Omid Hamid, MD
As investigators, we were always determined to find the drug to work with BRAF/MEK inhibitor combination therapy. It had come on like a storm and showed us that we could help even those with the most advanced metastatic melanoma, as long as it harbored the magical BRAF V600E mutation.1 Unfortunately, the issue with the Lazarus phenomenon was its durability. Patients would ultimately see tumors that shrank returning with a vengeance. With this understanding, we undertook “triplet” combination therapy trials with BRAF/MEK/VEGF inhibitors (ClinicalTrials.gov identifier NCT01495988) and BRAF/MEK/CTLA-4 inhibitors, each of which ended unceremoniously with significant toxicity, forcing closure of the trials.2
Then came the understanding that combining immunotherapy and BRAF-targeted therapies might elicit synergy of effect. As a result, we hoped to achieve a high response rate and improvement in morbidity with targeted therapy coupled with the long-term durability of responses seen with immunotherapy leading to improved survival.
Background on IMspire150 Trial
It is with this interest that we undertook the first phase I combination of BRAF/MEK/checkpoint inhibitor therapy—the phase Ib study of the anti–PD-L1 antibody atezolizumab with vemurafenib plus cobimetinib (NCT02908672, NCT01656642).3 This trial had a novel run-in phase with targeted therapy alone; surprisingly, biomarker data exposed that the run-in with cobimetinib plus vemurafenib was associated with an increase in proliferating CD4-positive T-helper cells, but not with an increase in T-regulatory cells—an initial confirmation we needed that led to the IMspire150 trial.4
As reviewed in this issue of The ASCO Post, this double-blind, randomized, placebo-controlled, phase III study evaluated the addition of atezolizumab to cobimetinib plus vemurafenib for patients with treatment-naive, unresectable, locally advanced or metastatic melanoma harboring a BRAF V600 mutation. Results presented during the American Association for Cancer Research Virtual Annual Meeting I5 and reported in The Lancet4 by Gutzmer and colleagues showed a significant improvement in investigator-assessed progression-free survival with the atezolizumab combination (median = 15.1 months vs 10.6 months, hazard ratio [HR] = 0.78, 95% confidence interval [CI] = 0.63–0.97, P = .025), although the difference was not statistically significant on independent review committee assessment (median = 16.1 months vs 12.3 months, HR = 0.85, 95% CI = 0.67–1.07, P = .16). These data served as the basis for the combination’s approval by the U.S. Food and Drug Administration in July 2020.
Comparing Data From IMspire150 and COMBI-i
The IMspire150 data are only the first step, as we continue to evaluate BRAF inhibitor–based triplet therapies. COMBI-i is an ongoing trial evaluating the anti–PD-1 antibody spartalizumab combined with dabrafenib plus trametinib.6 Whereas IMspire150 had a 1-month run-in with BRAF/MEK inhibition followed by the PD-L1 inhibitor, COMBI-i utilizes synchronous therapy with a PD-1 inhibitor. It should also be noted that full-dose dabrafenib and trametinib is used in COMBI-i, whereas the dose of vemurafenib was reduced in the triplet therapy in IMspire150.
COMBI-i showed an objective response rate of 75%, with a 33% complete response rate. The median duration of response, progression-free survival, and overall survival have not been reached, at median follow-up of 15.2 months. The combination also showed a manageable safety profile, and a phase III study is ongoing.
It will be important to evaluate these data with a clear understanding of the patient composition of both trials—since much of the importance of the trials will come in identifying benefit in subset analyses. Patients with central nervous system (CNS) metastases, high lactate dehydrogenase levels, and more than three organ sites with metastases have traditionally had the worst outcomes. How does triplet therapy work for these populations?7
The addition of anti–PD-1 therapy to BRAF/MEK inhibitor therapy is associated with numerically lower rates of interval development of CNS metastases, consistent with the overall benefit observed for triplet therapy seen in the IMspire150 study.8 The finding of increased complete response rate with an immunotherapy combination is notable, as these patients are the ones with the best outcomes and reduced likelihood of disease progression.
Combination Triplet Immunotherapy: Data Coming Soon
Triplet therapy has clouded the classic argument of initial BRAF/MEK vs CTLA-4/PD-1 therapy in patients with BRAF-mutant disease (NCT02224781). We cannot just give the triplet and be clear of this discussion. The true benefit must come in an overall survival advantage, which still is not presented in these trials. There must be benefit that surpasses that of sequential BRAF/MEK inhibition followed by anti–PD-1 therapy. At the current time, combination checkpoint inhibition has shown remarkable outcomes, with rapid response, median progression-free survival of 16.8 months, and 5-year survival of 60%.9 Coming soon will be data on combination triplet immunotherapy.
The current enthusiasm in this triplet approach relates to recent data showing increased responses with continuing PD-1 inhibition in combination with CTLA-4 inhibition after disease progression on PD-1 inhibition.10 Perhaps similar benefits might be seen when initiating BRAF inhibition after disease progression on PD-1–based combination checkpoint therapy. Future trials may focus on the utility of the IMspire150 regimen in second-line treatment. Clearly, IMspire150 is the first step in a journey that will be clarified through clinical trials.
DISCLOSURE: Dr. Hamid has received honoraria from Array BioPharma, Bristol Myers Squibb, Novartis, and Sanofi/Regeneron; has served as a consultant or advisor to Aduro, Akeso Biopharma, Amgen, Array BioPharma, BeiGene, Bristol Myers Squibb, Genentech, GlaxoSmithKline, Immunocore, Incyte, Janssen, Merck, NextCure, Novartis, Regeneron, Roche, Sanofi, Seattle Genetics, Tempus, and Zelluna; has participated in a speakers bureau for Array BioPharma, Bristol Myers Squibb, Novartis, and Sanofi/Regeneron; and has received institutional research funding from Aduro Biotech, Akeso Biopharma, Amgen, Arcus Biosciences, Array BioPharma, AstraZeneca, Bristol Myers Squibb, CytomX Therapeutics, Exelixis, Genentech, GlaxoSmithKline, Immunocore, Incyte, Iovance Biotherapeutics, MedImmune, Merck, Merck Serono, Moderna Therapeutics, NextCure, Novartis, Pfizer, Regeneron, Roche, Sanofi, Seattle Genetics, Torque, and Zelluna.
Dr. Hamid is Chief of Research/Immuno-Oncology at The Angeles Clinic & Research Institute and Co-Director of the Cutaneous Malignancy Program at Cedars-Sinai Cancer Center. He can be reached on Twitter @OmidHamidMD.
REFERENCES
1. Chapman PB, Hauschild A, Robert C, et al: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507-2516, 2011.
2. Ribas A, Hodi FS, Callahan M, et al: Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med 368:1365-1366, 2013.
3. Sullivan RJ, Hamid O, Gonzalez R, et al: Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat Med 25:929-935, 2019.
4. Gutzmer R, Stroyakovskiy D, Gogas H, et al: Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAF V600 mutation-positive melanoma (IMspire150): Primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 395:1835-1844, 2020.
5. McArthur GA, Stroyakovskiy D, Gogas H, et al: Evaluation of atezolizumab, cobimetinib, and vemurafenib in previously untreated patients with BRAF V600 mutation-positive advanced melanoma: Primary results from the phase 3 IMspire150 trial. 2020 AACR Virtual Annual Meeting I. Abstract CT012.
6. Long GV, Lebbe C, Atkinson V, et al: The anti–PD-1 antibody spartalizumab in combination with dabrafenib and trametinib in previously untreated patients with advanced BRAF V600–mutant melanoma: Updated efficacy and safety from parts 1 and 2 of COMBI-i. 2019 ASCO Annual Meeting. Abstract 9531.
7. Long GV, Grob J-, Nathan P, et al: Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: A pooled analysis of individual patient data from randomised trials. Lancet Oncol 17:1743-1754, 2016.
8. Ascierto PA, Robert C, Lewis KD, et al: Time to central nervous system metastases with atezolizumab or placebo combined with cobimetinib + vemurafenib in the phase III IMspire150 study. ASCO20 Virtual Scientific Program. Abstract 10023.
9. Larkin J, Chiarin-Sileni V, Gonzalez R, et al: Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 381:1535-1546, 2019.
10. Da Silva IP, Ahmed T, Lo S, et al: Ipilimumab alone or in combination with anti-PD-1 in patients with metastatic melanoma resistant to PD-1 monotherapy. ASCO20 Virtual Scientific Program. Abstract 10005.
