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Review
. 2020 Oct;8(2):e000948.
doi: 10.1136/jitc-2020-000948.

Evolving impact of long-term survival results on metastatic melanoma treatment

Olivier Michielin  1   2 , Michael B Atkins  3 , Henry B Koon  4 , Reinhard Dummer  5 , Paolo Antonio Ascierto  6
Affiliations
Review

Evolving impact of long-term survival results on metastatic melanoma treatment

Olivier Michielin et al. J Immunother Cancer. 2020 Oct.

Abstract

Melanoma treatment has been revolutionized over the past decade. Long-term results with immuno-oncology (I-O) agents and targeted therapies are providing evidence of durable survival for a substantial number of patients. These results have prompted consideration of how best to define long-term benefit and cure. Now more than ever, oncologists should be aware of the long-term outcomes demonstrated with these newer agents and their relevance to treatment decision-making. As the first tumor type for which I-O agents were approved, melanoma has served as a model for other diseases. Accordingly, discussions regarding the value and impact of long-term survival data in patients with melanoma may be relevant in the future to other tumor types. Current findings indicate that, depending on the treatment, over 50% of patients with melanoma may gain durable survival benefit. The best survival outcomes are generally observed in patients with favorable prognostic factors, particularly normal baseline lactate dehydrogenase and/or a low volume of disease. Survival curves from melanoma clinical studies show a plateau at 3 to 4 years, suggesting that patients who are alive at the 3-year landmark (especially in cases in which treatment had been stopped) will likely experience prolonged cancer remission. Quality-of-life and mixture-cure modeling data, as well as metrics such as treatment-free survival, are helping to define the value of this long-term survival. In this review, we describe the current treatment landscape for melanoma and discuss the long-term survival data with immunotherapies and targeted therapies, discussing how to best evaluate the value of long-term survival. We propose that some patients might be considered functionally cured if they have responded to treatment and remained treatment-free for at least 2 years without disease progression. Finally, we consider that, while there have been major advances in the treatment of melanoma in the past decade, there remains a need to improve outcomes for the patients with melanoma who do not experience durable survival.

Keywords: CTLA-4 antigen; immunomodulation; immunotherapy; programmed cell death 1 receptor; review.

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Conflict of interest statement

Competing interests: OM: Consulting or advisory role: Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche. Travel, accommodations, and expenses: Bristol Myers Squibb and Merck Sharp & Dohme. Expert testimony: Bristol Myers Squibb. Research funding: Bristol Myers Squibb, Merck Sharp & Dohme, and NeraCare GmbH. MBA: Advisory board: Arrowhead, Bristol Myers Squibb, Exelixis, Fathom, Leads, Merck, Novartis, PACT, Pfizer, Pneuma, Pyxis Oncology, and Werewolf. Consultant: Array, Aveo, Boehringer Ingelheim, Bristol Myers Squibb, Cota, Eisai, Galactone (personal fees), Genentech/Roche, ImmunoCore, Iovance, Merck, Newlink, Novartis, Pfizer, and Surface. Research support to institution: Bristol Myers Squibb, Merck, and Pfizer. Clinical trial involvement: Aveo (Tivo 3), Bristol Myers Squibb (CM-214, CM-004, CM-067, CM-204, CM-218, CM-238, CM-905, X4P-X4 RCCA, X4-RCCB), Genentech/Roche (ImMotion 150, ImMotion 151), Merck (KN- 426, KN-427, KN-029, KN-564), and Pfizer (029 Trial, Javelin 101). Speaker’s bureau: None. Stock options: Pyxis Oncology and Werewolf. HBK: Employment: Bristol Myers Squibb. Stock and other ownership interests: Bristol Myers Squibb. RD: Consulting or advisory role: Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, Sun Pharma, and Takeda. Honoraria: Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi, Sun Pharma, and Takeda. Research funding: Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche. PAA: Consulting or advisory role: 4SC, Alkermes, Amgen, Array BioPharma, AstraZeneca, Bristol Myers Squibb, Genmab, Idera, Immunocore, Incyte, Italfarmaco, MedImmune, Merck Serono, Merck Sharp & Dohme, Nektar, NewLink Genetics, Novartis, Pierre Fabre, Roche/Genentech, Sandoz, Sanofi, Sun Pharma, Syndax, and Ultimovacs. Travel, accommodations, and expenses: Merck Sharp & Dohme. Stock and other ownership interests: PrimeVax. Research funding: Array BioPharma, Bristol Myers Squibb, and Roche/Genentech.

Figures

Figure 1
Figure 1
US Food and Drug Administration approval of melanoma therapies. Agents shown are approved for metastatic melanoma unless stated and italicized. aFor patients whose tumors express BRAF V600E or V600K. bFor patients whose tumors express BRAF V600E.
Figure 2
Figure 2
Long-term OS in clinical trials with immuno-oncology agents and targeted therapies in patients with advanced melanoma. The data presented represent first-line treatment options, with the exception of those for IL-2 and pooled ipilimumab. The data were compiled from the references indicated. IL-2, interleukin 2; OS, overall survival.
Figure 3
Figure 3
Improving long-term survival in patients with metastatic melanoma. LDH, lactate dehydrogenase. (Figure from Ascierto and Dummer. Immunological effects of BRAF+MEK inhibition. Adapted with permission from Taylor & Francis Ltd, http://www.tandfonline.com).
See this image and copyright information in PMC

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