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  • Review Article
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Personalizing neoadjuvant immune-checkpoint inhibition in patients with melanoma

Nature Reviews Clinical Oncology volume 20, pages 408–422 (2023)Cite this article

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Abstract

Neoadjuvant immune-checkpoint inhibition is a promising emerging treatment approach for patients with surgically resectable macroscopic stage III melanoma. The neoadjuvant setting provides an ideal platform for personalized therapy owing to the very homogeneous nature of the patient population and the opportunity for pathological response assessments within several weeks of starting treatment, thereby facilitating the efficient identification of novel biomarkers. A pathological response to immune-checkpoint inhibitors has been shown to be a strong surrogate marker of both recurrence-free survival and overall survival, enabling timely analyses of the efficacy of novel therapies in patients with early stage disease. Patients with a major pathological response (defined as the presence of ≤10% viable tumour cells) have a very low risk of recurrence, which offers an opportunity to adjust the extent of surgery and any subsequent adjuvant therapy and follow-up monitoring. Conversely, patients who have only a partial pathological response or who do not respond to neoadjuvant therapy still might benefit from therapy escalation and/or class switch during adjuvant therapy. In this Review, we outline the concept of a fully personalized neoadjuvant treatment approach exemplified by the current developments in neoadjuvant therapy for patients with resectable melanoma, which could provide a template for the development of similar approaches for patients with other immune-responsive cancers in the near future.

Key points

  • The neoadjuvant setting provides an ideal platform for the personalized treatment of patients with resectable macroscopic stage III melanoma, with pathological response functioning as a surrogate outcome for recurrence-free survival.

  • Patients having a major pathological response to immune-checkpoint inhibitors have a low risk of recurrence, which offers an opportunity to omit completion lymph node dissection (CLND) and subsequent adjuvant therapy and avoid the associated adverse events.

  • Patients with a pathological partial or non-response could benefit from CLND and adjuvant systemic therapy. Further research is needed to support selection of the optimal adjuvant treatment.

  • Biomarkers predictive of a pathological response might enable the identification of subgroups that are most likely to respond to neoadjuvant anti-PD-1 antibodies as monotherapy and/or in combination regimens. Candidate biomarkers include tumour mutational burden, PD-L1 expression and immune-related gene expression profiles such as the IFNγ signature.

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Fig. 1: Pathological response categories.
Fig. 2: Proposed personalized approach for neoadjuvant immunotherapy in melanoma and the corresponding biological mechanism.

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Acknowledgements

The authors gratefully acknowledge B. A. van de Wiel of the Department of Pathology, Netherlands Cancer Institute, Amsterdam for providing images for Fig. 1b–e.

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Authors and Affiliations

  1. Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands

    Minke W. Lucas, Judith M. Versluis, Elisa A. Rozeman & Christian U. Blank

  2. Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands

    Christian U. Blank

  3. Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands

    Christian U. Blank

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M.W.L. wrote the manuscript, all authors made substantial contributions to researching data for this article, discussions of content and reviewing and/or editing prior to submission.

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Correspondence to Christian U. Blank.

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Competing interests

C.U.B. has acted as an advisor to AZ, BMS, GenMab, GSK, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche and Third Rock Ventures, has received research funding from 4SC, BMS, NanoString and Novartis, is a co-founder of and owns shares in Immagene BV and Signature Oncology, and is listed as an inventor on several related patents (including submitted): WO 2021/177822 A1, N2027907 and P091040NL2. The other authors declare no competing interests.

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Lucas, M.W., Versluis, J.M., Rozeman, E.A. et al. Personalizing neoadjuvant immune-checkpoint inhibition in patients with melanoma. Nat Rev Clin Oncol 20, 408–422 (2023). https://doi.org/10.1038/s41571-023-00760-3

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