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FDA Approvals in HCC, RCC, and CLL, and ODAC Recommendations

Gina Columbus
Published: Thursday, May 23, 2019



Today-

FDA approvals in liver cancer, renal cell carcinoma, and chronic lymphocytic leukemia, ODAC recommendations in tenosynovial giant cell tumor and acute myeloid leukemia, and highlights from a presscast ahead of 2019 ASCO Annual Meeting.

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

The FDA has approved single-agent ramucirumab for patients with hepatocellular carcinoma who have an alpha fetoprotein of at least 400 ng/ML and have been previously treated with sorafenib.

The approval was based on findings from the international, double-blind, placebo-controlled, multicenter phase III REACH-2 trial, in which the median overall survival was 8.5 months with ramucirumab compared with 7.3 months with placebo in patients who experienced progression on or intolerance to frontline sorafenib.

Results of REACH-2 also showed that the survival benefit was consistent across all prespecified subgroups. The 12- and 18-month OS rates both favored ramucirumab at 36.8% versus 30.3% and 24.5% versus 11.3%, respectively, and the median progression-free survival was 2.8 months with ramucirumab versus 1.6 months with placebo.

In the previously reported REACH trial of patients with advanced HCC, treatment with ramucirumab did not significantly improve OS in the intention-to-treat population. Yet, a prespecified subgroup analysis showed a significant survival benefit in those with AFP levels of at least 400 ng/mL. These data provided a rationale for a follow-up trial to evaluate ramucirumab in patients with elevated AFP.

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

In renal cell carcinoma, the FDA has approved the combination of avelumab and axitinib for the frontline treatment of patients with advanced disease.

The approval is based on results from the pivotal phase III JAVELIN Renal 101 trial, which showed that the combination was associated with a 31% reduction in disease progression or death compared with sunitinib in an intent-to-treat population of patients with treatment-naïve advanced RCC, regardless of PD-L1 expression.

Moreover, in the PD-L1–positive population, the median PFS was 13.8 months with avelumab/axitinib compared with 7.2 months with sunitinib, which led to a 39% reduction in the risk of disease progression or death. The ORR with the combination was 55.2%, which included 4 complete responses and 51 partial responses compared with a 25.5% ORR with sunitinib. Twenty-seven patients in the combination arm had stable disease and 11 had progressive disease.

In the overall population, the median PFS with the combination versus sunitinib was 13.8 months and 8.4 months, respectively. Overall, the ORR with avelumab plus axitinib was 51.4% and 25.7% with sunitinib.

At a follow-up for median OS of 19 months, the OS endpoint remains immature with 27% of deaths in the ITT population. Pfizer, which co-develops avelumab with Merck, stated in a press release that the trial is continuing as planned.

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

The FDA has approved the combination of venetoclax and obinutuzumab for the frontline treatment of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

The approval is based on data from the phase III CLL14 trial, which showed that the venetoclax combination led to a 67% reduction in the risk of disease progression or death versus obinutuzumab plus chlorambucil in patients with treatment-naïve CLL and co-existing medical conditions.

Results also showed that the overall response rate was 85% with venetoclax/obinutuzumab versus 71% in the control arm. The complete response or CR with incomplete hematologic recovery rates were 50% versus 23%, respectively.

The rate of minimal residual disease-negativity in the bone marrow was 57% in the venetoclax arm versus 17% in the obinutuzumab/chlorambucil arm. The MRD-negativity rates in the peripheral blood were 76% versus 35%, respectively.

The agency reviewed and approved the application for the venetoclax combination under the Real-Time Oncology Review pilot program, which is designed to have a more efficient review process to make therapies more quickly available to patients.

Full findings of CLL14 are scheduled to be presented at the 2019 ASCO Annual Meeting.

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

The FDA’s Oncologic Drugs Advisory Committee voted 12 to 3 in favor of pexidartinib for an indication as a treatment of adult patients with symptomatic tenosynovial giant cell tumor.

Under the Prescription Drug User Fee Act, the FDA will now make a decision on the pexidartinib indication by August 3, 2019.

A priority review designation was initially granted to the application for pexidartinib in February 2019, which was based on results from the international phase III ENLIVEN study. Results showed a 39.3% overall response rate with pexidartinib versus 0% with placebo following 24 weeks of treatment based on central review of MRI scans.

At the ODAC meeting, the committee assessed the clinical benefit of pexidartinib in this patient population, as the interpretation of the activity was limited due to a proportion of data missing at 25 weeks for several secondary endpoints, including range of motion, physical function, and worst stiffness.

The panel also aimed to characterize the risk of liver injury in patients with TGCT who received therapy with pexidartinib. In the phase III ENLIVEN trial, pexidartinib was associated with increases in alanine aminotransferase, aspartate aminotransferase, and total bilirubin. These adverse events reached at least grade 3 severity in one-third of patients. The FDA briefing document for ODAC also had stated that the long-term safety profile of pexidartinib was unknown.

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

In acute myeloid leukemia, the FDA’s Oncologic Drugs Advisory Committee voted 8-3 against approving a new drug application for quizartinib for adult patients with relapsed/refractory FLT3-ITD–positive disease.

The application was filed based on data from the phase III QuANTUM-R study, in which quizartinib reduced the risk of death by 24% compared with salvage chemotherapy in patients with FLT3-ITD–positive relapsed/refractory AML following frontline treatment with or without hematopoietic stem cell transplantation. At a median follow-up of 23.5 months, the median OS was 6.2 months with quizartinib compared with 4.7 months for chemotherapy.

Prior to the ODAC meeting, the FDA had conducted its own efficacy analysis. Here, it was determined that the median OS was 26.9 weeks with quizartinib compared with 20.4 weeks with salvage chemotherapy.

Although this analysis confirmed a benefit with quizartinib, the FDA explained in its ODAC briefing document that it found issues in its review raising concerns over the credibility and generalizability of the trial data.

These issues included imbalances in the rates of patients who were early-censored for OS prior to week 8 after randomization and in the number of patients randomized but not treated; inconsistent OS treatment effect by strata based on intensive versus low-intensity chemotherapy; confounding of the assessment of OS by the follow-on therapies which patients received after discontinuation from study treatment; and lack of treatment effect in additional efficacy endpoints.

The agency is now scheduled to make a final decision on the application for the FLT3 inhibitor by August 25, 2019.

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

In a presscast ahead of the 2019 ASCO Annual Meeting, investigators presented findings across various malignancies.

For example, in the phase I/Ib STARTRK-NG trial, results showed that entrectinib induced objective responses in 100% of pediatric patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions or mutations.

The multikinase inhibitor induced responses in all 11 patients with CNS and solid tumors with these abnormalities, as well as in 1 patient with ALK-mutated neuroblastoma. No responses occurred in patients with tumors lacking these genetic aberrations.

Secondly, findings from the National Cancer Institute-Children’s Oncology Group Pediatric MATCH trial Cancer showed that approximately one-quarter of pediatric patients with cancer could be screened for targetable alterations in their tumor and directed to a treatment targeting that alteration of pathway in the screening protocol of the study. This rate exceeded the projected rate of 10% of patients that would be assigned to a treatment arm.

Moreover, data from the GO2 study showed that a lower dose of oxaliplatin and capecitabine had comparable efficacy and minimized adverse events in elderly and frail patients with advanced gastroesophageal cancer.

In the study, patients were between the age of 51 and 96 and were randomly assigned to one of three dosage levels: Level A, Level B, and Level C. Progression-free survival was comparable among the groups, at 4.9 months, 4.1 months, and 4.3 months for Levels A, B, and C, respectively.

Overall survival, which was a secondary endpoint, did not vary much between the groups. Patients on Level A lived a median of 7.5 months; patients on Level B received an average of 6.7 months; and patients on Level C lived an average of 7.6 months.

Results of the ECOG E3A06 study, which was presented during the presscast, showed that lenalidomide induced a 72% reduction in the risk for progression to symptomatic disease at 3 years in patients with smoldering multiple myeloma. The time to develop multiple myeloma was also delayed with lenalidomide.

Finally, women who eat a balanced, low-fat diet and daily portions of vegetables, fruit, and grains have a 21% lower risk of dying of breast cancer. This was the first large, randomized clinical trial to show that diet can reduce the risk of dying of breast cancer.

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

This week, we sat down with Riccardo Lencioni MD, of the University of Miami Health System, to discuss the future of hepatocellular carcinoma management.

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

FDA approvals in liver cancer, renal cell carcinoma, and chronic lymphocytic leukemia, ODAC recommendations in tenosynovial giant cell tumor and acute myeloid leukemia, and highlights from a presscast ahead of 2019 ASCO Annual Meeting.

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

The FDA has approved single-agent ramucirumab for patients with hepatocellular carcinoma who have an alpha fetoprotein of at least 400 ng/ML and have been previously treated with sorafenib.

The approval was based on findings from the international, double-blind, placebo-controlled, multicenter phase III REACH-2 trial, in which the median overall survival was 8.5 months with ramucirumab compared with 7.3 months with placebo in patients who experienced progression on or intolerance to frontline sorafenib.

Results of REACH-2 also showed that the survival benefit was consistent across all prespecified subgroups. The 12- and 18-month OS rates both favored ramucirumab at 36.8% versus 30.3% and 24.5% versus 11.3%, respectively, and the median progression-free survival was 2.8 months with ramucirumab versus 1.6 months with placebo.

In the previously reported REACH trial of patients with advanced HCC, treatment with ramucirumab did not significantly improve OS in the intention-to-treat population. Yet, a prespecified subgroup analysis showed a significant survival benefit in those with AFP levels of at least 400 ng/mL. These data provided a rationale for a follow-up trial to evaluate ramucirumab in patients with elevated AFP.

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

In renal cell carcinoma, the FDA has approved the combination of avelumab and axitinib for the frontline treatment of patients with advanced disease.

The approval is based on results from the pivotal phase III JAVELIN Renal 101 trial, which showed that the combination was associated with a 31% reduction in disease progression or death compared with sunitinib in an intent-to-treat population of patients with treatment-naïve advanced RCC, regardless of PD-L1 expression.

Moreover, in the PD-L1–positive population, the median PFS was 13.8 months with avelumab/axitinib compared with 7.2 months with sunitinib, which led to a 39% reduction in the risk of disease progression or death. The ORR with the combination was 55.2%, which included 4 complete responses and 51 partial responses compared with a 25.5% ORR with sunitinib. Twenty-seven patients in the combination arm had stable disease and 11 had progressive disease.

In the overall population, the median PFS with the combination versus sunitinib was 13.8 months and 8.4 months, respectively. Overall, the ORR with avelumab plus axitinib was 51.4% and 25.7% with sunitinib.

At a follow-up for median OS of 19 months, the OS endpoint remains immature with 27% of deaths in the ITT population. Pfizer, which co-develops avelumab with Merck, stated in a press release that the trial is continuing as planned.

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

The FDA has approved the combination of venetoclax and obinutuzumab for the frontline treatment of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

The approval is based on data from the phase III CLL14 trial, which showed that the venetoclax combination led to a 67% reduction in the risk of disease progression or death versus obinutuzumab plus chlorambucil in patients with treatment-naïve CLL and co-existing medical conditions.

Results also showed that the overall response rate was 85% with venetoclax/obinutuzumab versus 71% in the control arm. The complete response or CR with incomplete hematologic recovery rates were 50% versus 23%, respectively.

The rate of minimal residual disease-negativity in the bone marrow was 57% in the venetoclax arm versus 17% in the obinutuzumab/chlorambucil arm. The MRD-negativity rates in the peripheral blood were 76% versus 35%, respectively.

The agency reviewed and approved the application for the venetoclax combination under the Real-Time Oncology Review pilot program, which is designed to have a more efficient review process to make therapies more quickly available to patients.

Full findings of CLL14 are scheduled to be presented at the 2019 ASCO Annual Meeting.

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

The FDA’s Oncologic Drugs Advisory Committee voted 12 to 3 in favor of pexidartinib for an indication as a treatment of adult patients with symptomatic tenosynovial giant cell tumor.

Under the Prescription Drug User Fee Act, the FDA will now make a decision on the pexidartinib indication by August 3, 2019.

A priority review designation was initially granted to the application for pexidartinib in February 2019, which was based on results from the international phase III ENLIVEN study. Results showed a 39.3% overall response rate with pexidartinib versus 0% with placebo following 24 weeks of treatment based on central review of MRI scans.

At the ODAC meeting, the committee assessed the clinical benefit of pexidartinib in this patient population, as the interpretation of the activity was limited due to a proportion of data missing at 25 weeks for several secondary endpoints, including range of motion, physical function, and worst stiffness.

The panel also aimed to characterize the risk of liver injury in patients with TGCT who received therapy with pexidartinib. In the phase III ENLIVEN trial, pexidartinib was associated with increases in alanine aminotransferase, aspartate aminotransferase, and total bilirubin. These adverse events reached at least grade 3 severity in one-third of patients. The FDA briefing document for ODAC also had stated that the long-term safety profile of pexidartinib was unknown.

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

In acute myeloid leukemia, the FDA’s Oncologic Drugs Advisory Committee voted 8-3 against approving a new drug application for quizartinib for adult patients with relapsed/refractory FLT3-ITD–positive disease.

The application was filed based on data from the phase III QuANTUM-R study, in which quizartinib reduced the risk of death by 24% compared with salvage chemotherapy in patients with FLT3-ITD–positive relapsed/refractory AML following frontline treatment with or without hematopoietic stem cell transplantation. At a median follow-up of 23.5 months, the median OS was 6.2 months with quizartinib compared with 4.7 months for chemotherapy.

Prior to the ODAC meeting, the FDA had conducted its own efficacy analysis. Here, it was determined that the median OS was 26.9 weeks with quizartinib compared with 20.4 weeks with salvage chemotherapy.

Although this analysis confirmed a benefit with quizartinib, the FDA explained in its ODAC briefing document that it found issues in its review raising concerns over the credibility and generalizability of the trial data.

These issues included imbalances in the rates of patients who were early-censored for OS prior to week 8 after randomization and in the number of patients randomized but not treated; inconsistent OS treatment effect by strata based on intensive versus low-intensity chemotherapy; confounding of the assessment of OS by the follow-on therapies which patients received after discontinuation from study treatment; and lack of treatment effect in additional efficacy endpoints.

The agency is now scheduled to make a final decision on the application for the FLT3 inhibitor by August 25, 2019.

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

In a presscast ahead of the 2019 ASCO Annual Meeting, investigators presented findings across various malignancies.

For example, in the phase I/Ib STARTRK-NG trial, results showed that entrectinib induced objective responses in 100% of pediatric patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions or mutations.

The multikinase inhibitor induced responses in all 11 patients with CNS and solid tumors with these abnormalities, as well as in 1 patient with ALK-mutated neuroblastoma. No responses occurred in patients with tumors lacking these genetic aberrations.

Secondly, findings from the National Cancer Institute-Children’s Oncology Group Pediatric MATCH trial Cancer showed that approximately one-quarter of pediatric patients with cancer could be screened for targetable alterations in their tumor and directed to a treatment targeting that alteration of pathway in the screening protocol of the study. This rate exceeded the projected rate of 10% of patients that would be assigned to a treatment arm.

Moreover, data from the GO2 study showed that a lower dose of oxaliplatin and capecitabine had comparable efficacy and minimized adverse events in elderly and frail patients with advanced gastroesophageal cancer.

In the study, patients were between the age of 51 and 96 and were randomly assigned to one of three dosage levels: Level A, Level B, and Level C. Progression-free survival was comparable among the groups, at 4.9 months, 4.1 months, and 4.3 months for Levels A, B, and C, respectively.

Overall survival, which was a secondary endpoint, did not vary much between the groups. Patients on Level A lived a median of 7.5 months; patients on Level B received an average of 6.7 months; and patients on Level C lived an average of 7.6 months.

Results of the ECOG E3A06 study, which was presented during the presscast, showed that lenalidomide induced a 72% reduction in the risk for progression to symptomatic disease at 3 years in patients with smoldering multiple myeloma. The time to develop multiple myeloma was also delayed with lenalidomide.

Finally, women who eat a balanced, low-fat diet and daily portions of vegetables, fruit, and grains have a 21% lower risk of dying of breast cancer. This was the first large, randomized clinical trial to show that diet can reduce the risk of dying of breast cancer.

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

This week, we sat down with Riccardo Lencioni MD, of the University of Miami Health System, to discuss the future of hepatocellular carcinoma management.

That’s all for today. Thank you for watching OncLive News Network! I’m Gina Columbus.
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