Since BRAF^V600 somatic mutations were identified in melanoma, clinical and scientific knowledge has evolved rapidly. Matching patients—particularly those with melanomas harbouring these mutations—to either selective BRAF inhibitors (eg, vemurafenib and dabrafenib) or selective MEK inhibitors (eg, trametinib) has induced considerable clinical benefit. Unfortunately, symptomatic and radiographic responses to these agents fade as resistance evolves. Use of a MEK inhibitor with a BRAF inhibitor could delay development of resistance while diminishing the paradoxical activation of the MAPK pathway, which happens in normal (unmutated) tissues.

Inhibition of two targets in the same signalling pathway can seem daunting, since overlapping toxic effects might restrict dose escalation before an efficacious dose and schedule is achieved. Despite being only one enzyme apart in the MAPK signalling cascade, adverse events associated with BRAF inhibition (eg, arthralgia, non-acneiform skin rash, and hyperproliferative skin lesions including squamous-cell carcinomas) contrast strikingly with those linked to MEK inhibition (eg, acneiform skin rash, diarrhoea, and central serous retinopathy). In The Lancet Oncology, Antoni Ribas and colleagues report findings of a phase 1b study of combined BRAF and MEK inhibition with vemurafenib and cobimetinib in patients with BRAF^V600-mutated melanoma who had either recently progressed on vemurafenib (n=66) or never received a BRAF inhibitor (n=63).  Doses of both drugs were escalated and administered to patients at their respective maximum tolerated doses and schedules (established as 960 mg twice a day for vemurafenib and 60 mg daily for 21 days, with a 7-day drug holiday, for cobimetinib). Of note, an intermittent schedule of both drugs in the group that had never received a BRAF inhibitor was not investigated. Such a schedule—less tractable in the case of trametinib because of its very prolonged half-life—could allow dose escalation beyond the maximum tolerated doses of each drug alone, which could lead to more profound pathway inhibition and potentially greater efficacy.

Intratumour heterogeneity and evolution of branching tumour subclones challenge initiatives for precision medicine. Genetic diversity within tumours initiates polyclonal drug-resistance mechanisms—ie, many distinct somatic events can contribute to drug resistance in a patient with melanoma, which are acquired during exposure to targeted treatment. During BRAF monotherapy, selection of drug-resistant events could take place that might be distinct between or within metastatic sites, through mechanisms that are both dependent and independent of MAPK. After addition of a MEK inhibitor at progression, even if sites of disease with reactivation of the MAPK pathway are controlled, failure might happen because of selection of subclones that have acquired MAPK-independent resistance mechanisms, resulting in early progression. Alternatively, since MAPK reactivation happens via many routes rather than by one mechanism, the efficacy of the combination might not be equally potent across every resistance mechanism. Defining how resistance is acquired with the BRAF and MEK inhibitor combination will help resolve this conundrum. Research is needed to ascertain whether early use of a combination of BRAF and MEK inhibitors—while disease burden and permutations of genomic alterations brought about by intratumour heterogeneity are limited—is the best strategy to forestall resistance, or whether a sequential approach with appropriate patient selection could result in equivalent efficacy.