Cobimetinib–Vemurafenib ‘Clear, Definitive Benefit’ For Advanced BRAFV600-Positive Melanoma

coBRIM study findings support the first-line use of cobimetinib and vemurafenib for patients with advanced melanoma harbouring BRAFV600 mutations

medwireNews: Updated survival results from the coBRIM trial support the combination of the MEK inhibitor cobimetinib and the BRAF inhibitor vemurafenib for the first-line treatment of advanced BRAFV600-mutant melanoma.

After a median follow-up of 14.2 months, median progression-free survival was 12.3 months for patients with unresectable stage IIIC or IV BRAFV600-positive melanoma who were randomly assigned to receive both agents versus 7.2 months for those given vemurafenib plus placebo, with a significant hazard ratio (HR) of 0.58.

And the final overall survival analysis, at which point 52% of the 495 trial participants had died, demonstrated significantly longer median overall survival with cobimetinib plus vemurafenib than vemurafenib plus placebo, at 22.3 versus 17.4 months and an HR of 0.70.

“These data confirm the clear and definitive clinical benefit of the addition of cobimetinib to vemurafenib”, say Grant McArthur, from the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia, and co-authors in The Lancet Oncology.

They describe the safety profile of cobimetinib plus vemurafenib as “tolerable and manageable”, with similar patient-reported quality of life to that for vemurafenib plus placebo.

Serious adverse events were more common with cobimetinib plus vemurafenib than in the vemurafenib plus placebo group (37 vs 28%), with grade 3 or more severe side effects occurring in 60% and 52%, respectively.

Side effects resulted in discontinuation in 14% of patients given cobimetinib plus vemurafenib and 7% of those given vemurafenib plus placebo; aspartate aminotransferase elevation and gamma-glutamyl transferase increase plus fatigue were the most common reasons given, respectively.

The authors of an accompanying comment say the coBRIM study results add “four key messages” to existing knowledge, including the reassurance, in the absence of new safety signals, that “chronic BRAF–MEK inhibition is safe”.

Nikhil Khushalani and Vernon Sondak, from Moffitt Cancer Center in Tampa, Florida, USA, note that the number of complete responses increased from 10% at the primary analysis to 16% in this updated report, “showing that delayed conversion from partial to complete response is possible with these agents – something we believed was seen mainly or exclusively with immunotherapy.”

However, the commentators observe that disease progression continued, which “reinforces concerns about whether cure is possible with the use of targeted agents, and emphasises the need to define the optimal sequencing of targeted therapy and immunotherapy in patients who are candidates for both”.

Indeed, they note that many of the patients given second-line therapy after progression in the coBRIM trial received ipilimumab, which has shown poor efficacy after failure of targeted treatment, possibly related to changes in tumour kinetics or the immune microenvironment after MAPK inhibition.

Nikhil Khushalani and Vernon Sondak hypothesise that “it might be more prudent to use anti-PD1-based treatment first, reserving targeted agents for second-line therapy”.

“Alternatively, identification of resistance to MAPK inhibition before it becomes clinically apparent would be a game-changer, enabling us to switch therapy before the point of no return”, they suggest.

“Trials assessing the combination and sequencing of available agents are crucial.” 

References

Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 2016; Advance online publication 29 July. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30122-X

Khushalani NI, Sondak VK. Are we there yet? Prolonged MAPK inhibition in BRAFV600-mutant melanoma. Lancet Oncol 2016; Advance online publication 29 July. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30368-0

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