On July 6, 2015 Array BioPharma reported Array BioPharma’s wholly-owned RAF inhibitor, encorafenib, was showcased this past weekend at the 2015 ESMO (Free ESMO Whitepaper) World Congress of Gastrointestinal Cancer during an oral presentation (Press release, Array BioPharma, JUL 6, 2015, View Source;p=RssLanding&cat=news&id=2064825 [SID:1234506165]).

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At the meeting, data were shared from a Phase 1b trial and preliminary data from a 100-patient randomized Phase 2 expansion of that trial testing the combination of encorafenib and cetuximab, an EGFR inhibitor, with or without the addition of alpelisib (BYL719) 1, an investigational PI3K inhibitor in patients with BRAF-mutant colorectal cancer (BRAFmut CRC). Results from the study indicate that these combinations can be administered with good tolerability and show promising clinical activity in this patient population with high unmet medical needs. Patient enrollment is now complete in the Phase 2 study.

The preliminary Phase 2 results show an objective response rate (complete or partial response) and disease control rate (complete or partial response or stable disease) of 29% and 81%, respectively, for patients receiving the combination of encorafenib and cetuximab (encorafenib doublet), and 35% and 79%, respectively, for patients receiving the combination of encorafenib, cetuximab and alpelisib (encorafenib triplet).

Across both the encorafenib doublet and triplet treatment groups, most treatment related adverse events were grade 1 or 2 with few grade 3 or 4 adverse events. The most frequent treatment related adverse events across all grades for the encorafenib doublet were fatigue (36%), nausea (31%), lipase increased (24%), diarrhea (21%) and decreased appetite (21%), while for the encorafenib triplet they were diarrhea (39%), nausea (37%), fatigue (33%) and hyperglycemia (31%).

These results are consistent with the Phase 1b portion of the trial and are encouraging when compared to currently available therapies for BRAFmut CRC patients, as well as with other recently published investigational approaches in this population. Historically, response rates are very low for either single-agent EGFR or RAF inhibitor therapy in patients with BRAFmut CRC, which suggests a synergistic effect for the combination of encorafenib and cetuximab in this population.

"The combination of encorafenib and cetuximab demonstrated promising activity in this hard-to-treat subset of colorectal cancer patients," said Josep Tabernero, M.D., Head of the Medical Oncology Department at the Vall d’Hebron University Hospital and the Director of the Vall d’Hebron Institute of Oncology. "It is critical to identify new, effective treatments for BRAF mutant colorectal cancer patients, and I look forward to rapid development of this combination in a subsequent clinical trial."

1 alpelisib (BYL719) is an investigational Novartis Pharmaceuticals compound.

About Colorectal Cancer
Colorectal cancer is the third most common cancer among men and women in the United States, with approximately 132,000 new cases and nearly 50,000 deaths from the disease projected in 2015. BRAF mutations occur in approximately 10% percent of patients with colorectal cancer and predict for a poor response to standard therapies and an overall poorer prognosis relative to patients without these mutations.

About RAF and encorafenib
RAF is a key protein kinase in the MAPK signaling pathway that regulates several key cellular activities including proliferation, migration, survival and angiogenesis. Inappropriate activation of this pathway has been shown to occur in many cancers, such as melanoma, colorectal, lung and thyroid cancers. Encorafenib is a selective, small molecule, oral inhibitor which targets the RAF enzyme in this pathway. It is currently being developed in eleven active clinical trials, including the COLUMBUS trial, a Phase 3 study of encorafenib and binimetinib (MEK inhibitor) for patients with BRAF mutant melanoma. Array expects updated BRAF melanoma data from the Phase 2 combination trial (LOGIC-2) of binimetinib, encorafenib and a third agent (LEE011, BKM120, BFJ398 or INC280) will be submitted to a scientific conference later this year.

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