The speed of innovation continues to accelerate in metastatic melanoma and the battle between Roche/Genentech and GlaxoSmithKline (GSK) is heating up. GSK is looking to challenge Zelboraf® (vemurafenib), Roche’s BRAF inhibitor, with its own BRAF targeting molecule, dabrafenib. In addition to BRAF, GSK is looking to make an impact in melanoma with its first-in-class MEK inhibitor, trametinib. At ASCO 2012, GSK presented data from two Phase III trials; the BREAK-3 trial of dabrafenib versus dacarbazine (Hauschild, Abstract LBA8500), and the METRIC trial of trametinib versus chemotherapy (Robert, Abstract LBA8509). With both trials showing strongly positive data, GSK then gave a glimpse into the future of melanoma therapy with the interim results of a Phase I/II trial that examined the combination of dabrafenib plus trametinib in treatment naïve patients with metastatic melanoma (Weber, Abstract 8510). During the melanoma oral session this weekend at the annual ESMO meeting in Vienna, GSK presented updated data from the randomized Part C portion of the Phase I/II study (Long, Abstract LBA27). In this portion, 162 patients were randomized to receive either dabrafenib monotherapy (150 mg BID), or dabrafenib plus trametinib (150 mg BID/1 mg QD), or dabrafenib plus trametinib (150 mg BID/2 mg QD; “full dose”). Overall response rates were 54%, 50%, and 76%, respectively. Of note, in the full dose cohort, the CR rate was 9%. The median PFS was 5.8, 9.2 (HR=0.56, p=0.006), and 9.4 months (HR=0.39, p<0.0001). The rate of squamous cell carcinoma/keratoacanthoma was 7% in the full dose arm, compared to 19% in the dabrafenib alone arm.
In order not to get left behind, in the same melanoma session at ESMO Roche presented Phase Ib data of their own BRAF/MEK combination (Zelboraf plus GDC-0973). The trial included 10 different dosing cohorts as Roche attempted to optimize the regimen for their new combination. The maximum tolerated dose was Zelboraf 960 mg BID and GDC-0973 60 mg QD 21days on/7 days off. Across all doses (n=32), the combination showed reasonable activity in Zelboraf-pretreated patients with a 16% response rate (all partial responses) and a 66% disease control rate. However, the highlight of the presentation was the waterfall plot for the BRAF-inhibitor naïve patients. Although this was a small sample (25 patients), all patients showed benefit from the drug combination and the response rate was estimated to be 88% (Gonzalez, Abstract LBA28). Also, the three patients who did not achieve a partial response were just shy of the 30% reduction cut-off, according to the waterfall plot. With a response rate approaching 90% in this early study, Roche has plenty to be enthusiastic about.
Although data from such a small sampling of patients must be taken with a grain a salt, the contrast between GSK’s combination and Roche’s combination gets interesting when depth of response is considered with the ORR. There were no complete responses in the 25 patients who received Zelboraf plus GDC-0973, while the best response was about a 65% reduction in tumor burden. The impressive ~90% ORR with Roche’s combination is tempered by the fact that dabrafenib/trametinib demonstrated a 9% CR rate in the larger Phase II study. If all of this early data were to hold up in Phase III trials, it would be very interesting to see the marketing battle between a combination with higher response rate versus one with deeper responses.
GSK has a 5-month lead, starting two Phase III trials of dabrafenib/trametinib versus dabrafenib monotherapy and versus Zelboraf monotherapy back in April and May 2012 (NCT01584648 and NCT01597908, respectively). Roche just recently announced plans for a Phase III front-line study of their combination versus Zelboraf alone (NCT01689519), but the trial has yet to begin enrolling patients. In just a few short years melanoma has gone from an oncology afterthought to a crowded battleground; such rapid development should be encouraging to both patients and pharmaceutical companies alike.
By Stephanie Hawthorne, PhD, Director, Commercial Development, Kantar Health and Josh Garcia, Associate Consultant, Kantar Health
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