The melanoma field exploded two years ago, with the 2011 and 2012 approvals of Yervoy® (ipilimumab, Bristol-Myers Squibb) and Zelboraf® (vemurafenib, Genentech/Roche/Daiichi Sankyo). The approval of Zelboraf also ushered in the era of personalized medicine in melanoma, effectively segmenting the market in half – those patients with BRAF V600E mutation (approximately 44% of patients), and those without. In May 2013, the field expanded again following the FDA approvals of Tafinlar® (dabrafenib, GlaxoSmithKline) and Mekinist® (trametinib, GlaxoSmithKline), and one month later the European Medicines Agency (EMA) approval of Tafinlar, for treatment of BRAF-mutant unresectable or metastatic melanoma.
According to Kantar Health’s CancerMPact® Treatment Architecture 2013 data, which was surveyed prior to the recent approvals of Tafinlar and Mekinist, 77% of U.S. and 48% of Western European BRAF-mutant metastatic melanoma patients receive Zelboraf as first-line therapy. However despite impressive responses and improved outcomes, resistance to these agents develops and relapse occurs within six months. In these resistant patients, reactivation of the RAF-MEK-ERK pathway and mutations in MEK have been documented. These observations, coupled with preclinical examination of the hypothesis that targeting both BRAF and MEK simultaneously could provide greater efficacy, more durable responses and reduced toxicity, has led to testing of the combination of BRAF and MEK inhibitors in melanoma patients.
At the 2013 American Society of Clinical Oncology (ASCO) annual meeting, we saw data from a Phase I/II trial of the combination of BRAF and MEK inhibitors (Sosman, Abstract 9005), Tafinlar and Mekinist. The combination had impressive objective response rates (63-76% ORR including 8-9% complete responses, CR) in BRAF inhibitor-naïve patients, nearly additive of the ORRs for the monotherapies (50% for Tafinlar and 23% for Mekinist). The PFS ranged from 9.2 to 9.4 months across all dose cohorts (Flaherty et al., NEJM, 2012). Based on this promising data, we expect the combination data to shift market share away from single agents to the combination of Tafinlar and Mekinist. Indeed, this is already occurring, despite lack of approval for the combination therapy. In late June 2012, Kantar Health surveyed 30 U.S. community oncologists about their preferred choice of first line therapy for BRAF-mutant metastatic melanoma patients. The results show nearly one-fifth of patients receiving the Tafinlar-Mekinist combination off-label.
Genentech/Roche is hoping to capitalize on this trend by testing its own BRAF and MEK inhibitor combination. Updated results for the Phase Ib BRIM7 trial were presented on September 28 at the 2013 European Cancer Congress (ECCO-ESMO-EORTC) annual meeting (McArthur, Abstract 3703), examined the combination of Zelboraf (BRAF inhibitor) and cobimetinib (MEK inhibitor) in 63 Zelboraf-naïve and 65 Zelboraf -resistant patients. In the BRAF inhibitor-naïve patients the ORR was an impressive 85%, including a 10% CR rate. The median PFS had not yet been reached despite 10 months of median follow-up. This updated data from the original 2012 publication reflects a slight strengthening of the data, with ORR remaining similar but now observing complete responses in this larger data set. In patients who had progressed on prior Zelboraf there was only a 15% ORR, identical to what was observed in the GSK combination study. This lack of significant efficacy when using the combination therapy after progression on BRAF inhibitor therapy is a strong argument for using the combination therapies upfront.
Generally, there were more adverse events with the combinations than with the monotherapies (with the notable exception of less squamous cell carcinoma with the combination therapy) and differential toxicity profiles between the two combination regimens. The Tafinlar + Mekinist regimen had higher rates of fever than the Zelboraf + cobimetinib combination (71% and 43%, respectively); the Zelboraf + cobimetinib combination had higher rates of diarrhea (all grades: 81% and 36%, respectively; grade 3/4: 8% and 2%, respectively) and rash (all grades: 89% and 27%, respectively; grade 3/4: 13% and 0%, respectively). The incidence of squamous cell carcinoma was similar between the two regimens (5% grade 3/4).
In terms of efficacy it appears that the Genentech/Roche combination has the advantage; however, the GSK combination has a significant first-mover advantage. Not only are both GSK agents already approved in the U.S., but GSK has already received FDA priority review for accelerated approval of its combination based on the randomized Phase II data, with a Prescription Drug User Fee Act (PDUFA) target date of January 8, 2014. In Europe, the pending approval for Mekinist includes a broad label which includes use in combination with Tafinlar. Further, GSK was the first to initiate two phase III trials in mid-2012 – one in comparison with Tafinlar monotherapy (NCT01584648) and one in comparison with Zelboraf (NCT01597908). Genentech/Roche initiated a trial of their combination against Zelboraf (NCT01689519) six months later, in January 2013, putting it two or more years behind GSK. Will the first-to-market advantage favor the GSK combination? Or will physicians, more familiar with Zelboraf, favor the Genentech/Roche combination? It is too early to predict what the phase III data will show, but it will certainly be a showdown.
By: Stephanie Hawthorne, PhD, Director, Clinical and Scientific Assessment, Kantar Health and Mara Jeffress, PhD, Associate Consultant, Clinical and Scientific Assessment, Kantar Health
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