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FDA Approval in Melanoma, Priority Review in DLBCL, RCC, and NTRK Fusion-Positive Tumors

Gina Columbus
Published: Sunday, Feb 24, 2019



Today-

An FDA approval in melanoma, priority review designations in diffuse large B-cell lymphoma, renal cell carcinoma, and NTRK fusion–positive tumors and non–small cell lung cancer, and proposed CMS coverage for CAR T-cell therapy.

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

The FDA has approved pembrolizumab for the adjuvant treatment of patients with high-risk stage III melanoma with lymph node involvement following complete resection, making it the first anti–PD-1 therapy evaluated in the adjuvant setting across patients with stage IIIA, stage IIIB, and stage IIIC melanoma.

The decision is based on findings from the pivotal phase III EORTC 1325/KEYNOTE-054 trial, in which adjuvant pembrolizumab led to a 43% reduction in the risk of disease recurrence or death compared with placebo in this patient population.

Results also showed that the 18-month recurrence-free survival rate was 71.4% with pembrolizumab versus 53.2% with placebo. Moreover, an RFS benefit with the PD-1 inhibitor was observed across patients with either stage IIIA, IIIB, or IIIC disease.

The median RFS was not reached with adjuvant pembrolizumab versus 20.4 months with placebo, and th benefit was observed regardless of PD-L1 expression or BRAF mutation status.

The European Commission approved the PD-1 inhibitor for this indication in December 2018.

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In diffuse large B-cell lymphoma, the FDA granted a priority review designation to a biologics license application to the combination of polatuzumab vedotin with bendamustine and rituximab for the treatment of patients with relapsed/refractory disease.

The application is based on findings from the phase Ib/II GO29365 study, in which 40% of patients receiving the polatuzumab vedotin regimen reached a complete response compared with 18% of patients in the BR-alone arm. The addition of the antibody-drug conjugate also showed an improvement in overall survival; the median OS was 12.4 months versus 4.7 months with BR alone.

Additional data showed that the median PFS by independent review was 11.1 months with polatuzumab vedotin and 3.7 months without. By investigator assessment, the median values were 7.6 versus 2.0 months without the antibody-drug conjugate.

With continued follow-up, no new safety signals emerged, and the safety data remained consistent with initial reports from the study.

The FDA is expected to make a decision on the approval on or before August 19, 2019.

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The FDA has granted a priority review designation to a supplemental biologics license application for the combination of pembrolizumab and axitinib as a frontline treatment for patients with advanced renal cell carcinoma.

The sBLA is primarily based on data from the phase III KEYNOTE-426 study, which demonstrated that the frontline combination significantly improved progression-free and overall survival versus sunitinib in patients with advanced RCC. Results showed that pembrolizumab and axitinib led to a 47% reduction in the risk of death versus sunitinib.

At a median follow-up of 12.8 months, results showed that the median OS was not reached in either arm. The median progression-free survival was 15.1 months for pembrolizumab/axitinib and 11.1 months with sunitinib. With the combination, there was a 31% reduction in the risk of disease progression.

The FDA will also review data from the phase Ib KEYNOTE-035 trial, which showed that the combination had a tolerable safety profile and elicited a 73% objective response rate in this patient population.

Under the Prescription Drug User Fee Act, the FDA is expected to make a decision on the sBLA by June 20, 2019.

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

The FDA granted a priority review designation to a new drug application for entrectinib as a treatment for select adult and pediatric patients with NTRK fusion–positive locally advanced or metastatic solid tumors, as well as patients with metastatic ROS1-positive non–small cell lung cancer.

For NTRK fusion–positive tumors, the multikinase inhibitor would be indicated for those who have either progressed following prior therapies or as initial treatment when no standard acceptable therapies are available. The FDA is expected to decide on the application by August 18, 2019.

The NDA is based on findings from an integrated analysis of the phase II STARTRK-2, phase I STARTRK-1, and the phase I ALKA-372-001 trials, which demonstrated a 57.4% overall response rate in patients with NTRK fusion–positive solid tumors and a median duration of response of 10.4 months. The application is also based on results from the phase I/Ib STARTRK-NG study. Overall, the trials enrolled patients across 15 countries and 150 clinical trial sites.

Findings from the integrated analysis showed that the responses were observed across 10 solid tumor types, and in patients with and without CNS metastases at baseline. The intracranial ORR was 54.5%, with more than one-quarter of these patients achieving a complete response.

In ROS1-positive NSCLC, the pooled findings from STARTRK-2, STARTRK-1, and ALKA-372-001 showed that entrectinib demonstrated a 77.4% ORR and a median DOR of 24.6 months in patients locally advanced or metastatic disease. Also, the IC ORR was 55.0%.

Results of the STARTRK-NG trial demonstrated that 3 pediatric and young adult patients with advanced, previously treated CNS tumors with targeted gene fusions also responded to entrectinib.

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

The Centers for Medicare & Medicaid Services has proposed to cover chimeric antigen receptor T-cell therapies approved by the FDA, under Coverage with Evidence Development.

There is currently no national Medicare policy in place to provide coverage for CAR T-cell therapy, which has shown success in select patients with relapsed/refractory hematologic cancers. Without such a policy, local Medicare Administrative Contractors have been conflicted over whether or not they should pay for the treatment.

The proposal has been issued in response to a formal request made by Efrem Castillo, MD, who is chief medical officer of Medicare & Retirement at UnitedHealthcare. Castillo had asked for clarification of the circumstances under which FDA-approved CAR T-cell therapies will be covered in order to create consistent patient access to this treatment nationwide as well as financial sustainability in the Medicare Advantage program.

In the proposed NCD, Medicare will cover the therapy on a national level when the treatment is offered through a CMS-approved registry or clinical study in which patients are monitored for at least 2 years after completing therapy.

These data will help the CMS determine the types of patients who will benefit most from the therapy, which, in turn, will help the agency eventually decide which kinds of cases Medicare will cover without a registry or trial requirement.

The CMS plans to leverage the FDA’s requirements for post-approval studies for these agents when reviewing studies for CMS approval.

The CMS will issue a final decision on the proposal no later than 60 days after the conclusion of a 30-day public comment period, which was initiated on February 15, 2019. The expected date for National Coverage Analysis completion is May 17, 2019.

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This week, we sat down with Dr Bijal Shah, of Moffitt Cancer Center, to discuss differences in trial design between BTK inhibitors for mantle cell lymphoma.

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 melanoma, priority review designations in diffuse large B-cell lymphoma, renal cell carcinoma, and NTRK fusion–positive tumors and non–small cell lung cancer, and proposed CMS coverage for CAR T-cell therapy.

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

The FDA has approved pembrolizumab for the adjuvant treatment of patients with high-risk stage III melanoma with lymph node involvement following complete resection, making it the first anti–PD-1 therapy evaluated in the adjuvant setting across patients with stage IIIA, stage IIIB, and stage IIIC melanoma.

The decision is based on findings from the pivotal phase III EORTC 1325/KEYNOTE-054 trial, in which adjuvant pembrolizumab led to a 43% reduction in the risk of disease recurrence or death compared with placebo in this patient population.

Results also showed that the 18-month recurrence-free survival rate was 71.4% with pembrolizumab versus 53.2% with placebo. Moreover, an RFS benefit with the PD-1 inhibitor was observed across patients with either stage IIIA, IIIB, or IIIC disease.

The median RFS was not reached with adjuvant pembrolizumab versus 20.4 months with placebo, and th benefit was observed regardless of PD-L1 expression or BRAF mutation status.

The European Commission approved the PD-1 inhibitor for this indication in December 2018.

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

In diffuse large B-cell lymphoma, the FDA granted a priority review designation to a biologics license application to the combination of polatuzumab vedotin with bendamustine and rituximab for the treatment of patients with relapsed/refractory disease.

The application is based on findings from the phase Ib/II GO29365 study, in which 40% of patients receiving the polatuzumab vedotin regimen reached a complete response compared with 18% of patients in the BR-alone arm. The addition of the antibody-drug conjugate also showed an improvement in overall survival; the median OS was 12.4 months versus 4.7 months with BR alone.

Additional data showed that the median PFS by independent review was 11.1 months with polatuzumab vedotin and 3.7 months without. By investigator assessment, the median values were 7.6 versus 2.0 months without the antibody-drug conjugate.

With continued follow-up, no new safety signals emerged, and the safety data remained consistent with initial reports from the study.

The FDA is expected to make a decision on the approval on or before August 19, 2019.

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

The FDA has granted a priority review designation to a supplemental biologics license application for the combination of pembrolizumab and axitinib as a frontline treatment for patients with advanced renal cell carcinoma.

The sBLA is primarily based on data from the phase III KEYNOTE-426 study, which demonstrated that the frontline combination significantly improved progression-free and overall survival versus sunitinib in patients with advanced RCC. Results showed that pembrolizumab and axitinib led to a 47% reduction in the risk of death versus sunitinib.

At a median follow-up of 12.8 months, results showed that the median OS was not reached in either arm. The median progression-free survival was 15.1 months for pembrolizumab/axitinib and 11.1 months with sunitinib. With the combination, there was a 31% reduction in the risk of disease progression.

The FDA will also review data from the phase Ib KEYNOTE-035 trial, which showed that the combination had a tolerable safety profile and elicited a 73% objective response rate in this patient population.

Under the Prescription Drug User Fee Act, the FDA is expected to make a decision on the sBLA by June 20, 2019.

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

The FDA granted a priority review designation to a new drug application for entrectinib as a treatment for select adult and pediatric patients with NTRK fusion–positive locally advanced or metastatic solid tumors, as well as patients with metastatic ROS1-positive non–small cell lung cancer.

For NTRK fusion–positive tumors, the multikinase inhibitor would be indicated for those who have either progressed following prior therapies or as initial treatment when no standard acceptable therapies are available. The FDA is expected to decide on the application by August 18, 2019.

The NDA is based on findings from an integrated analysis of the phase II STARTRK-2, phase I STARTRK-1, and the phase I ALKA-372-001 trials, which demonstrated a 57.4% overall response rate in patients with NTRK fusion–positive solid tumors and a median duration of response of 10.4 months. The application is also based on results from the phase I/Ib STARTRK-NG study. Overall, the trials enrolled patients across 15 countries and 150 clinical trial sites.

Findings from the integrated analysis showed that the responses were observed across 10 solid tumor types, and in patients with and without CNS metastases at baseline. The intracranial ORR was 54.5%, with more than one-quarter of these patients achieving a complete response.

In ROS1-positive NSCLC, the pooled findings from STARTRK-2, STARTRK-1, and ALKA-372-001 showed that entrectinib demonstrated a 77.4% ORR and a median DOR of 24.6 months in patients locally advanced or metastatic disease. Also, the IC ORR was 55.0%.

Results of the STARTRK-NG trial demonstrated that 3 pediatric and young adult patients with advanced, previously treated CNS tumors with targeted gene fusions also responded to entrectinib.

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

The Centers for Medicare & Medicaid Services has proposed to cover chimeric antigen receptor T-cell therapies approved by the FDA, under Coverage with Evidence Development.

There is currently no national Medicare policy in place to provide coverage for CAR T-cell therapy, which has shown success in select patients with relapsed/refractory hematologic cancers. Without such a policy, local Medicare Administrative Contractors have been conflicted over whether or not they should pay for the treatment.

The proposal has been issued in response to a formal request made by Efrem Castillo, MD, who is chief medical officer of Medicare & Retirement at UnitedHealthcare. Castillo had asked for clarification of the circumstances under which FDA-approved CAR T-cell therapies will be covered in order to create consistent patient access to this treatment nationwide as well as financial sustainability in the Medicare Advantage program.

In the proposed NCD, Medicare will cover the therapy on a national level when the treatment is offered through a CMS-approved registry or clinical study in which patients are monitored for at least 2 years after completing therapy.

These data will help the CMS determine the types of patients who will benefit most from the therapy, which, in turn, will help the agency eventually decide which kinds of cases Medicare will cover without a registry or trial requirement.

The CMS plans to leverage the FDA’s requirements for post-approval studies for these agents when reviewing studies for CMS approval.

The CMS will issue a final decision on the proposal no later than 60 days after the conclusion of a 30-day public comment period, which was initiated on February 15, 2019. The expected date for National Coverage Analysis completion is May 17, 2019.

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

This week, we sat down with Dr Bijal Shah, of Moffitt Cancer Center, to discuss differences in trial design between BTK inhibitors for mantle cell lymphoma.

That’s all for today.

Thank you for watching OncLive News Network! I’m Gina Columbus.
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Community Practice Connections™: 22nd Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas and MyelomaMay 30, 20192.0
Online Medical Crossfire®: 5th Annual Miami Lung Cancer ConferenceMay 30, 20196.5
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