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. 2020 May:130:126-138.
doi: 10.1016/j.ejca.2020.02.021. Epub 2020 Mar 13.

Survival of patients with advanced metastatic melanoma: The impact of MAP kinase pathway inhibition and immune checkpoint inhibition - Update 2019

Selma Ugurel  1 , Joachim Röhmel  2 , Paolo A Ascierto  3 , Jürgen C Becker  4 , Keith T Flaherty  5 , Jean J Grob  6 , Axel Hauschild  7 , James Larkin  8 , Elisabeth Livingstone  9 , Georgina V Long  10 , Paul Lorigan  11 , Grant A McArthur  12 , Antoni Ribas  13 , Caroline Robert  14 , Lisa Zimmer  9 , Dirk Schadendorf  9 , Claus Garbe  15
Affiliations

Survival of patients with advanced metastatic melanoma: The impact of MAP kinase pathway inhibition and immune checkpoint inhibition - Update 2019

Selma Ugurel et al. Eur J Cancer. 2020 May.

Abstract

Background: Recent therapeutic strategies, particularly MAP kinase pathway inhibitors (BRAF, MEK) and immune checkpoint blockers (CTLA-4, PD-1), have been put on the test for their differential impact on long-term survival of metastatic melanoma patients. Various agents, dose regimens and combinations have been tested against each other vigorously within these two therapy groups. However, results from prospective head-to-head comparative trials comparing both strategies against each other are still lacking.

Methods: We performed an exploratory analysis of survival data from selected clinical trials representative for these two treatment strategies in advanced metastatic melanoma. 84 Kaplan-Meier survival curves from 26 trials were digitised and grouped by therapy strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging.

Results: Survival curves grouped together by therapy strategy revealed a high concordance, with a larger extent in the first-line setting compared to higher treatment lines. In first-line therapy, the averaged 3-year OS proportions were 41.3% for BRAF plus MEK inhibition, 49.9% for PD-1 inhibition, and 58.4% for CTLA-4 plus PD-1 inhibition. Comparison of the mean PFS and OS curves of kinase inhibition and checkpoint blockade revealed a superiority of combined BRAF plus MEK inhibition within the first 12 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockade. In second-line or higher, BRAF plus MEK inhibition was superior to anti-PD-1 monotherapy throughout the first three years; averaged 3-year OS proportions were 42.4% for BRAF plus MEK inhibition, and 40.1% for PD-1 inhibition.

Conclusions: and relevance: These results need confirmation by head-to-head comparative randomised clinical trials.

Keywords: Immune checkpoint blockers; Kinase inhibitors; Melanoma; Survival; Therapy.

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Conflict of interest statement

Conflict of interest statement Selma Ugurel: relevant financial activities (research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp, and Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp, and Dohme). Joachim Röhmel: none. Paolo A. Ascierto: relevant financial activities (advisory board/consultant for Bristol Myers-Squibb, Roche-Genentech, Merck Sharp & Dohme, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, NewLink Genetics, Genmab, Medimmune, AstraZeneca, Syndax, SunPharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes; research funds from Bristol Myers-Squibb, Roche-Genentech, Array; travel support from Merck Sharp & Dohme). Jürgen C. Becker: relevant financial activities (speaker honoraria from Amgen, MerckSerono, Pfizer, Sanofi; advisory board honoraria from 4SC, Amgen, CureVac, eTheRNA, MerckSerono, Novartis and InProTher; research funding from Alcedis, Boehringer Ingelheim, Bristol-Myers Squibb, IQVIA, and MerckSerono; travel support from 4SC and Incyte). Keith T. Flaherty: relevant financial activities (consultant for Amgen, Array BioPharma, Bristol-Myers Squibb, Merck, Novartis, Pierre-Fabre, Roche). Jean Jacques Grob: relevant financial activities (Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche). Axel Hauschild: relevant financial activities (Amgen, Bristol-Myers Squibb, MerckSerono, Merck Sharp & Dohme, Novartis, Oncosec, Philogen, Pierre Fabre, Provectus, Regeneron, Roche). James Larkin: relevant financial activities (Bristol-Myers Squibb, Merck, Novartis, Roche). Elisabeth Livingstone: relevant financial activities (served as consultant or/and has received honoraria from Amgen, Actelion, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Janssen, Medac, and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Amgen, Pierre Fabre, SunPharma, and Novartis). Georgina V. Long: relevant financial activities (consultant advisor to Aduro, Amgen, Array, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Oncosec, Pierre-Fabre, Roche). Paul Lorigan: relevant financial activities (Support for research: Bristol-Myers Squibb; Advisory work/speaker bureau: Bristol-Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Novartis, Amgen, Glaxo Smith Kline, Roche; Support for travel: Bristol-Myers Squibb and Merck Sharp & Dohme). Grant A. McArthur: relevant financial activities (Research funding for reimbursement of clinical trials from Array Biopharma and Genentech/Roche). ‘Antoni Ribas: relevant financial activities (Bristol-Myers Squibb, Merck, Novartis, Roche). Caroline Robert: relevant financial activities (Roche, Novartis, CureVac, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck, Sanofi, Amgen, Pierre Fabre, Biothera). Lisa Zimmer: relevant financial activities (consultant and/or honoraria from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and travel support from Bristol-Myers Squibb, Merck Sharp & Dohme, Amgen, Pierre Fabre, Sanofi, and Novartis). Dirk Schadendorf: relevant financial activities (Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Sanofi, Regeneron, Array, Pierre Fabre, 4SC, Helsinn, Philogen, InFlarX, Merck-Serono, SunPharma, Ultimovacs, Sandoz). Claus Garbe: relevant financial activities (Roche, GSK, Novartis, Bristol-Myers Squibb, Merck Sharp & Dsohme).

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