Array Rises As COLUMBUS Clears Phase III Melanoma Hurdle
Executive Summary
Shares in Array Biopharma shot up by more than 80% on the release of top-line Phase III data from its COLUMBUS study of encorafenib and binimetinib, but more details are needed to gauge how the combination may fare against Novartis and Roche’s more established combos, and the newer IO therapies.
Early data from the Phase III COLUMBUS study looking at a combination of Array BioPharma Inc.’s BRAF inhibitor encorafenib (LGX818) and MEK inhibitor binimetinib (MEK162) proved positive, sending the company's stock price soaring, though more information is needed to assess the competitive prospects for what would be the third BRAF/MEK inhibitor duo to market.
Top-line data from the first part of the Phase III study in patients with BRAF-mutant advanced, unresectable or metastatic melanoma met its primary endpoint, significantly improving progression-free survival (PFS) with encorafenib/binimetinib compared with Roche/Genentech Inc.’s BRAF inhibitor Zelboraf (vemurafenib) alone.
The news sent Array’s share price up by 81% to close at $6.61 on Sept. 27 on NASDAQ, even though the products will be entering an increasingly crowded market.
In the multinational study, 1,577 patients were randomized to receive 450 mg encorafenib plus 45 mg binimetinib, or 300 mg encorafenib alone, or 960 mg vemurafenib. The median PFS for patients treated with the combination of encorafenib plus binimetinib was 14.9 months versus 7.3 months for patients treated with vemurafenib (p<0.001). However, the secondary endpoint analysis comparing the combination to patients treated with encorafenib alone showed a median PFS of 14.9 months versus 9.6 months (p=0.051), a non-significant difference.
The combination was generally well-tolerated with adverse events consistent with previous combination encorafenib plus binimetinib clinical trial results in BRAF-mutant melanoma patients, Array said.
Array gained rights to both products (or regained in the case of binimetinib) under attractive terms from Novartis AG in the months before the Swiss firm completed its ground-breaking asset-swapping deal with GlaxoSmithKline PLC in 2015, which brought it the MEK inhibitor Mekinist (trametinib) and BRAF inhibitor Tafinlar (dabrafenib). (Also see "Array paying next to nothing for Novartis BRAF inhibitor" - Scrip, 24 Jan, 2015.) Later that year, Array signed up private French company Pierre Fabre Group as a development and commercialization partner for the two drugs in Europe and emerging markets.
Neither encorafenib nor binimetinib is currently approved, although Array submitted an NDA for binimetinib monotherapy in patients with advanced NRAS-mutant melanoma (a relatively small indication) in June based on the positive results of the pivotal Phase III NEMO study. A user fee goal date is set for June 30, 2017. (Also see "Array Rises On Binimetinib Data, 2016 Regulatory Submissions" - Scrip, 17 Dec, 2015.)
If approved, the Array combination will encroach on territory held by Novartis's Mekinist and Tafinlar, which are approved alone and in combination with each other to treat unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation, as well as by Roche’s similar MEK/BRAF combination of Zelboraf with its MEK inhibitor Cotellic (cobimetinib). (Also see "Will Genentech's Cotellic Survive Alternative Pricing Demands?" - Scrip, 11 Nov, 2015.)
But all of these therapy duos are expected struggle in the melanoma market against the immunotherapies, namely the PD-1 inhibitors, Bristol-Myers Squibb Co.’s Opdivo (nivolumab) and Merck & Co. Inc.’s Keytruda (pembrolizumab), given their strong efficacy and rapid uptake in the disease.
“Looking ahead, the real issue the combination therapy will face is the steady march of PD-1 immunotherapies into melanoma," according to analysts at Informa Pharma Intelligence's Biomedtracker. "Officials even acknowledged that anti-PD-1s are becoming the preferred front-line treatment, even for BRAF mutant patients. Nevertheless, a targeted treatment to this biomarker-defined population would likely experience good uptake as well.”
No Overall Survival Data, Yet
The Biomedtracker analysts say the data for Array’s combination so far are positive overall despite the fact that some key details remain unknown and not expected to be forthcoming in the short term. In particular, they mean the overall survival (OS) results that Array said may not be disclosed until after the regulatory submission is filed. The analysts say it is likely that the OS results would be required for approval. Overall survival data is included in the labeling for all of the other BRAF and MEK inhibitors.
They added that the failure of the combination to differentiate from the encorafenib monotherapy arm complicated the positive results. “This is not likely to pose much barrier to approval, but it does not help in the general understanding of how much each individual agent is contributing to the combination,” the analysts said.
This comparison will be made again in Part 2 of the study, which is comparing the same encorafenib dose in the monotherapy and combination (i.e., 300 mg vs 300 mg plus 45 mg) in 344 patients to provide additional data to help evaluate the contribution of binimetinib to the combination. Data from Part 2 of the COLUMBUS trial are anticipated in mid-2017, and the results of both parts of the study will be submitted to regulators as part of the approval filings.
Array says further results from COLUMBUS Part 1, including objective response rates and disease control rates, will be presented at an upcoming medical meeting, but the secondary endpoint analysis of OS was not planned as part of these initial results.