Patients with BRAF-mutant colorectal cancer respond poorly, if at all, to BRAF inhibitors such as vemurafenib. Research has shown that this is likely due to rapid feedback activation of EGFR, and investigators are exploring dual suppression of BRAF and EGFR, with or without PI3K inhibition, as a new therapeutic avenue.

The BRAF V600E mutation, well documented in melanoma, is also present in approximately 8% of patients with colorectal cancer. However, whereas BRAF inhibitors like vemurafenib (Zelboraf; Genentech) are highly effective for the treatment of melanoma, their benefit as monotherapy in BRAF-mutant colorectal cancer is limited at best.

“This type of metastatic colorectal cancer has a very poor prognosis compared to BRAF–wild-type disease,” says Josep Tabernero, MD, PhD, director of the Vall d'Hebron Institute of Oncology in Barcelona, Spain.

At the recent 2014 Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, sponsored by the European Organization for Research and Treatment of Cancer, the NCI, and the American Association for Cancer Research, Tabernero presented data from a multicenter phase I study in which patients were treated with a combination of encorafenib (LGX818; Novartis), an investigational BRAF inhibitor, and the EGFR inhibitor cetuximab (Erbitux; Bristol-Myers Squibb). The researchers also tested a combination of encorafenib, cetuximab, and a third drug, alpelisib (BYL719; Novartis), an investigational PI3K inhibitor.

The decision to target BRAF and EGFR simultaneously was spurred by research showing that BRAF inhibition in colorectal cancer cell lines leads to rapid feedback activation of EGFR, resulting in constitutive signaling through the MAPK–ERK pathway and continued tumor cell proliferation. “This finding could explain the limited efficacy of BRAF inhibitor monotherapy in these patients,” Tabernero says.

In addition, “according to TCGA [The Cancer Genome Atlas] data, the PI3K pathway is dysregulated in roughly 30% of cases, so we decided to add alpelisib to the combination.”

Fifty-four patients with BRAF-mutant colorectal cancer enrolled in the study; 26 received encorafenib and cetuximab, and 28 received encorafenib, cetuximab, and alpelisib. The objective response rates for the two- and three-drug combinations were 23% and 32%, respectively. The median progression-free survival (PFS) was 3.7 months for patients on dual therapy and 4.3 months for those given the trio. Although not directly compared in this study, Tabernero notes that these PFS times are almost double those seen with standard therapy. The dual therapy's main adverse effects included fatigue and infusion reactions; adding alpelisib also caused nausea and diarrhea.

So far, the study's findings “suggest that PI3K activation may not play a clinically significant role,” Tabernero says. However, he adds, these are only preliminary efficacy data, and the question of PI3K's significance remains to be definitively resolved.

The trial is now enrolling patients into a phase II expansion cohort. Investigators are also collecting tumor and blood samples from patients before and after treatment to assess the drugs' pharmacodynamic effects, while a comprehensive genomic analysis is under way to potentially identify predictive biomarkers.

“We're encouraged by what we've found so far,” Tabernero says. “This study is an example of how understanding tumor biology is highly relevant when it comes to improving therapeutic strategies.”

For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.

©2015 American Association for Cancer Research.
2015