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Atezolizumab Triplet Therapy for BRAF V600-Mutant Melanoma: Paolo A. Ascierto, MD

Paolo A. Ascierto, MD.

Recently, the FDA approved a new indication for atezolizumab (Tecentriq®, Genentech) in combination with vemurafenib (Zelboraf®, Genentech and Daiichi-Sankyo) and cobimetinib (Cotellic®, Genentech) for the treatment of BRAF V600-mutant advanced melanoma. In this interview with i3 Health, Paolo A. Ascierto, MD, principal investigator of the IMspire150 trial, on which the approval was based, discusses the approval's significance and the most promising research developments in the treatment of BRAF V600-mutant advanced melanoma.

What are the greatest challenges of treating patients with BRAF V600-mutant advanced melanoma?

Paolo A. Ascierto, MD: At the moment, with targeted therapies and immunotherapy, we are able to reach a long-term benefit in more than 50% of metastatic patients, but there is an additional 50% who continue to die. We need to increase the number of patients who experience long-term benefit.

Today, we also have the possibility of using such strategies as adjuvant therapy, and patients who fail adjuvant treatment have different needs compared to those who do not. The triplet combination with atezolizumab/vemurafenib/cobimetinib could have a role in this subgroup of patients, as well as in those patients with symptomatic brain metastasis.

How does atezolizumab/vemurafenib/cobimetinib compare with other treatment options for BRAF V600-mutant advanced melanoma, in terms of both efficacy and adverse events?

Dr. Ascierto: This triplet combination with atezolizumab/vemurafenib/cobimetinib increases the median progression-free survival and duration of response compared with the classical combination of BRAF and MEK inhibitors. However, the real comparator of this combination should be considered the combination of ipilimumab/nivolumab, which showed a five-year overall survival rate of 52%. The five-year overall survival from atezolizumab/vemurafenib/cobimetinib is not mature yet, but we will see. Both of these strategies have significant toxicities; these are mainly immune-related adverse events in both treatments, with the addition of pyrexia and arthralgia in the triplet therapy. In addition, while with ipilimumab/nivolumab we can discontinue treatment after two years with a high probability of maintaining benefit, we don't yet have such information for the triplet therapy. However, atezolizumab/vemurafenib/cobimetinib is surely an additional option for metastatic melanoma patients.

How is the treatment landscape evolving for patients with BRAF V600-mutated advanced melanoma? What additional research advances are on the horizon?

Dr. Ascierto: For the patients with BRAF-mutated as well as BRAF wild-type disease, several studies are ongoing. New combinations in phase 3 trials that deserve to be mentioned include nivolumab/relatlimab, pembrolizumab/lenvatinib, and nivolumab/bempegaldesleukin. There are also some ongoing studies which will give us additional information about the best sequence of treatment (targeted therapy versus immuno-oncology as the first regimen), different schedules, and innovative treatments as the neoadjuvant therapy.

What advice can you offer to oncologists and other members of the cancer care team as they treat patients with advanced melanoma?

Dr. Ascierto: There has been an important revolution in the field of melanoma since 2011. At that time, almost all metastatic melanoma patients died, while now we can cure half of them. With the adjuvant therapies, the neoadjuvant therapies, and the new combination treatments, I'm sure that we will increase this number. In this context, the triplet of BRAF/MEK inhibition plus anti–PD-1/PD-L1 inhibition will be an important option for patients.

About Dr. Ascierto

Paolo Ascierto, MD, is Director of the Unit of Melanoma, Cancer Immunotherapy, and Innovative Therapy at the National Tumor Institute Fondazione G. Pascale in Naples, Italy. Dr. Ascierto specializes in the treatment of melanoma and solid tumors, with a focus on immunotherapy. He has served as the principal investigator of more than 100 clinical trials investigating novel melanoma therapies, including immunotherapies, targeted therapies, and combination approaches. He is a member of the Steering Committee of the Society for Melanoma Research and serves on the Board of Directors of the Society for Immunotherapy of Cancer (SITC). Dr. Ascierto is an active reviewer for several international journals and is Associate Editor for the Onco-Immunology section of Annals of Oncology, Chief Section Editor of the Combination Strategies section of the Journal of Translational Medicine, and Associate Editor of the Journal for ImmunoTherapy of Cancer. He has authored more than 400 publications in peer-reviewed journals.

For More Information

Gutzmer R, Stroyakovskiy D, Gogas H, et al (2020). 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, 395(10240):1835-1844. DOI:10.1016/S0140-6736(20)30934-X

Larkin J, Chiarion-Sileni V, Gonzalez R, et al (2019). Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med, 381:1535-1546. DOI:10.1056/NEJMoa1910836

Lipson EJ, Long GV, Tawbi H, et al (2018). CA224-047: a randomized, double-blind, phase 2/3 study of relatlimab (anti–LAG-3) in combination with nivolumab (anti–PD-1) versus nivolumab alone in previously untreated metastatic or unresectable melanoma. Ann Oncol (ESMO Congress Abstracts), 29(suppl_8):viii442-viii466. Abstract 4158. DOI:10.1093/annonc/mdy289

Eggermont AMM, Carlino MS, Hauschild A, et al (2019). Pembrolizumab (pembro) plus lenvatinib (len) for first-line treatment of patients with advanced melanoma: phase 3 LEAP-003 study. Ann Oncol (ESMO Congress Abstracts), 30(suppl_5):v533-v563. Abstract 4440. DOI:10.1093/annonc/mdz255

Khushalani NI, Diab A, Ascierto PA, et al (2019). CA045-001: A phase III, randomized, open label study of bempegaldesleukin (NKTR-214) plus nivolumab (NIVO) versus NIVO monotherapy in patients (pts) with previously untreated, unresectable or metastatic melanoma (MEL). J Clin Oncol (ASCO Annual Meeting Abstracts), 37(15_suppl). Abstract TPS9601. DOI:10.1200/JCO.2019.37.15_suppl.TPS9601

Tecentriq® (atezolizumab) prescribing information (2020). Genentech, Inc. Available at: https://www.gene.com/download/pdf/tecentriq_prescribing.pdf

Zelboraf® (vemurafenib) prescribing information (2020). Genentech, Inc., and Daiichi Sankyo, Inc. Available at: https://www.gene.com/download/pdf/zelboraf_prescribing.pdf

Cotellic® (cobimetinib) prescribing information (2018). Genentech, Inc. Available at: https://www.gene.com/download/pdf/cotellic_prescribing.pdf

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