ESMO 2014: Cobimetinib in Combination with Vemurafenib Improves PFS in BRAF-Mutant Unresectable Locally-Advanced or Metastatic Melanoma

Results of a phase III study in previously untreated patients with BRAFV600 mutation-positive melanoma

coBRIM, a phase III, double-blind, placebo-controlled study of vemurafenib vs vemurafenib plus cobimetinib in previously untreated patients with BRAFV600 mutation-positive unresectable locally-advanced or metastatic melanoma met its primary endpoint. Cobimetinib in combination with vemurafenib significantly improved progression-free survival (PFS) among patients with BRAFV600-mutant tumours. The results were reported by Prof. Grant McArthur of the Cancer Therapeutics, Peter MacCallum Cancer Centre, Melbourne, Australia in the Presidential Symposium 2 during ESMO Congress 2014 in Madrid, Spain.

Combined inhibition of BRAF and MEK is hypothesised to improve clinical outcomes by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. The most common mechanism of acquired resistance to vemurafenib is MAPK reactivation through MEK. MEK plus BRAF inhibition prevents the development of acquired resistance in preclinical models. Dabrafenib plus trametinib in phase III and vemurafenib plus cobimetinib in phase I/II study improved response rates and PFS in BRAF inhibitor–naive melanoma patients. Reduced incidence of hyperproliferative lesions is seen by blocking paradoxical activation of the MAPK pathway from RAF inhibition.

This randomised phase III study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. Cobimetinib is an oral, small molecule, highly selective, allosteric inhibitor of MEK.  

Between January 2013 and January 2014, 495 patients were randomly assigned (1:1) to receive vemurafenib/cobimetinib or vemurafenib/placebo. In a 28-day treatment cycle, vemurafenib was administered at 960 mg twice daily from days 1 to 28 and cobimetinib or placebo was administered at 60 mg daily from days 1 to 21.

The study eligibility criteria included treatment-naive patients with BRAFV600 mutation–positive (detected by cobas® 4800) unresectable locally-advanced or metastatic melanoma, adequate performance status (PS) and organ function, and no prior therapy for advanced disease. The treatment was foreseen until disease progression, unacceptable toxicity, or withdrawal of consent. The patients were stratified by geographic region and extent of disease (M1c vs other).

The MEK inhibitor cobimetinib in combination with the BRAF-inhibitor vemurafenib improves progression free survival compared to vemurafenib alone in patients with BRAFV600-mutated melanoma

The MEK inhibitor cobimetinib in combination with the BRAF-inhibitor vemurafenib improves progression free survival compared to vemurafenib alone in patients with BRAFV600-mutated melanoma. © Grant McArthur

The primary endpoint was investigator-assessed PFS. Secondary endpoints included overall survival (OS), objective response rate, duration of response, PFS assessed by Independent Radiology Committee (IRC), safety, pharmacokinetics, quality of life assessed by QLQ-C30 and EQ-5.

Statistical assumptions were 95% power to detect an improvement in median PFS from 6 to 11 months (hazard ratio, HR = 0.55) and 80% power to detect an improvement in median OS from 15 to 20 months (HR = 0.75).

Patient characteristics were well balanced, except PS 1 that was slightly higher in the vemurafenib plus placebo arm.

Prof. McArthur reported that median investigator-assessed PFS was 9.9 months with the combination compared with 6.2 months in the control arm (HR 0.51; p < 0.0001). Investigators-assessed PFS based on key demographic and tumour characteristics were consistent with PFS in the intent-to-treat population. The PFS assessed by independent review was comparable with investigator-assessed PFS (11.3 months vs 6.0 months, HR 0.60, p = 0.0003).

The rate of complete and partial responses was 68% in the combination arm and 45% in the vemurafenib arm (p < 0.0001), including complete response in 10% of patients treated with the combination and 4% of patients in the vemurafenib group.

9-months OS rate was 81.1% in the combination arm vs 72.5% in the vemurafenib arm (HR 0.65, p= 0.046).

Vemurafenib/cobimetinib combination, compared with vemurafenib alone, was associated with a higher incidence of grade ≥ 3 adverse events (65% vs 59%). However, there was no difference in the rate of adverse events leading to study drug discontinuation.

The study investigators found a decrease in the occurrence of secondary cutaneous neoplasms with the combination treatment.

A rate of grade 1 and 2 serous retinopathy (includes specific terms chorioretinopathy and retinal detachment) was higher in the cobimetinib/vemurafenib arm, but there were no cases of retinal veinocclusion reported. In the combination arm, there was also higher rate of grade 2 of decreased ejection fraction.

Conclusion

Prof. McArthur concluded that the coBRIM study provides clear and definitive evidence that combined BRAF and MEK inhibition results in improved clinical outcomes. The combination of vemurafenib plus cobimetinib vs vemurafenib alone resulted in 49% reduction in risk of progression. Interim OS showed a reduction in risk of death of 35%. The study is ongoing to evaluate mature OS.

Prof. McArthur said that the study results are published simultaneously with the presentation at the ESMO 2014 Congress in the New England Journal of Medicine.

Dr Christian Blank, who discussed the study results, congratulated the authors and said that confirmed objective response of 68% as well as complete response rate of 10%, partial response rate of 58% and stable disease seen in 20% of patients in the coBRIM study are in line with the results from other dual-MAPK targetting. The resemblance between the arms in the coBRIM study showed a higher ECOG PS 0 rate in vemurafenib and cobimetinib treated patients. Progression-free survival and overall survival were more favourable in the vemurafenib and cobimetinib arm. However, overall survival data were immature at the time of presentation.

coBRIM confirms improved efficacy for combinations of BRAF inhibitor and MEK inhibitor as compared to single BRAF inhibition in BRAFV600 mutant melanoma. The combination therapy lead to decreased toxicity occurring from paradoxical MAPK pathway activation in BRAF wild-type cells. Vemurafenib and cobimetinib toxicity is similar to the toxicity observed from single treatment. If the mature data confirm the presented observations, BRAF and MEK inhibition would be the new standard targeted therapy in BRAFV600 melanoma.

Reference

Abstract LBA5_PR - Phase 3, Double-blind, Placebo-controlled Study of Vemurafenib Versus Vemurafenib + Cobimetinib in Previously Untreated BRAFV600 Mutation-Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma (NCT01689519)

James Larkin, Paolo A. Ascierto, Brigitte Dréno, et al. Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma. NEJM 2014; published online September 29. DOI: 10.1056/NEJMoa1408868

The coBRIM study was sponsored by F. Hoffmann-La Roche, Ltd. Cobimetinib is being developed by Genentech, Inc, a member of the Roche Group, under a collaboration agreement with Exelixis.