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Priority Review in Merkel Cell Carcinoma, Breakthrough Designation in RET-Altered Cancers, and More

Gina Columbus
Published: Monday, Sep 10, 2018



Today-

A priority review designation in Merkel cell carcinoma, a breakthrough therapy designation in select RET-altered cancers, an application submitted in pediatric ALL, and European approvals in multiple myeloma, melanoma, and ALL.

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

The FDA has granted a priority review to a supplemental biologics license application for pembrolizumab for the treatment of pediatric and adult patients with recurrent locally advanced or metastatic Merkel cell carcinoma.

The sBLA is based on findings from the phase II KEYNOTE-017 trial, which included 50 patients with metastatic or locally advanced MCC who were treated with at least 1 dose of pembrolizumab in the frontline setting.

At a median follow-up of 14.9 months, the objective response rate per independent review was 56%, including a 24% complete response rate and a 32% partial response rate. An additional 5 patients had stable disease, while 16 patients had progressive disease and 1 patient was not assessed for response.

Moreover, the median progression-free survival was 16.8 months with pembrolizumab, which was higher than historical data for chemotherapy, for which the median PFS ranges from 3.1 to 4.6 months. This was also true for median overall survival, which had not been reached for pembrolizumab versus historical data ranging from 9.5 to 10.2 months with frontline chemotherapy in this disease.

Under the Prescription Drug User Fee Act, the FDA is scheduled to decide on the sBLA by December 28, 2018.

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The FDA has granted LOXO-292 a breakthrough therapy designation for the treatment of patients with RET fusion–positive non–small cell lung cancer or RET-mutant medullary thyroid cancer.

The breakthrough designation is specifically for the treatment of patients with metastatic RET fusion–positive NSCLC who require systemic therapy and have progressed following platinum-based chemotherapy and an anti–PD-1 or PD-L1 therapy; and for the treatment of patients with RET-mutant MTC who require systemic therapy, have progressed following prior treatment, and have no acceptable alternative treatment options.

The designation is based on data from the ongoing phase I LIBRETTO-001 study, in which the objective response rate was 77% for patients with RET fusion–positive NSCLC. At the April 2018 data cutoff, no patients with NSCLC had developed progressive disease with 90% remaining on treatment with LOXO-292. All patients with measurable intracranial lesions responded to LOXO-292.

In those with RET-mutated MTC, the ORR was 45%, with 1 complete response and 1 additional CR awaiting confirmation. Two patients in this group developed PD and 93% continued to receive treatment with LOXO-292. Moreover, in 2 patients with a resistance mutation in V804M, there was a substantial reduction in tumor size. In 4 enrolled patients with no known activating RET alteration, there was no response with LOXO-292.

In acute lymphoblastic leukemia, the FDA has accepted a supplemental biologics license application for dasatinib in combination with chemotherapy for the treatment of pediatric patients with newly diagnosed Philadelphia chromosome–positive disease.

The application is based on data from the phase II CA180-372 trial, in which pediatric patients with newly diagnosed Ph+ ALL received dasatinib plus a chemotherapy regimen modelled on a Berlin-Frankfurt-Munster high-risk backbone.

Findings presented at the 2017 ASH Annual Meeting showed that the 3-year event-free survival rate for the dasatinib combination was 65.5%, and the 3-year overall survival rate was 91.5%.

The FDA is scheduled to make its decision on the application by December 29, 2018.

Dasatinib previously received an indication by the FDA in November 2017 for the treatment of pediatric patients with Ph+ chronic myeloid leukemia in chronic phase.

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

The European Commission has approved daratumumab for use in combination with bortezomib, melphalan, and prednisone as a treatment for adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

The decision was based on the pivotal, open-label phase III ALCYONE study, in which daratumumab plus VMP led to a 50% reduction in the risk of progression or death versus VMP alone.

In the trial, 706 with newly diagnosed multiple myeloma were randomized to receive VMP alone or in combination with daratumumab. VMP was administered at standard doses and daratumumab was added at 16 mg/kg once weekly in cycle 1 and every 3 weeks in cycles 2 through 9. Beyond month 9 in the investigational arm, daratumumab was continued every 4 weeks until disease progression.

Results also showed that median progression-free survival was 18.1 months in the VMP arm and was not yet reached for those treated with the daratumumab regimen. Follow-up remained ongoing for overall survival at the 16.5-month assessment.

This regimen was approved by the FDA in May 2017.

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

In melanoma, the European Commission has approved the combination of dabrafenib and trametinib for the adjuvant treatment of patients with BRAF V600–positive stage III disease following complete resection.

The approval is based on data from the phase III COMBI-AD study, in which the primary analysis showed that adjuvant treatment with dabrafenib and trametinib reduced the risk of relapse or death by 53% versus placebo for patients with BRAF-mutant stage III melanoma.

After a median follow-up of 2.8 years, the median relapse-free survival was not reached with the combination versus 16.6 months for placebo.

Moreover, RFS was improved with dabrafenib/trametinib across all subgroups. The hazard ratios across all subgroups ranged from 0.33 to 0.55 in favor of dabrafenib and trametinib versus placebo.

Early data for overall survival showed that 86% of patients in the combination arm were alive at 3 years versus 77% with placebo. However, at the interim analysis, the OS advantage was not yet deemed statistically significant.

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

The European Commission has approved blinatumomab for the treatment of pediatric patients with Philadelphia chromosome–negative, CD19-positive B-cell precursor acute lymphoblastic leukemia that is refractory or in relapse after receiving at least 2 prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation.

The approval was based on data from the single-arm phase I/II Study 205 trial, which met its primary phase II endpoint of complete remission within the first 2 cycles of blinatumomab. Overall, 20 patients had a CR or CR with partial hematologic recovery within 2 treatment cycles. Eighty-five percent of the responses occurred within the first cycle.

In September 2016, the FDA approved blinatumomab for use in this setting based on the same study. At the time of the approval, it was reported that the most common grade 3 or higher adverse events receiving the recommended dose were anemia, thrombocytopenia, febrile neutropenia, hypokalemia, and neutropenia.

In June 2018, the European Commission granted blinatumomab full marketing authorization for the treatment of adult patients with Ph- relapsed/refractory B-cell precursor ALL. The agency had previously awarded the agent a conditional marketing authorization in this setting in 2015 that was contingent on data from a confirmatory trial.

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

This week, we sat down with Dr Chung-Han Lee, of Memorial Sloan Kettering Cancer Center, to discuss second-line combination therapy in renal cell carcinoma.

That’s all for today.

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

A priority review designation in Merkel cell carcinoma, a breakthrough therapy designation in select RET-altered cancers, an application submitted in pediatric ALL, and European approvals in multiple myeloma, melanoma, and ALL.

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

The FDA has granted a priority review to a supplemental biologics license application for pembrolizumab for the treatment of pediatric and adult patients with recurrent locally advanced or metastatic Merkel cell carcinoma.

The sBLA is based on findings from the phase II KEYNOTE-017 trial, which included 50 patients with metastatic or locally advanced MCC who were treated with at least 1 dose of pembrolizumab in the frontline setting.

At a median follow-up of 14.9 months, the objective response rate per independent review was 56%, including a 24% complete response rate and a 32% partial response rate. An additional 5 patients had stable disease, while 16 patients had progressive disease and 1 patient was not assessed for response.

Moreover, the median progression-free survival was 16.8 months with pembrolizumab, which was higher than historical data for chemotherapy, for which the median PFS ranges from 3.1 to 4.6 months. This was also true for median overall survival, which had not been reached for pembrolizumab versus historical data ranging from 9.5 to 10.2 months with frontline chemotherapy in this disease.

Under the Prescription Drug User Fee Act, the FDA is scheduled to decide on the sBLA by December 28, 2018.

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

The FDA has granted LOXO-292 a breakthrough therapy designation for the treatment of patients with RET fusion–positive non–small cell lung cancer or RET-mutant medullary thyroid cancer.

The breakthrough designation is specifically for the treatment of patients with metastatic RET fusion–positive NSCLC who require systemic therapy and have progressed following platinum-based chemotherapy and an anti–PD-1 or PD-L1 therapy; and for the treatment of patients with RET-mutant MTC who require systemic therapy, have progressed following prior treatment, and have no acceptable alternative treatment options.

The designation is based on data from the ongoing phase I LIBRETTO-001 study, in which the objective response rate was 77% for patients with RET fusion–positive NSCLC. At the April 2018 data cutoff, no patients with NSCLC had developed progressive disease with 90% remaining on treatment with LOXO-292. All patients with measurable intracranial lesions responded to LOXO-292.

In those with RET-mutated MTC, the ORR was 45%, with 1 complete response and 1 additional CR awaiting confirmation. Two patients in this group developed PD and 93% continued to receive treatment with LOXO-292. Moreover, in 2 patients with a resistance mutation in V804M, there was a substantial reduction in tumor size. In 4 enrolled patients with no known activating RET alteration, there was no response with LOXO-292.

In acute lymphoblastic leukemia, the FDA has accepted a supplemental biologics license application for dasatinib in combination with chemotherapy for the treatment of pediatric patients with newly diagnosed Philadelphia chromosome–positive disease.

The application is based on data from the phase II CA180-372 trial, in which pediatric patients with newly diagnosed Ph+ ALL received dasatinib plus a chemotherapy regimen modelled on a Berlin-Frankfurt-Munster high-risk backbone.

Findings presented at the 2017 ASH Annual Meeting showed that the 3-year event-free survival rate for the dasatinib combination was 65.5%, and the 3-year overall survival rate was 91.5%.

The FDA is scheduled to make its decision on the application by December 29, 2018.

Dasatinib previously received an indication by the FDA in November 2017 for the treatment of pediatric patients with Ph+ chronic myeloid leukemia in chronic phase.

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

The European Commission has approved daratumumab for use in combination with bortezomib, melphalan, and prednisone as a treatment for adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

The decision was based on the pivotal, open-label phase III ALCYONE study, in which daratumumab plus VMP led to a 50% reduction in the risk of progression or death versus VMP alone.

In the trial, 706 with newly diagnosed multiple myeloma were randomized to receive VMP alone or in combination with daratumumab. VMP was administered at standard doses and daratumumab was added at 16 mg/kg once weekly in cycle 1 and every 3 weeks in cycles 2 through 9. Beyond month 9 in the investigational arm, daratumumab was continued every 4 weeks until disease progression.

Results also showed that median progression-free survival was 18.1 months in the VMP arm and was not yet reached for those treated with the daratumumab regimen. Follow-up remained ongoing for overall survival at the 16.5-month assessment.

This regimen was approved by the FDA in May 2017.

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

In melanoma, the European Commission has approved the combination of dabrafenib and trametinib for the adjuvant treatment of patients with BRAF V600–positive stage III disease following complete resection.

The approval is based on data from the phase III COMBI-AD study, in which the primary analysis showed that adjuvant treatment with dabrafenib and trametinib reduced the risk of relapse or death by 53% versus placebo for patients with BRAF-mutant stage III melanoma.

After a median follow-up of 2.8 years, the median relapse-free survival was not reached with the combination versus 16.6 months for placebo.

Moreover, RFS was improved with dabrafenib/trametinib across all subgroups. The hazard ratios across all subgroups ranged from 0.33 to 0.55 in favor of dabrafenib and trametinib versus placebo.

Early data for overall survival showed that 86% of patients in the combination arm were alive at 3 years versus 77% with placebo. However, at the interim analysis, the OS advantage was not yet deemed statistically significant.

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

The European Commission has approved blinatumomab for the treatment of pediatric patients with Philadelphia chromosome–negative, CD19-positive B-cell precursor acute lymphoblastic leukemia that is refractory or in relapse after receiving at least 2 prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation.

The approval was based on data from the single-arm phase I/II Study 205 trial, which met its primary phase II endpoint of complete remission within the first 2 cycles of blinatumomab. Overall, 20 patients had a CR or CR with partial hematologic recovery within 2 treatment cycles. Eighty-five percent of the responses occurred within the first cycle.

In September 2016, the FDA approved blinatumomab for use in this setting based on the same study. At the time of the approval, it was reported that the most common grade 3 or higher adverse events receiving the recommended dose were anemia, thrombocytopenia, febrile neutropenia, hypokalemia, and neutropenia.

In June 2018, the European Commission granted blinatumomab full marketing authorization for the treatment of adult patients with Ph- relapsed/refractory B-cell precursor ALL. The agency had previously awarded the agent a conditional marketing authorization in this setting in 2015 that was contingent on data from a confirmatory trial.

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

This week, we sat down with Dr Chung-Han Lee, of Memorial Sloan Kettering Cancer Center, to discuss second-line combination therapy in renal cell carcinoma.

That’s all for today.

Thank you for watching OncLive News Network! I’m Gina Columbus.
 
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: Oncology Best Practice™ Decision Points in Advanced NSCLC: Assessing Treatment Options Beyond Disease ProgressionNov 30, 20181.0
Community Practice Connections™: Precision Medicine for Community Oncologists: Assessing the Role of Tumor-Testing Technologies in Cancer CareNov 30, 20181.0
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