Survival Advantage With Drug Combination Confirmed in Subset of Patients With Melanoma

Patients with BRAF-positive advanced melanoma saw a 30 percent reduced risk of death with the combination of Cotellic (cobimetinib) and Zelboraf (vemurafenib), compared to treatment with Zelboraf alone, according to the final survival analysis of the phase 3 coBRIM study published in The Lancet Oncology.

The targeted combination improved median overall survival (OS) by 4.9 months versus single-agent Zelboraf. The OS rates for the combination at one and two years were 74.5 percent and 48.3 percent, respectively.

“Melanoma is one of the few cancers that has increased in incidence over the past 30 years, and until recently, people with advanced forms of the disease have had few treatment options. Five years ago, the survival of people with advanced melanoma was measured in months, and now we have medicines that are helping people live years,” Josina Reddy, senior group medical director at Genentech, the company that manufactures the combination, said in an interview with CURE.

“By understanding the biology of the tumor, we are learning how to best combine or sequence targeted medicines to improve outcomes for patients. The combination of Cotellic and Zelboraf was the first treatment to help people with a BRAF mutation live for a year without their disease worsening. The coBRIM overall survival results confirm the combination is an important treatment option for people with BRAF-mutant advanced melanoma,” added Reddy.

The phase 3 coBRIM study included 495 treatment-naïve patients with BRAF V600E/K—positive unresectable locally advanced or metastatic melanoma. Patient demographics were well balanced across the two arms, including disease stage, ECOG performance status, age and geographic region. Over half of the patients had stage 4, M1c melanoma.

Patients were randomized to continuous Zelboraf at 960 mg twice daily plus placebo (248 patients) or Cotellic (247 patients) at 60 mg once daily on days one to 21 of a 28-day cycle. The primary endpoint for the study was progression-free survival (PFS), with secondary outcome measures including OS, objective response rate (ORR), and duration of response.

Median OS was 22.3 months with the combination versus 17.4 months with Zelboraf alone. The median PFS was 12.3 months versus 7.2 months, respectively.

The ORR with Cotellic / Zelboraf was 69.6 percent compared with 50 percent for Zelboraf alone. In the combination arm, 15.8 percent of patients had complete responses versus 10.5 percent with single-agent Zelboraf. The median duration of response was 13 months versus 9.2 months, respectively.

“No new safety signals were observed with the longer follow-up,” said Reddy.

The most frequently reported grade 3/4 adverse events (AEs) in the combination arm versus the control group were gamma-glutamyl transferase increase (15 percent vs 10 percent), CPK increase (12 percent vs less than 1 percent), and ALT increase (11 percent vs 6 percent). Thirty-seven percent of patients in the Cotellic / Zelboraf arm and 28 percent in the single-agent Zelboraf group experienced serious AEs. The most common serious AEs in the combination arm were pyrexia and dehydration, at 2 percent each. There were five deaths related to AEs in the Cotellic arm and 3 in the control arm.

The FDA and European Commission approved the Cotellic / Zelboraf combination in November 2015 as a treatment for patients with BRAF-positive metastatic or unresectable melanoma.

“This continues to be an exciting time to be involved in skin cancer research. Advancements with targeted therapies and immunotherapies both provide important treatment options for patients with advanced melanoma, as each person’s clinical situation is different,” said Reddy.