This article is more than 5 years old. Information may no longer be current.
Combined BRAF, MEK inhibition improves survival in advanced, mutated melanoma
The addition of cobimetinib to vemurafenib improved survival outcomes among patients with advanced BRAFV600–mutated melanoma, according to updated results from the phase 3 coBRIM trial.
This combination should be considered a standard first-line treatment for these patients, according to researchers.
Nikhil I. Khushalani
Vernon K. Sondak
“Around 40% of cutaneous melanomas harbor mutations in the BRAF gene, resulting in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway,” Grant A. McArthur, MBBS, PhD, professor of medicine at University of Melbourne and director of the skin and melanoma service at Peter MacCallum Cancer Centre, and colleagues wrote. “The treatment of advanced BRAF–mutant melanoma has been revolutionized by the introduction of new therapeutic agents, such as the BRAF inhibitors vemurafenib [Zelboraf, Genentech] or dabrafenib [Tafinlar, Novartis].”
Acquired resistance to BRAF inhibitor monotherapy is a frequent cause of treatment failure in this patient population, which has led researchers to consider combined treatment with BRAF and MEK inhibitors.
Initial results of the double blind, randomized coBRIM trial showed vemurafenib plus the MEK inhibitor cobimetinib [Cotellic, Genentech] improved PFS compared with vemurafenib and placebo among previously untreated patients. In the current analysis, McArthur and colleagues evaluated OS and safety after longer follow-up.
The study included data from 495 patients with a confirmed diagnosis of unresectable stage IIIC or stage IV BRAFV600–mutated melanoma.
The researchers randomly assigned patients to 960 mg twice-daily oral vemurafenib plus 60 mg daily cobimetinib (n = 247; median age, 56 years; range, 23-88) or placebo (n = 248; median age, 55 years; range, 25-85).
Patients received cobimetinib or placebo for the first 21 days of a 28-day treatment cycle, followed by a 7-day rest period. Treatment continued until patient withdrawal, disease progression or unacceptable toxicity.
PFS served as the study’s primary endpoint. OS served as the secondary endpoint.
Median follow-up was 14.2 months (interquartile range [IQR], 8.5-17.3).
Patients assigned cobimetinib and vemurafenib demonstrated a median PFS of 12.3 months (95% CI, 9.5-13.4), compared with 7.2 months (95% CI, 5.6-7.5) for vemurafenib and placebo (HR = 0.58; 95% CI, 0.46-0.72).
A confirmed objective response occurred in 70% (n = 172) of patients assigned cobimetinib and vemurafenib and 50% (n = 124) of patients assigned vemurafenib and placebo.
Median duration of response was 13 months (95% CI, 11.1-16.6) in the cobimetinib arm and 9.2 months (95% CI, 7.5-12.8) in the placebo arm.
Disease progression occurred in 49% (n = 84) of responding patients in the cobimetinib arm and 59% (n = 73) of responding patients in the placebo arm.
The researchers conducted an OS analysis after 52% (n = 255) of patients died. The median follow-up for this analysis was 18.5 months (IQR, 8.5-23.5).
Median OS was 22.3 months (95% CI, 20.3-not estimable) among patients assigned cobimetinib and vemurafenib, compared with 17.4 months (95% CI, 15-19.8) among patients assigned vemurafenib and placebo.
Nearly all patients experienced at least one adverse event; serious adverse events occurred in 92 patients (37%) assigned cobimetinib and vemurafenib and 69 patients (28%) assigned vemurafenib and placebo.
Grade 3 or worse adverse events that occurred more frequently in the cobimetinib arm included gamma-glutamyl transferase increase (cobimetinib vs. placebo, 15% vs. 10%), blood creatine phosphokinase increase (12% vs. < 1%) and alanine transaminase increase (11% vs. 6%).
Serious adverse events in the cobimetinib group included pyrexia (n = 6; 2%) and dehydration (n = 5; 2%).
A total of 259 patients have died (cobimetinib, n = 117; placebo, n = 142). Disease progression served as the most common cause of death in both arms (cobimetinib, n = 109; placebo, n = 133).
“The combination of cobimetinib and vemurafenib was recently approved by the U.S. FDA and the European Medicines Agency for the treatment of advanced BRAFV600–mutant melanoma and represents a new standard of treatment for patients with this disease,” McArthur and colleagues wrote.
The updated reports from the coBRIM trial add valuable knowledge to the growing body of literature on the treatment of advanced melanoma, Nikhil I. Khushalani, MD, medical oncology at Moffitt Cancer Center, and Vernon K. Sondak, MD, chair of the department of cutaneous oncology and director of surgical education, Moffitt Cancer Center, as well as a HemOnc Today Editorial Board member, wrote in an accompanying editorial.
“First, no additional safety concerns were reported with longer administration, reassuring us that chronic BRAF–MEK inhibition is safe,” Khushalani and Sondak wrote. “Second, the number of complete responses in this report is higher than initially reported (ie, in the cobimetinib and vemurafenib group, an increase from 25 [10%] of 247 at the primary analysis to 39 [16%] of 247 in the updated analysis), showing that delayed conversion from partial to complete response is possible with these agents — something we believed was seen mainly or exclusively with immunotherapy.”
However, further research is needed to regularly improve outcomes for patients with advanced melanoma.
“[I]f we are to realize hopes of routinely achieving cures in this disease, we need to better understand the interplay between host and tumor factors through trials going beyond the existing approved standards,” Khushalani and Sondak wrote. “International collaboration, as was evident in coBRIM, is a key step in this direction. Now local collaboration is needed, between community oncologists who finally have viable methods to treat advanced melanoma, academic clinical trialists, and translational researchers who are aiming for something once viewed as unattainable.” – by Cameron Kelsall
Disclosure: Genentech/Roche provided funding for this study. McArthur reports grants from Celgene, Pfizer and Ventana, as well as a consultant role with Provectus, outside the submitted work. Please see the full study for a list of all other researchers’ relevant financial disclosures. Khushalani reports grants and/or personal fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Castle Biosciences, Merck, the National Comprehensive Cancer Network, Novartis and Prometheus outside the submitted work. Sondak reports personal fees from Amgen, Array, Bristol-Myers Squibb, Genentech/Roche, Merck, Novartis, Pfizer, Polynoma and Provectus outside the submitted work.
Editor’s Note: On Sept. 1, we corrected the body of this article to clarify that the median age of the patients was different in each treatment group. We also clarified that the researchers reported median duration of response. The Editors regret these errors.