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| Jun 04, 2012
Following decades of frustration and failure, recent advances for the treatment of metastatic melanoma have resulted in approvals of Yervoy (ipilimumab) in 2011 and, for patients with BRAFV600E, Zelboraf (vemurafenib) in 2012. The progress and excitement continues in the treatment of metastatic melanoma with today’s ASCO presentations of data from two Phase III trials sponsored by GSK; the BREAK3 trial of dabrafenib versus dacarbazine (Abstract LBA8500, Hauschild), and the METRIC trial of trametinib versus chemotherapy (Abstract LBA8509, Robert).
BREAK3, is a randomized, Phase III trial designed to compare safety and efficacy of GlaxoSmithKline‘s BRAF inhibitor, dabrafenib (GSK2118436) with dacarbizine (DTIC) in previously untreated patients (except IL-2, radiotherapy and surgery) with advanced (stage III or stage IV) metastatic melanoma. In BREAK3, patients were randomized (3:1) to receive either dabrafenib or DTIC and the primary endpoint was progression-free survival. Median PFS was 5.1 months for the dabrafenib arm versus 2.7 months for DTIC treated patients (p=0.0001; HR=0.30) as determined by investigator assessment. The ORR for the dabrafenib arm was 53% including CRs (3%) and PRs (50%) compared with an ORR of 19% for DTIC. Serious adverse events were observed in 23% and 22% in the respective groups including the 2% incidence of squamous cell carcinoma also observed with Zelboraf.
METRIC is a randomized Phase III trial designed to compare safety and efficacy of GSK’s MEK inhibitor, trametinib (GSK1120212) with chemotherapy (DTIC or paclitaxel) in patients with BRAFV600E/K metastatic melanoma with chemo. In METRIC, patients were randomized (2:1) to receive either trametinib or chemotherapy with the primary endpoint as PFS in BRAFV600E patients. The trametinib arm comprised 186 (86%) patients with V600E mutations and 29 (14%) patients with V600K compared to 97 (90%) patients with V600E mutations and 11 (10%) patients with V600K patients in the chemotherapy arm. The median PFS was 4.8 months versus 1.4 months in favor of trametinib therapy (HR, 95% CI = 0.44; p=0.0001). The confirmed ORR was 22% in the trametinib are versus 8% in the chemotherapy and the preliminary overall survival at 6 months was 85% versus 67%. As previously observed with trametinib, no patients developed squamous cell carcinoma as observed with BRAF inhibitors.
Additionally, extremely promising data was presented from a Phase I/II trial that examined the combination of dabrafenib plus trametinib in treatment naïve patients with metastatic melanoma (Ascierto, Abstract 8511). The rational for this combination is the proposed compensatory increase MEK signal transduction as a possible mechanism of resistance to BRAF inhibition. This study demonstrated that both drugs could be safely administered at full monotherapy dose levels. The ORR was 67% with an impressive median duration of response of 11.3 months and median PFS of 10.8 months. This combination yielded a lower incidence of BRAF-induced squamous cell carcinomas in 3% of patients. Phase III combination studies of dabrafenib and trametinib are ongoing (NCT01584648 and NCT01597908).
Based on data presented today, it is likely that dabrafenib and trametinib will receive regulatory approval though GSK has yet to file for approval. With a somewhat better safety profile than Zelboraf, it will be a worthy competitor in the market and provide a treatment alternative for patients with BRAF mutations. Preliminary data from the combination of dabrafenib and trametinib looks very impressive in terms of safety and efficacy and may ultimately prove superior to the BRAF inhibitor monotherapy. Questions still remain as to sequencing of the new agents in metastatic melanoma, particularly with regard to Yervoy versus BRAF/MEK inhibition. What is clear is that GlaxoSmithKline is staking a major claim to this segment of melanoma following the success of Roche’s Zelboraf.