Combined Inhibition of BRAF and MEK Improves Progression-Free Survival in BRAF-Mutated Melanoma

Reported results from the coBRIM study have shown that combining the BRAF inhibitor vemurafenib with cobimetinib, a MEK inhibitor, increases progression-free survival (PFS) in patients withBRAF-mutated advanced melanoma compared with vemurafenib alone.^1,2In addition, although the authors reported a nonsignificant increase in adverse events (AEs) of grade 3 or higher in the combination arm, there was a reduction in the number of keratoacanthomas and cutaneous squamous cell carcinomas observed.

Nearly 50% of malignant melanomas have an activatingV600mutation in theBRAFgene, and clinical trials have demonstrated that administration of BRAF inhibitors, such as vemurafenib and dabrafenib, produces an increase in PFS and overall survival (OS) in patients with mutation-positive cancers. However, rapid emergence of drug resistance and the frequent induction of secondary cutaneous neoplasms, including keratoacanthoma and invasive squamous cell carcinoma, limit the benefits of single-agent therapy with BRAF inhibitors.

“We wondered why it was that we were getting the melanoma to shrink, but another skin cancer was developing,” study coauthor Antoni Ribas, MD, PhD, of the Jonsson Comprehensive Cancer Center, University of California, Los Angeles, said in a statement.³Both the acquired resistance to BRAF inhibitors and the induction of secondary skin tumors are mediated in many instances by the induction of mitogen-activated protein kinase (MAPK) signaling through BRAF-independent pathways. Therefore, the investigators hypothesized that by combining vemurafenib with an inhibitor of MEK, another component of the MAPK cascade, resistance, could be prevented or delayed and secondary tumor induction could be minimized.

A total of 495 patients from the United States, Canada, Australia, New Zealand, Europe, Russia, Turkey, and Israel were enrolled in the coBRIM study. Eligibility was restricted to individuals with unresectable, locally advanced, or metastatic melanoma that had not been previously treated and was positive for aV600mutation of theBRAFgene. Patients were randomized to receive 960-mg vemurafenib twice daily plus either placebo or 60- mg once daily cobimetinib for 21 days followed by 7 days off.

Patients receiving the vemurafenib/cobimetinib combination achieved a significant improvement in median PFS, 9.9 months, compared with 6.2 with vemurafenib alone (hazard ratio [HR] = 0.51;P<.001). An independent review found an increase in median PFS that was similar to the investigator- assessed results; 11.3 months in the combination arm compared with 6.0 months in the control arm (HR = 0.60;P= .0003;Figure 1).

&ldquo;With these results, we&rsquo;ve found a way of circumventing an evasive tactic employed by the cancer to resist the effects of vemurafenib, leading to an extension in PFS that is incredibly important for these patients,&rdquo; study coauthor Grant McArthur, MBBS, PhD, of the Peter Mac-Callum Cancer Centre, Melbourne, Australia, said in a statement.⁴

Response rate, a secondary endpoint, also improved with the BRAF/ MEK inhibitor combination to 68% compared with 45% with vemurafenib alone (P<.0001), and 10% of patients in the combination arm and 4% in the control arm achieved complete responses (Figure 2). An interim analysis demonstrated that 9-month survival rates were 81% with combination therapy and 73% with control therapy, although these data are still immature because the median OS has not yet been achieved in either group.

Hazard ratio of key outcomes with combination vs monotherapy. first-line treatment of BRAF-mutation positive melanoma. Researchers are now also turning their at- tention to the question of whether or not a BRAF/MEK combina- tion could contribute to immunotherapeutic regimens.

The AEs of grade &ge;3 were more common in the group receiving the vemurafenib/cobimetinib combination than in the group receiving vemurafenib alone (65% vs 59%), but this difference was not significant. Neither was there a significant difference in the rate of patients withdrawing from the study because of treatment- related toxicity: 13% in the combination arm com- pared with 12% in the control arm. Patients in the combination arm experienced more gastrointesti- nal AEs such as diarrhea, nausea, and vomiting than those in the control arm, although most of these were grade 1 or 2.

The vemurafenib/cobimetinib combination also reduced the occurrence of grade &ge;3 secondary cutaneous malignancies, a notable side effect of single-agent BRAF inhibitor therapy. Specifically, the incidence of keratoacanthomas dropped from 18% in the control group to 2% in the combination group, while the rate of grade 3 cutaneous squamous cell carcinoma was reduced from 27% to 6%.

Taken together, the results of the coBRIM study demonstrate improved patient outcomes by using a combination of vemurafenib and cobimetinib, and possibly other BRAF/MEK inhibitors, in first-line treatment of BRAF-mutation positive melanoma. Researchers are now also turning their attention to the question of whether or not a BRAF/MEK combination could contribute to immunotherapeutic regimens.

&ldquo;Given the rapid shift toward immunotherapy in melanoma, it is going to be of great interest to see whether these kinds of combinations can be used to enhance response to immunotherapeutic agents like ipilimumab and pembrolizumab,&rdquo; said Ashani Weeraratna, PhD, of the Wistar Institute in Philadelphia, who was not involved in the coBRIM study.

&ldquo;So far, single-agent vemurafenib in combination with ipilimumab has shown significant toxicity, but perhaps the combination of BRAF, MEK, and immunotherapy will overcome this,&rdquo; Weeraratna said.

References

1. Larkin J, Ascierto PA, Dréno B, et al. Combined vemu- rafenib and cobimetinib in BRAF-mutated melanoma. [published online September 29, 2014].N Engl J Med.PMID: 25265494.
2. NIH Clinical Trials registry. ClinicalTrials.gov. http:// clinicaltrials.gov/ct2/show/NCT01689519. Accessed October 29, 2014.
3. Melanoma drug combo improves patient survival rate, decreases risk of harsh side effect [news release]. UCLA&rsquo;s Jonsson Comprehensive Cancer Center website. http://www.cancer.ucla.edu/index. aspx?recordid=750&page=644. Accessed October 29, 2014.
4. Global landmark clinical trial defines new treatment combination for people with advanced melanoma [news release]. Peter MacCallum Cancer Centre website. http:// www.petermac.org/news/global-landmark-clinical-trial- defines-new-treatment-combination-people-advanced- melanoma. Accessed October 29, 2014.