR or HER2 exon 20 insertions, one with EGFR patients who failed prior osimertinib treatment, and one with patients who have atypical EGFR or HER2 mutations.
Rather than the once-daily dosing used in cohorts 1-4, twice-daily dosing will be evaluated in these cohorts, Dr. Le said, explaining that the half-life of poziotinib is about 8 hours.
“Recent pharmacological modeling showed that a [twice-daily] regimen would reduce the maximal serum concentration and increase trough, which could lead to optimized drug coverage,” she said. “This may potentially reduce toxicity and improve patient compliance and efficacy.”
ZENITH20 is sponsored by Spectrum Pharmaceuticals Inc. Dr. Le disclosed relationships with Spectrum as well as Eli Lilly, AstraZeneca, EMD Serono, and Boehringer Ingelheim. Dr. Owonikoko disclosed relationships with many companies, not including Spectrum.
SOURCE: Le X et al. AACR 2020, Abstract CT081.
The overall response rate (ORR) in the 115 patients was 14.8%, according to Xiuning Le, MD, PhD, of MD Anderson Cancer Center in Houston, who reported these results at the AACR virtual meeting I.
The ORR fell short of the greater than 17% required to meet the primary endpoint, but 65% of patients experienced tumor shrinkage, Dr. Le noted.
Overall, 17 patients had a confirmed partial response, 5 had an unconfirmed partial response, and 62 had stable disease, for a disease control rate of 68.7%.
Responses occurred early and were durable, Dr. Le said. The median duration of response was 7.4 months.
Responses were also consistent across subgroups based on the number of prior lines of therapy and prior EGFR tyrosine kinase inhibitor (TKI) therapy.
The median progression-free survival was 4.2 months.
Patients, treatment, and safety
The patients, who were enrolled in the first cohort of the ZENITH20 study, had a median age of 61 years. They had received a median of two prior therapies, with most having received both chemotherapy and immunotherapy.
Poziotinib was given at a once-daily dose of 16 mg for 28-day cycles, with follow-up of 24 months. Dose reductions were allowed for adverse events (AEs).
AEs were on target and consistent with EGFR TKI class effects. The most common AEs were rash, diarrhea, stomatitis, and paronychia.
Grade 3 AEs included rash (28%) and diarrhea (25%). No grade 5 treatment-related AEs occurred.
Dose reductions were common, occurring in 68% of patients. The median relative poziotinib dose intensity was 72%, suggesting that response can be maintained at lower dose levels, Dr. Le said.
Drug interruptions were also common, occurring in 88% of patients. Ten percent of patients discontinued treatment permanently, Dr. Le said, noting that this is consistent with findings in prior large trials of second-generation TKIs.
Implications
The results of this study are of note because EGFR is a known driver of NSCLC, Dr. Le said. She explained that, while effective treatments exist for more common EGFR mutations, such as the classic sensitizing exon 21 mutation L858R and exon 19 deletion, no approved targeted therapies are available for the approximately 10% of lung cancer patients whose tumors harbor EGFR exon 20 insertions.
“Those EGFR exon 20 insertions are not sensitive to most of the approved EGFR inhibitors,” Dr. Le said. She noted that, in one study, the median progression-free survival following treatment with an approved agent was 14 months in patients with classical mutations, compared with 2 months in those with exon 20 insertions.
The difference is attributable to molecular structural differences. Exon 20 insertions create a smaller and more shallow EGFR protein interaction surface, Dr. Le explained. “So some of the approved inhibitors don’t fit well into the oncogenic molecule,” she said.
Poziotinib has a small size and shape that can fit into the binding pocket of exon 20, and that, along with its mechanism of action, made it a promising candidate for this population, Dr. Le said. She referenced a study of 44 patients at MD Anderson Cancer Center in which poziotinib produced an ORR of 43%.
In the current study, “[p]oziotinib has further demonstrated clinical activity in previously treated lung cancer patients with EGFR exon 20 insertions ... with a toxicity profile similar to that of other second-generation TKIs,” she said.
The findings underscore the promise of EGFR exon 20 insertions as targets for therapeutic intervention, said invited discussant Taofeek Owonikoko, MD, PhD, of Winship Cancer Institute of Emory University in Atlanta.
“Poziotinib showed modest but meaningful efficacy,” he said. “However, its safety remains a challenge. It is expected that ongoing modifications in the dosing schedule will make it a more tolerable agent.”
“Future studies to systematically explore differential sensitivity of various exon 20 insertion mutations by location will be informative, as will [elucidation of] mechanisms of resistance to prioritize combinatorial strategies to further enhance the efficacy of this drug,” Dr. Owonikoko added.
Next steps
Analyses of other cohorts in the ZENITH20 trial will be reported at upcoming conferences as the data mature, Dr. Le noted. Cohorts 2-4 include patients with previously treated HER2 exon 20 insertions and treatment-naive patients with EGFR and HER2 exon 20 insertions, respectively.
Additionally, three new cohorts are being added, including one with patients who have EGFR or HER2 exon 20 insertions, one with EGFR patients who failed prior osimertinib treatment, and one with patients who have atypical EGFR or HER2 mutations.
Rather than the once-daily dosing used in cohorts 1-4, twice-daily dosing will be evaluated in these cohorts, Dr. Le said, explaining that the half-life of poziotinib is about 8 hours.
“Recent pharmacological modeling showed that a [twice-daily] regimen would reduce the maximal serum concentration and increase trough, which could lead to optimized drug coverage,” she said. “This may potentially reduce toxicity and improve patient compliance and efficacy.”
ZENITH20 is sponsored by Spectrum Pharmaceuticals Inc. Dr. Le disclosed relationships with Spectrum as well as Eli Lilly, AstraZeneca, EMD Serono, and Boehringer Ingelheim. Dr. Owonikoko disclosed relationships with many companies, not including Spectrum.
SOURCE: Le X et al. AACR 2020, Abstract CT081.
The overall response rate (ORR) in the 115 patients was 14.8%, according to Xiuning Le, MD, PhD, of MD Anderson Cancer Center in Houston, who reported these results at the AACR virtual meeting I.
The ORR fell short of the greater than 17% required to meet the primary endpoint, but 65% of patients experienced tumor shrinkage, Dr. Le noted.
Overall, 17 patients had a confirmed partial response, 5 had an unconfirmed partial response, and 62 had stable disease, for a disease control rate of 68.7%.
Responses occurred early and were durable, Dr. Le said. The median duration of response was 7.4 months.
Responses were also consistent across subgroups based on the number of prior lines of therapy and prior EGFR tyrosine kinase inhibitor (TKI) therapy.
The median progression-free survival was 4.2 months.
Patients, treatment, and safety
The patients, who were enrolled in the first cohort of the ZENITH20 study, had a median age of 61 years. They had received a median of two prior therapies, with most having received both chemotherapy and immunotherapy.
Poziotinib was given at a once-daily dose of 16 mg for 28-day cycles, with follow-up of 24 months. Dose reductions were allowed for adverse events (AEs).
AEs were on target and consistent with EGFR TKI class effects. The most common AEs were rash, diarrhea, stomatitis, and paronychia.
Grade 3 AEs included rash (28%) and diarrhea (25%). No grade 5 treatment-related AEs occurred.
Dose reductions were common, occurring in 68% of patients. The median relative poziotinib dose intensity was 72%, suggesting that response can be maintained at lower dose levels, Dr. Le said.
Drug interruptions were also common, occurring in 88% of patients. Ten percent of patients discontinued treatment permanently, Dr. Le said, noting that this is consistent with findings in prior large trials of second-generation TKIs.
Implications
The results of this study are of note because EGFR is a known driver of NSCLC, Dr. Le said. She explained that, while effective treatments exist for more common EGFR mutations, such as the classic sensitizing exon 21 mutation L858R and exon 19 deletion, no approved targeted therapies are available for the approximately 10% of lung cancer patients whose tumors harbor EGFR exon 20 insertions.
“Those EGFR exon 20 insertions are not sensitive to most of the approved EGFR inhibitors,” Dr. Le said. She noted that, in one study, the median progression-free survival following treatment with an approved agent was 14 months in patients with classical mutations, compared with 2 months in those with exon 20 insertions.
The difference is attributable to molecular structural differences. Exon 20 insertions create a smaller and more shallow EGFR protein interaction surface, Dr. Le explained. “So some of the approved inhibitors don’t fit well into the oncogenic molecule,” she said.
Poziotinib has a small size and shape that can fit into the binding pocket of exon 20, and that, along with its mechanism of action, made it a promising candidate for this population, Dr. Le said. She referenced a study of 44 patients at MD Anderson Cancer Center in which poziotinib produced an ORR of 43%.
In the current study, “[p]oziotinib has further demonstrated clinical activity in previously treated lung cancer patients with EGFR exon 20 insertions ... with a toxicity profile similar to that of other second-generation TKIs,” she said.
The findings underscore the promise of EGFR exon 20 insertions as targets for therapeutic intervention, said invited discussant Taofeek Owonikoko, MD, PhD, of Winship Cancer Institute of Emory University in Atlanta.
“Poziotinib showed modest but meaningful efficacy,” he said. “However, its safety remains a challenge. It is expected that ongoing modifications in the dosing schedule will make it a more tolerable agent.”
“Future studies to systematically explore differential sensitivity of various exon 20 insertion mutations by location will be informative, as will [elucidation of] mechanisms of resistance to prioritize combinatorial strategies to further enhance the efficacy of this drug,” Dr. Owonikoko added.
Next steps
Analyses of other cohorts in the ZENITH20 trial will be reported at upcoming conferences as the data mature, Dr. Le noted. Cohorts 2-4 include patients with previously treated HER2 exon 20 insertions and treatment-naive patients with EGFR and HER2 exon 20 insertions, respectively.
Additionally, three new cohorts are being added, including one with patients who have EGFR or HER2 exon 20 insertions, one with EGFR patients who failed prior osimertinib treatment, and one with patients who have atypical EGFR or HER2 mutations.
Rather than the once-daily dosing used in cohorts 1-4, twice-daily dosing will be evaluated in these cohorts, Dr. Le said, explaining that the half-life of poziotinib is about 8 hours.
“Recent pharmacological modeling showed that a [twice-daily] regimen would reduce the maximal serum concentration and increase trough, which could lead to optimized drug coverage,” she said. “This may potentially reduce toxicity and improve patient compliance and efficacy.”
ZENITH20 is sponsored by Spectrum Pharmaceuticals Inc. Dr. Le disclosed relationships with Spectrum as well as Eli Lilly, AstraZeneca, EMD Serono, and Boehringer Ingelheim. Dr. Owonikoko disclosed relationships with many companies, not including Spectrum.
SOURCE: Le X et al. AACR 2020, Abstract CT081.
FROM AACR 2020