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Atezolizumab, Vemurafenib, and Cobimetinib as First-Line Treatment for Unresectable Advanced BRAFV600 Mutation–Positive Melanoma
TAKE-HOME MESSAGE
- This randomized, double-blind, placebo-controlled phase III study, completed across 112 institutions, evaluated the use of BRAF-targeted therapy (vemurafenib plus cobimetinib) with or without atezolizumab in melanoma patients with BRAF V600 mutations, with atezolizumab added in cycle two. Overall, 256 patients were randomized to the atezolizumab arm and 258 control patients were included. At a median follow-up of 18.9 months, PFS was 15.1 months for the atezolizumab arm and 10.6 months for the placebo arm (HR, 0.78; P = .025). The 18-month PFS was 43.6% for the atezolizumab arm versus 31.6% for the placebo arm. In all, 13% of those receiving atezolizumab and 16% of the controls stopped treatment due to adverse events.
- IMspire150 showed that the addition of atezolizumab to BRAF-targeted therapy prolonged PFS in advanced melanoma patients harboring BRAF V600 mutations. Of note, similar findings were seen with KEYNOTE-022, namely that combining BRAF and MEK inhibitors with immune checkpoint inhibition shows similar response rates to BRAF plus MEK inhibition alone, but the duration of response is prolonged (21.0 vs 12.6 months favoring the atezolizumab arm in IMspire150). Although the triple combination of BRAF plus MEK inhibitors plus anti–PD-L1 is appealing, longer follow-up with overall survival analysis and cross-trial comparison (unfortunately) to 5-year survival data reported for nivolumab and ipilimumab will likely be needed. However, triple therapy could be considered for BRAF V600–mutated melanoma patients for whom BRAF plus MEK inhibition is planned as frontline therapy (eg, patients who need a fast response).
– Matthew Stein, MD
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
IMspire150 aimed to evaluate first-line combination treatment with BRAF plus MEK inhibitors and immune checkpoint therapy in BRAFV600 mutation-positive advanced or metastatic melanoma.
METHODS
IMspire150 was a randomised, double-blind, placebo-controlled phase 3 study done at 112 institutes in 20 countries. Patients with unresectable stage IIIc-IV, BRAFV600 mutation-positive melanoma were randomly assigned 1:1 to 28-day cycles of atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) or atezolizumab placebo, vemurafenib, and cobimetinib (control group). In cycle 1, all patients received vemurafenib and cobimetinib only; atezolizumab placebo was added from cycle 2 onward. Randomisation was stratified by lactate dehydrogenase concentration and geographical region. Blinding for atezolizumab was achieved by means of an identical intravenous placebo, and blinding for vemurafenib was achieved by means of a placebo tablet. The primary outcome was investigator-assessed progression-free survival. This trial (ClinicalTrials.gov, NCT02908672) is ongoing but no longer recruiting patients.
FINDINGS
Between Jan 13, 2017, and April 26, 2018, 777 patients were screened and 514 were enrolled and randomly assigned to the atezolizumab group (n=256) or control group (n=258). At a median follow-up of 18·9 months (IQR 10·4-23·8), progression-free survival as assessed by the study investigator was significantly prolonged with atezolizumab versus control (15·1 vs 10·6 months; hazard ratio [HR] 0·78; 95% CI 0·63-0·97; p=0·025). Common treatment-related adverse events (>30%) in the atezolizumab and control groups were blood creatinine phosphokinase increased (51·3% vs 44·8%), diarrhoea (42·2% vs 46·6%), rash (40·9%, both groups), arthralgia (39·1% vs 28·1%), pyrexia (38·7% vs 26·0%), alanine aminotransferase increased (33·9% vs 22·8%), and lipase increased (32·2% vs 27·4%); 13% of patients in the atezolizumab group and 16% in the control group stopped all treatment because of adverse events.
INTERPRETATION
The addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAFV600 mutation-positive advanced melanoma.
Additional Info
Atezolizumab, Vemurafenib, and Cobimetinib as First-Line Treatment for Unresectable Advanced BRAFV600 Mutation-Positive Melanoma (IMspire150): Primary Analysis of the Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial
Lancet 2020 Jun 13;395(10240)1835-1844, R Gutzmer, D Stroyakovskiy, H Gogas, C Robert, K Lewis, S Protsenko, RP Pereira, T Eigentler, P Rutkowski, L Demidov, GM Manikhas, Y Yan, KC Huang, A Uyei, V McNally, GA McArthur, PA AsciertoFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
IMspire150 is a phase III trial of 514 patients randomized to vemurafenib plus cobimetinib alone or combined with the anti–PD-L1 antibody atezolizumab. Although there was no difference in tumor response rates of 66% versus 65%, progression-free survival was significantly longer at 15.1 months with triplet therapy versus 10.6 with a doublet regimen (P = .025). The rate of grade 3/4 adverse events was also quite high at 79% with the triplet and 73% with vemurafenib plus cobimetinib. The results from these randomized BRAF/MEK inhibitor plus anti–PD-1/PD-L1 antibody studies raise several questions—foremost, how a first-line triplet regimen may compare with an upfront anti–PD-1 or ipilimumab plus nivolumab regimen in clinical benefit for BRAFV600-mutant metastatic melanoma.
How would a sequential treatment of switching from anti–PD-1–based immunotherapy to BRAF-targeted therapy at time of progression compare in terms of efficacy, toxicity, and cost with upfront triplet therapy? Should triplet regimens be considered in the first-line setting for most patients or reserved for treatment-refractory patients? We also do not yet know which specific groups of patients may especially benefit from triplet regimens. There are also questions on how to manage some of the overlapping toxicity of BRAF-targeted therapy and immunotherapy drugs administered in combination, particularly skin or liver toxicities. Future studies may shed light on some of these questions; for example, patients with melanoma brain metastases will be randomized to a triplet regimen of encorafenib/ binimetinib/ nivolumab versus ipilimumab plus nivolumab in an upcoming cooperative group clinical trial (SWOG S2000).