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FDA Approval in Gastric/GEJ Cancer, Priority Reviews in NHL, AML, SCLC, and More

Gina Columbus
Published: Friday, Mar 01, 2019



Today-

An FDA approval in gastric and gastroesophageal junction adenocarcinoma, priority review designations in non-Hodgkin lymphoma, acute myeloid leukemia, and small cell lung cancer, an ODAC recommendation in multiple myeloma, an approval sought in prostate cancer, and disappointing findings in hepatocellular carcinoma.

Welcome to OncLive News Network! I'm Gina Columbus.

The FDA has approved TAS-102 for adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least 2 prior lines of chemotherapy that included a fluoropyrimidine, a platinum, and if appropriate, HER2/neu-targeted therapy.

The approval is based on findings from the international phase III TAGS trial, in which TAS-102 reduced the risk of death by approximately one-third versus placebo in patients with heavily pretreated gastric or GEJ cancer. The TAGS study also showed improvements in progression-free survival and disease control, and demonstrated a predictable and manageable safety profile.

Specifically, results showed that median overall survival was 5.7 months for patients who received TAS-102 versus 3.6 months for those randomized to placebo. The 12-month OS rate for the TAS-102 group was 21% versus 13% for the placebo group. The median PFS was 2.0 months versus 1.8 months with TAS-102 and placebo, respectively, and the PFS benefit was observed across subgroups.

***********************************

In non-Hodgkin lymphoma, the FDA granted a priority review designation to a supplemental new drug application for the R-squared regimen of lenalidomide plus rituximab for use in patients with previously treated follicular lymphoma and marginal zone lymphoma.

The application is based on results from the double-blind, phase III AUGMENT trial, in which R-squared reduced the risk of disease progression or death by 54% versus rituximab alone in patients with relapsed/refractory indolent non-Hodgkin lymphoma.

At a median follow-up of 28.3 months, the median progression-free survival per independent review was 39.4 months with R-squared versus 14.1 months with rituximab alone. By investigator assessment, the median PFS was 25.3 months compared with 14.3 months, respectively.

Additionally, overall response rate was also significantly improved with the combination, which was 78% versus 53% with rituximab alone. The ORR in the R-squared arm comprised a 44% complete response rate and a 34% partial response rate.

Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the sNDA by June 27, 2019.

*********************************

The FDA granted a priority review to a supplemental new drug application for ivosidenib for the frontline treatment of patients with IDH1-mutant acute myeloid leukemia who are ineligible for standard chemotherapy.

The sNDA is based on findings from a phase I trial, which demonstrated that ivosidenib induced a 57.6% overall response rate among newly diagnosed patients with IDH1-positive AML. This ORR included a 42.4% combined rate of complete remission plus CR with partial hematologic recovery.

Regarding safety findings, which included 34 patients with untreated AML, all-grade adverse events that occurred in more than 25% of patients were diarrhea, fatigue, nausea, decreased appetite, leukocytosis, anemia, and peripheral edema.

Under the expedited priority review, the FDA will review the sNDA within 6 months from the acceptance of the filing, compared with the standard 10 months. An approval decision is scheduled to be made on or before June 21, 2019. Ivosidenib was previously approved by the FDA in July 2018 for the treatment of adult patients with relapsed/refractory IDH1-mutant AML.

*********************************

In small cell lung cancer, the FDA granted a priority review designation to a supplemental biologics license application for pembrolizumab as a treatment for patients with advanced small cell lung cancer whose disease has progressed following at least 2 prior lines of therapy.

The application is based on data from cohorts of the phase II KEYNOTE-158 and phase Ib KEYNOTE-028 studies, in which pembrolizumab elicited 19% and 33% overall response rates in patients with advanced and extensive-stage SCLC, respectively.

In KEYNOTE-158, a basket study of patients with 10 tumor types, results also showed that the disease control rate with pembrolizumab in patients with SCLC was 30%, and the median duration of response was not reached. Moreover, the median PFS was 2.0 months and the median OS was 8.7 months.

In the KEYNOTE-028 basket trial, investigators evaluated pembrolizumab in patients with advanced solid tumors. Results showed that the median time to response was 2.0 months and the median duration of response was 19.4 months.

Moreover, the median PFS was 1.9 months, the estimated 6-month PFS rate was 28.6%, and the estimated 12-month PFS rate was 23.8%. The median OS was 9.7 months, and the estimated 6- and 12-month OS rates were 66.0% and 37.7%, respectively.

*************************************

The FDA's Oncologic Drugs Advisory Committee voted 8 to 5 against accelerated approval of a new drug application for selinexor for the treatment of patients with penta-refractory multiple myeloma, recommending delaying a decision on the drug until results are available from the pivotal phase III BOSTON trial.

Karyopharm Therapeutics, the manufacturer of selinexor, submitted the NDA for an accelerated approval of selinexor for patients with myeloma who have received 3 or more prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-targeted antibody, and to their most recent treatment.

The application is based on Part 2 of the phase IIb STORM study, which showed that the combination of selinexor and dexamethasone elicited a 26.2% overall response rate and an 8.6-month median overall survival.

However, several questions arose during the ODAC meeting. First, STORM was a single-arm combination trial and a prior phase I study had not demonstrated strong single-agent activity with selinexor. Therefore, isolating the specific impact of selinexor is difficult.

Additionally, there was significant toxicity with selinexor in the STORM trial, including treatment-emergent adverse events, serious adverse events, and treatment-emergent adverse events that resulted in patient deaths.

It is hoped that the phase III BOSTON trial will allow the FDA to make a more informed decision on the agent. BOSTON is evaluating the addition of selinexor to bortezomib and low-dose dexamethasone compared with bortezomib and low-dose dexamethasone alone in patients with relapsed/refractory multiple myeloma who have received 1 to 3 prior regimens.

The NDA for the accelerated approval of selinexor is being reviewed under the FDA’s priority review program. The FDA now has until April 6, 2019, to consider ODAC’s recommendation and make a final decision on whether or not to grant selinexor an accelerated approval.

*********************************

In prostate cancer, a new drug application has been filed with the FDA for darolutamide for the treatment of patients with nonmetastatic castration-resistant prostate cancer.

The application is based on data from the phase III ARAMIS trial, in which darolutamide plus androgen deprivation therapy significantly improved metastasis-free survival versus placebo plus ADT in patients with nonmetastatic CRPC.

At a median follow-up of 17.9 months, results showed that the median MFS was 40.4 months with darolutamide versus 18.4 months with placebo, corresponding to a 59% reduction in the risk of metastases or death in favor of darolutamide. The MFS benefit was reported across patient subgroups.

At an interim analysis for overall survival, the 3-year rates of OS were 83% in the darolutamide arm versus 73% in the placebo arm, corresponding to a 29% reduction in the risk of death. The median OS was not yet reached in either arm.

*********************************

The combination of pembrolizumab plus best supportive care for the treatment of patients with advanced hepatocellular carcinoma who were previously treated with systemic therapy did not improve progression-free or overall survival versus placebo plus best supportive care alone, missing the coprimary endpoints of the KEYNOTE-240 trial.

Results of the final analysis showed that the pembrolizumab regimen did improve OS versus placebo. However, the 22% reduction in the risk of death was not deemed statistically significant per the prespecified statistical plan.

Additionally, there was a progression-free survival improvement with pembrolizumab that also did not reach statistical significance. Since superiority was not reached in either primary endpoint, overall response rate, which was a key secondary endpoint, was not formally tested.

KEYNOTE-240 is the confirmatory trial for pembrolizumab, which was granted an accelerated approval in November 2018 for patients with HCC who were previously treated with sorafenib, which was based on data from the phase II KEYNOTE-224 trial.

The safety profile of pembrolizumab in KEYNOTE-240 was consistent with what has been observed in prior studies with the PD-1 inhibitor. Full findings will be presented at an upcoming medical meeting and have been shared with the FDA for discussions.

*********************************

This week, we sat down with Dr Kenneth Anderson, of Dana-Farber Cancer Institute and Harvard Medical School, to discuss current treatment for patients with transplant-eligible multiple myeloma.

That’s all for today.

Thank you for watching OncLive News Network! I’m Gina Columbus.
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Today-

An FDA approval in gastric and gastroesophageal junction adenocarcinoma, priority review designations in non-Hodgkin lymphoma, acute myeloid leukemia, and small cell lung cancer, an ODAC recommendation in multiple myeloma, an approval sought in prostate cancer, and disappointing findings in hepatocellular carcinoma.

Welcome to OncLive News Network! I'm Gina Columbus.

The FDA has approved TAS-102 for adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least 2 prior lines of chemotherapy that included a fluoropyrimidine, a platinum, and if appropriate, HER2/neu-targeted therapy.

The approval is based on findings from the international phase III TAGS trial, in which TAS-102 reduced the risk of death by approximately one-third versus placebo in patients with heavily pretreated gastric or GEJ cancer. The TAGS study also showed improvements in progression-free survival and disease control, and demonstrated a predictable and manageable safety profile.

Specifically, results showed that median overall survival was 5.7 months for patients who received TAS-102 versus 3.6 months for those randomized to placebo. The 12-month OS rate for the TAS-102 group was 21% versus 13% for the placebo group. The median PFS was 2.0 months versus 1.8 months with TAS-102 and placebo, respectively, and the PFS benefit was observed across subgroups.

***********************************

In non-Hodgkin lymphoma, the FDA granted a priority review designation to a supplemental new drug application for the R-squared regimen of lenalidomide plus rituximab for use in patients with previously treated follicular lymphoma and marginal zone lymphoma.

The application is based on results from the double-blind, phase III AUGMENT trial, in which R-squared reduced the risk of disease progression or death by 54% versus rituximab alone in patients with relapsed/refractory indolent non-Hodgkin lymphoma.

At a median follow-up of 28.3 months, the median progression-free survival per independent review was 39.4 months with R-squared versus 14.1 months with rituximab alone. By investigator assessment, the median PFS was 25.3 months compared with 14.3 months, respectively.

Additionally, overall response rate was also significantly improved with the combination, which was 78% versus 53% with rituximab alone. The ORR in the R-squared arm comprised a 44% complete response rate and a 34% partial response rate.

Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the sNDA by June 27, 2019.

*********************************

The FDA granted a priority review to a supplemental new drug application for ivosidenib for the frontline treatment of patients with IDH1-mutant acute myeloid leukemia who are ineligible for standard chemotherapy.

The sNDA is based on findings from a phase I trial, which demonstrated that ivosidenib induced a 57.6% overall response rate among newly diagnosed patients with IDH1-positive AML. This ORR included a 42.4% combined rate of complete remission plus CR with partial hematologic recovery.

Regarding safety findings, which included 34 patients with untreated AML, all-grade adverse events that occurred in more than 25% of patients were diarrhea, fatigue, nausea, decreased appetite, leukocytosis, anemia, and peripheral edema.

Under the expedited priority review, the FDA will review the sNDA within 6 months from the acceptance of the filing, compared with the standard 10 months. An approval decision is scheduled to be made on or before June 21, 2019. Ivosidenib was previously approved by the FDA in July 2018 for the treatment of adult patients with relapsed/refractory IDH1-mutant AML.

*********************************

In small cell lung cancer, the FDA granted a priority review designation to a supplemental biologics license application for pembrolizumab as a treatment for patients with advanced small cell lung cancer whose disease has progressed following at least 2 prior lines of therapy.

The application is based on data from cohorts of the phase II KEYNOTE-158 and phase Ib KEYNOTE-028 studies, in which pembrolizumab elicited 19% and 33% overall response rates in patients with advanced and extensive-stage SCLC, respectively.

In KEYNOTE-158, a basket study of patients with 10 tumor types, results also showed that the disease control rate with pembrolizumab in patients with SCLC was 30%, and the median duration of response was not reached. Moreover, the median PFS was 2.0 months and the median OS was 8.7 months.

In the KEYNOTE-028 basket trial, investigators evaluated pembrolizumab in patients with advanced solid tumors. Results showed that the median time to response was 2.0 months and the median duration of response was 19.4 months.

Moreover, the median PFS was 1.9 months, the estimated 6-month PFS rate was 28.6%, and the estimated 12-month PFS rate was 23.8%. The median OS was 9.7 months, and the estimated 6- and 12-month OS rates were 66.0% and 37.7%, respectively.

*************************************

The FDA's Oncologic Drugs Advisory Committee voted 8 to 5 against accelerated approval of a new drug application for selinexor for the treatment of patients with penta-refractory multiple myeloma, recommending delaying a decision on the drug until results are available from the pivotal phase III BOSTON trial.

Karyopharm Therapeutics, the manufacturer of selinexor, submitted the NDA for an accelerated approval of selinexor for patients with myeloma who have received 3 or more prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-targeted antibody, and to their most recent treatment.

The application is based on Part 2 of the phase IIb STORM study, which showed that the combination of selinexor and dexamethasone elicited a 26.2% overall response rate and an 8.6-month median overall survival.

However, several questions arose during the ODAC meeting. First, STORM was a single-arm combination trial and a prior phase I study had not demonstrated strong single-agent activity with selinexor. Therefore, isolating the specific impact of selinexor is difficult.

Additionally, there was significant toxicity with selinexor in the STORM trial, including treatment-emergent adverse events, serious adverse events, and treatment-emergent adverse events that resulted in patient deaths.

It is hoped that the phase III BOSTON trial will allow the FDA to make a more informed decision on the agent. BOSTON is evaluating the addition of selinexor to bortezomib and low-dose dexamethasone compared with bortezomib and low-dose dexamethasone alone in patients with relapsed/refractory multiple myeloma who have received 1 to 3 prior regimens.

The NDA for the accelerated approval of selinexor is being reviewed under the FDA’s priority review program. The FDA now has until April 6, 2019, to consider ODAC’s recommendation and make a final decision on whether or not to grant selinexor an accelerated approval.

*********************************

In prostate cancer, a new drug application has been filed with the FDA for darolutamide for the treatment of patients with nonmetastatic castration-resistant prostate cancer.

The application is based on data from the phase III ARAMIS trial, in which darolutamide plus androgen deprivation therapy significantly improved metastasis-free survival versus placebo plus ADT in patients with nonmetastatic CRPC.

At a median follow-up of 17.9 months, results showed that the median MFS was 40.4 months with darolutamide versus 18.4 months with placebo, corresponding to a 59% reduction in the risk of metastases or death in favor of darolutamide. The MFS benefit was reported across patient subgroups.

At an interim analysis for overall survival, the 3-year rates of OS were 83% in the darolutamide arm versus 73% in the placebo arm, corresponding to a 29% reduction in the risk of death. The median OS was not yet reached in either arm.

*********************************

The combination of pembrolizumab plus best supportive care for the treatment of patients with advanced hepatocellular carcinoma who were previously treated with systemic therapy did not improve progression-free or overall survival versus placebo plus best supportive care alone, missing the coprimary endpoints of the KEYNOTE-240 trial.

Results of the final analysis showed that the pembrolizumab regimen did improve OS versus placebo. However, the 22% reduction in the risk of death was not deemed statistically significant per the prespecified statistical plan.

Additionally, there was a progression-free survival improvement with pembrolizumab that also did not reach statistical significance. Since superiority was not reached in either primary endpoint, overall response rate, which was a key secondary endpoint, was not formally tested.

KEYNOTE-240 is the confirmatory trial for pembrolizumab, which was granted an accelerated approval in November 2018 for patients with HCC who were previously treated with sorafenib, which was based on data from the phase II KEYNOTE-224 trial.

The safety profile of pembrolizumab in KEYNOTE-240 was consistent with what has been observed in prior studies with the PD-1 inhibitor. Full findings will be presented at an upcoming medical meeting and have been shared with the FDA for discussions.

*********************************

This week, we sat down with Dr Kenneth Anderson, of Dana-Farber Cancer Institute and Harvard Medical School, to discuss current treatment for patients with transplant-eligible multiple myeloma.

That’s all for today.

Thank you for watching OncLive News Network! I’m Gina Columbus.
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Community Practice Connections™: Addressing Post-Transplant Obstacles: Current and Emerging Strategies to Evolve the Standard of Care for Patients With Graft-Versus-Host DiseaseMar 28, 20192.0
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