Research in context
Evidence before this study
At the time of the drafting of these results, the approved systemic options for patients with advanced melanoma were immunotherapy (all patients) or BRAF and MEK inhibitors for the subset of patients with BRAF mutations in their tumours. Although immunotherapy provides durable responses, a substantial proportion of patients with melanoma have a poor response to immunotherapy; conversely, although most patients respond to MAPK pathway inhibitors, responses are often short-lived. It is clinically desirable to combine the higher response rates observed with targeted therapy with long-term clinical benefit associated with immune modulation, without compromising patient safety. On the basis of emerging preclinical and clinical evidence for potential synergy between immune checkpoint inhibition and BRAF and MEK inhibitors, IMspire150 explored whether a combination of atezolizumab, vemurafenib, and cobimetinib would prolong progression-free survival in patients with BRAF-mutation-positive advanced melanoma versus vemurafenib and cobimetinib. We searched PubMed for any clinical reports published until Feb 20, 2020, that explored similar systemic options. We used the search string “melanoma AND ((BRAF OR MEK inhibitor) AND (immune checkpoint inhibitor))” restricted to articles reporting on a clinical trial. We identified two previous publications reporting data from early phase clinical reports (KEYNOTE 022 and GP28384/NCT01656642) investigating this combination in melanoma, but no controlled phase 3 clinical studies.
Added value of this study
IMspire150 is the first phase 3 study to evaluate an immune checkpoint inhibitor combined with BRAF plus MEK inhibitors in patients with advanced BRAFV600 mutation-positive melanoma. The IMspire150 study met its primary progression-free survival endpoint and provided high-level evidence to show that combined inhibition with vemurafenib, cobimetinib, and atezolizumab prolongs progression-free survival in previously untreated patients with BRAF mutation-positive advanced melanoma. Reassuringly, the safety profile and treatment discontinuation rates with this combination were similar to those of the control group of vemurafenib and cobimetinib, which is an approved treatment option for patients with BRAF-mutation-positive advanced melanoma.
Implications of all the available evidence
The analysis reported here shows that atezolizumab combined with vemurafenib and cobimetinib is a safe and efficacious treatment option for patients with BRAF mutation-positive advanced melanoma. Survival data from this and other ongoing studies on treatment sequencing will inform the optimal treatment paradigm in this patient population.