Vemurafenib/Cobimetinib Extends PFS in Phase III Melanoma Study

Sandra Horning, MD

The combination of the BRAF inhibitor vemurafenib (Zelboraf) and the MEK inhibitor cobimetinib significantly improved progression-free survival (PFS) compared with vemurafenib alone for patients with untreated BRAFV600-mutated advanced melanoma, according to topline results from the phase III coBRIM study.

Genentech and Exelixis, the companies collaborating on the combination’s development, released the positive results in joint press releases. Full data from the study will be presented at a medical meeting later this year. Additionally, Genentech announced that it plans to submit an application to the FDA.

“Despite great progress in our understanding and therapy in recent years, advanced melanoma remains a difficult and deadly disease that requires more treatment options,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Roche, said in a statement. “These encouraging data support the potential combined use of cobimetinib with Zelboraf to block tumor growth longer than Zelboraf alone. We hope this combination therapy will lead to a new option for patients.”

The phase III coBRIM study was launched in 2012 and compared cobimetinib plus vemurafenib to single-agent vemurafenib in previously untreated BRAFV600 mutation-positive patients with unresectable locally advanced or metastatic melanoma.

The study randomized 495 patients to continuous vemurafenib at 960 mg twice daily plus placebo or continuous vemurafenib at 960 mg twice daily plus cobimetinib at 60 mg once daily on days 1-21 of a 28-day cycle. The primary endpoint for the study was PFS, with secondary endpoints focused on overall survival (OS), objective response rate (ORR), and duration of response.

In a preceding open-label phase Ib trial, 66 vemurafenib-refractory patients and 63 BRAF inhibitor-naïve patients with BRAFV600 mutation-positive metastatic melanoma were treated with the combination. Results from this analysis were presented in May at the 10th European Association of Dermato Oncology Congress in Vilnius, Lithuania.

In treatment-naïve patients, the median PFS was 13.7 months and the ORR was 87%, with 10% achieving a complete response. Additionally, 10% of patients had stable disease, for a disease control rate of 97%. The median OS had not been reached after a median 12.7-month follow-up. The 1-year survival estimate was 83%.

In patients refractory to vemurafenib, the median PFS was 2.8 months and the median OS was 8.3 months, with an estimated 1-year survival of 32%. ORR was 15% and 42% of patients achieved stable disease.

The most common all-grade adverse events were diarrhea (64%), non-acneiform rash (60%), fatigue (48%), nausea (45%), liver laboratory test abnormality (40%), and photosensitivity/sunburn (40%). The most frequently reported grade ≥3 adverse events were liver laboratory test abnormality (11%), cutaneous squamous cell carcinoma (9%), non-acneiform rash (8%), anemia (7%), joint pain (6%), fatigue (5%), and diarrhea (5%).

“Despite recent therapeutic innovations, BRAFV600 mutation-positive advanced melanoma can be difficult to treat due to the emergence of resistance," Michael M. Morrissey, PhD, president and chief executive officer of Exelixis, said in a statement. "We look forward to the full presentation of the data later this year. If ultimately approved, we will execute on our collaborative US copromotion effort with Genentech and work alongside our partner to bring this important new therapeutic option to melanoma patients in need.”

The dual inhibition of both MEK and BRAF is thought to circumvent treatment resistance that commonly occurs with single-agent therapy. Moreover, this combination is thought to reduce the incidence of secondary skin cancers associated with BRAF-targeted monotherapy.

In January 2014, the FDA approved the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) for patients with unresectable or metastatic melanoma who harbor a BRAF V600E or V600K mutation. This approval was based on an open-label phase I/II trial that demonstrated a 9.4-month PFS with the combination compared with 5.8 months for dabrafenib alone. In the phase III COMBI-d study, the median PFS was 9.3 versus 8.8 months (HR = 0.75; P = .035) and the median ORR was 67% versus 51%, for the combination versus dabrafenib monotherapy, respectively.