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Review
. 2023 Jun 30;15(13):3448.
doi: 10.3390/cancers15133448.

Medical Needs and Therapeutic Options for Melanoma Patients Resistant to Anti-PD-1-Directed Immune Checkpoint Inhibition

Jessica C Hassel  1 , Lisa Zimmer  2   3 , Thomas Sickmann  4 , Thomas K Eigentler  5 , Friedegund Meier  6 , Peter Mohr  7 , Tobias Pukrop  8   9 , Alexander Roesch  2 , Dirk Vordermark  10 , Christina Wendl  11 , Ralf Gutzmer  12
Affiliations
Review

Medical Needs and Therapeutic Options for Melanoma Patients Resistant to Anti-PD-1-Directed Immune Checkpoint Inhibition

Jessica C Hassel et al. Cancers (Basel). .

Erratum in

Abstract

Available 4- and 5-year updates for progression-free and for overall survival demonstrate a lasting clinical benefit for melanoma patients receiving anti-PD-directed immune checkpoint inhibitor therapy. However, at least one-half of the patients either do not respond to therapy or relapse early or late following the initial response to therapy. Little is known about the reasons for primary and/or secondary resistance to immunotherapy and the patterns of relapse. This review, prepared by an interdisciplinary expert panel, describes the assessment of the response and classification of resistance to PD-1 therapy, briefly summarizes the potential mechanisms of resistance, and analyzes the medical needs of and therapeutic options for melanoma patients resistant to immune checkpoint inhibitors. We appraised clinical data from trials in the metastatic, adjuvant and neo-adjuvant settings to tabulate frequencies of resistance. For these three settings, the role of predictive biomarkers for resistance is critically discussed, as well as are multimodal therapeutic options or novel immunotherapeutic approaches which may help patients overcome resistance to immune checkpoint therapy. The lack of suitable biomarkers and the currently modest outcomes of novel therapeutic regimens for overcoming resistance, most of them with a PD-1 backbone, support our recommendation to include as many patients as possible in novel or ongoing clinical trials.

Keywords: PD-1; brain metastases; immune checkpoint inhibition; melanoma; resistance.

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Conflict of interest statement

J.C.H. reports grants or contracts from Bristol Myers Squibb, Sanofi, and Sun Pharma; consulting fees from Onkowissen and Glaxo Smith Kline; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, Bristol Myers Squibb, Glaxo Smith Kline, Immunocore, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and Sun Pharma; support for attending meetings and/or travel from Bristol Myers Squibb, Iovance Biotherapeutics, and Sun Pharma; participation in a data safety monitoring board or advisory board for Merck Sharp & Dohme, Pierre Fabre, Sun Pharma, Bristol Myers Squibb, Immunocore, Novartis, Philogen, Sanofi, and Nekvax. L.Z. reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and Sun Pharma; support for attending meetings and/or travel from Merck Sharp & Dohme, Bristol Myers Squibb, Pierre Fabre, Sanofi, Sun Pharma and Novartis; participation in a data safety monitoring board or advisory board for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and Sun Pharma. T.S. reports employment as a senior manager and medical advisor and stock or stock options at Bristol Myers Squibb. T.E. reports payment or honoraria for lectures, presentations, speakers bureaus’, manuscript writing or educational events and participation in advisory boards for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Immunocore, CureVac and Almirall Hermal; an unpaid leadership position as board member of DeCOG. F.M. reports consulting fees from Novartis, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi, and Immunocore; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Novartis, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi, and Immunocore; support for attending meetings and/or travel from Novartis, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi, and Immunocore; participation in a data safety monitoring board or advisory board for Novartis, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Sanofi, and Immunocore. A.R. reports grants or contracts from Bristol Myers Squibb and Novartis; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Bristol Myers Squibb and Novartis; an unpaid leadership (DeCOG committee Translational Research & Biobank). D.V. reports grants or contracts from Merck, Pfizer, and AstraZeneca; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Roche, Astra Zeneca, Sun Pharma, Merck, Lilly, Ferring, Takeda, and Sanofi; participation in an advisory board for Boehringer, Bristol Myers Squibb, Chugai, Merck, and Roche. C.W. reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Novartis, Sun Pharma, Medac, Sanofi, and Recordati; support for attending meetings and/or travel from Bristol Myers Squibb, Novartis, Medac, Pierre Fabre, and Sun Pharma; participation in a data safety monitoring board or advisory board for Bristol Myers Squibb, Sun Pharma, Sanofi, and Novartis. R.G. reports grants or contracts from Novartis, Sun Pharma, Amgen, Sanofi/Regeneron, Merck-Serono, Kyowa-Kirin, and Almirall-Hermal; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Roche Pharma, Bristol Myers Squibb, Novartis, Merck Sharp & Dohme, Almirall-Hermal, Amgen, Merck-Serono, Sanofi/Regeneron, Pierre Fabre; support for attending meetings and/or travel from Sun Pharma, Pierre Fabre, and Boehringer-Ingelheim; participation in a data safety monitoring board or advisory board for Roche Pharma, Bristol Myers Squibb, Novartis, Merck Sharp & Dohme, Almirall-Hermal, Amgen, Pierre Fabre, Merck-Serono, Sun Pharma, Merck-Serono, Sanofi/Regeneron, Immunocore, 4SC and Delcath; an unpaid leadership position as the chairman of Arbeitsgemeinschaft Dermatologische Onkologie (ADO). All other authors declare no conflicts of interest. The funder had the following involvements in the review: contributions to the conceptualization; the decision to publish, in agreement with the Steering Committee; and the provision of funding for manuscript preparation and submission.

Figures

Figure 1
Figure 1
Schematic response and patterns of resistance to immunotherapy in the metastatic setting considering the SITC consensus’ clinical definition of resistance to PD-(L)1 inhibitors [23]. Primary resistance (blue line) indicates non-response to therapy including that of patients with PD or SD lasting less than 6 months. Secondary resistance (purple line) indicates resistance after initial benefit (CR, PR, and SD lasting > 6 months) and may comprise singular, oligoprogression or multiple progression emerging from a residual and/ or newly formed tumor mass. * As an extension of this rule, a progression occurring after a substantial initial benefit (PR and CR) within 6 months after the start of treatment is also considered “secondary”.
Figure 2
Figure 2
SITC scenarios and definitions of primary and secondary resistance to PD-1 therapy in the adjuvant, neo-adjuvant and metastatic treatment settings (modified to [23]). Abbreviations: ICI, immune checkpoint inhibition; MPR, major pathological response. * Complete or partial response, or stable disease for 6 months. ** As an extension of this rule, a progression occurring after a substantial benefit (PR and CR), within 6 months after the start of the treatment start is also considered “secondary”.
Figure 3
Figure 3
Mechanisms of resistance.
See this image and copyright information in PMC

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