On February 19, 2015 Roche reported that the U.S. Food and Drug Administration (FDA) has accepted and granted priority review for the company’s New Drug Application (NDA) for cobimetinib in combination with Zelboraf (vemurafenib) for the treatment of people with BRAF V600 mutation-positive advanced melanoma (Press release Hoffmann-La Roche , FEB 18, 2015, View Source [SID:1234501708]). The FDA will make a decision on approval by August 11, 2015.

“We are pleased the FDA has accepted our application for cobimetinib in combination with Zelboraf and granted it priority review status,” said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. “We look forward to working with the FDA to bring this new treatment option to people with BRAF mutation-positive advanced melanoma as soon as possible.”

A priority review designation is granted to medicines that the FDA determines have the potential to provide significant improvements in the treatment, prevention or diagnosis of a disease. The NDA is based on results of the coBRIM Phase III study, which showed the MEK inhibitor cobimetinib plus Zelboraf reduced the risk of disease worsening or death by half in people who received the combination (hazard ratio [HR]=0.51, 95 percent confidence interval [CI] 0.39-0.68; p<0.0001), with a median PFS of 9.9 months for cobimetinib plus Zelboraf compared to 6.2 months with Zelboraf alone. The safety profile was consistent with a previous study of the combination. The most common Grade 3 or higher adverse events in the combination arm included liver lab value abnormalities, elevated creatine phosphokinase (CPK, an enzyme released by muscles) and diarrhea. The most common adverse events seen in the combination arm included diarrhea, nausea, rash, photosensitivity and lab value abnormalities.

On February 18, 2015 Seattle Genetics reported that it has submitted a supplemental Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) based on data from the phase 3 AETHERA trial of ADCETRIS (brentuximab vedotin) as consolidation therapy immediately following an autologous stem cell transplant (ASCT) in Hodgkin lymphoma (HL) patients at high risk of relapse (Press release Seattle Genetics, FEB 18, 2015, View Source [SID:1234501704]). ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, which is expressed in classical HL and systemic anaplastic large cell lymphoma (sALCL). ADCETRIS is approved in relapsed HL and sALCL but is currently not approved for consolidation therapy in HL patients immediately after ASCT.

“With approximately half of all Hodgkin lymphoma patients who undergo an autologous stem cell transplant experiencing disease relapse, there is a significant need to identify regimens that extend progression-free survival,” said Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. “Results from the AETHERA trial demonstrated that treating high risk Hodgkin lymphoma patients with ADCETRIS in following autologous stem cell transplant resulted in a statistically significant improvement in progression-free survival with a manageable safety profile. We believe that this is clinically meaningful and supports a label expansion for ADCETRIS in this setting.”

The supplemental BLA is based on positive results from a phase 3 clinical trial called AETHERA that were presented at the 56th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2014. Results from the AETHERA trial in 329 HL patients at high risk of relapse included:

The trial achieved its primary endpoint and demonstrated a significant increase in progression-free survival (PFS) per independent review facility, with a hazard ratio of 0.57 and a p-value of 0.001. Median PFS was 43 months for patients who received ADCETRIS versus 24 months for patients who received placebo. The two-year PFS rate was 63 percent in the ADCETRIS arm compared to 51 percent in the placebo arm.
The PFS benefit was consistent across all pre-specified subgroups, including primary refractory patients, patients who relapsed within twelve months of frontline therapy and patients who relapsed after twelve months with extranodal disease.
The most common adverse events in the ADCETRIS arm were peripheral sensory neuropathy (56 percent), neutropenia (35 percent), upper respiratory tract infection (26 percent), fatigue (24 percent) and peripheral motor neuropathy (23 percent). The most common adverse events in the placebo arm were upper respiratory tract infection (23 percent), fatigue (18 percent), peripheral sensory neuropathy (16 percent), cough (16 percent) and neutropenia (12 percent). Eighty-five percent of patients with peripheral neuropathy on the ADCETRIS arm had resolution or improvement in symptoms with a median time to improvement of 23.4 weeks.

Submission of safety data from the AETHERA trial to the FDA is a post-marketing requirement that Seattle Genetics will fulfill with this submission of the supplemental BLA.