Findings from a phase I/II study indicate a higher response rate among patients with BRAF-mutant metastatic colorectal cancer treated with an EGFR inhibitor alongside dual, as opposed to single-level, MAPK blockade. Panitumumab combined with trametinib and dabrafenib only modestly increased median progression-free survival, however; a short-lived decrease in responders' BRAF V600E mutant allele fraction and the emergence of RAS mutations may have been contributing factors.

Findings from a phase I/II study indicate a higher response rate among patients with BRAF-mutant metastatic colorectal cancer treated with an EGFR inhibitor alongside dual, as opposed to single-level, MAPK blockade. The data were presented by Ryan Corcoran, MD, PhD, a gastrointestinal cancer specialist at Massachusetts General Hospital in Boston, during the European Society for Medical Oncology's 2016 Congress in Copenhagen, Denmark, October 7–11.

The BRAF V600E mutation is present in approximately 10% of metastatic colorectal cancer cases and “clearly represents a molecular subtype for which new and effective therapies are critically needed,” Corcoran said. Median overall survival for these patients is just 10 months, compared with 30 months for those with BRAF–wild-type disease.

For this colorectal cancer subtype, the response rate to BRAF inhibitors is “only 5%, whereas it's 50% or higher for BRAF-mutant melanoma, illustrating a striking difference in sensitivity between tumor types,” Corcoran added. Preclinically, he and others have shown that in the wake of BRAF inhibition, an adaptive feedback loop reactivates constitutive MAPK signaling and continued colorectal tumor cell proliferation. “EGFR is a major driver of this loop, which is absent in melanoma,” he explained. As such, his team decided to test a trio of therapies against BRAF-mutant colorectal cancer: the EGFR inhibitor panitumumab (Vectibix; Amgen) plus trametinib (Mekinist; GlaxoSmithKline) and dabrafenib (Tafinlar; GlaxoSmithKline), which suppress the MAPK pathway by inhibiting MEK1/2 and BRAF, respectively.

Researchers randomly assigned 142 patients to receive panitumumab and trametinib (P+T); panitumumab and dabrafenib (P+D); or all three drugs. In the P+T arm, no objective responses were seen, and the median progression-free survival (PFS) was 2.6 months. The objective response rates were 10% and 21% in the P+D and triple combination arms, and the median PFS was 3.5 months and 4.2 months, respectively.

When the investigators analyzed circulating tumor DNA (ctDNA) from 24 patients in the three-drug arm after 4 weeks of treatment, they observed that responders had a markedly reduced BRAF V600E mutant allele fraction. This decrease was temporary, however, and its subsequent reversal tracked with disease progression, Corcoran said. Further examining ctDNA from 22 patients whose disease had progressed on triple therapy, he and his group detected RAS mutations in nine, including four different alterations in a single patient. These were not present at the start of treatment and could represent a mechanism of resistance, he observed.

To Volker Heinemann, MD, PhD, director of the University of Munich Comprehensive Cancer Center in Germany, “the rather short-lived decrease in BRAF V600E mutant fraction may explain the less-than-extensive effects on survival” seen with panitumumab plus trametinib and dabrafenib. Despite an improved response rate, Heinemann opined that the modest difference in median PFS may not warrant patients receiving this triple combination.

The study data won't change medical practice, but should stimulate further research, Heinemann added—for instance, profiling BRAF-mutant colorectal tumors for additional molecular features such as microsatellite instability, and determining the clinical relevance of late-emerging RAS mutations. –Alissa Poh

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.