MELANOMA

Early responses indicate remission

Immune-checkpoint inhibitors have dramatically improved the outcomes of a subset of patients with melanoma across several different disease settings; however, the ability to identify patients who are most likely to respond remains largely elusive. Now, data from a single-institution trial reveal several early indicators of long-term disease-free survival in patients receiving a single dose of pembrolizumab.

A total of 27 patients with stage IIIB/C or stage IV melanoma received a single neoadjuvant dose (200 mg) of pembrolizumab 3 weeks before surgery, followed by adjuvant treatment. Explaining the rationale for this approach, first author Alex Huang explains: “we knew that an immune response was detectable in the blood at 3 weeks after administration of an anti-PD-1 antibody,” and therefore “we designed a clinical trial of a single dose of neoadjuvant pembrolizumab to study early immune and pathological events in the tumour.”

Approximately 30% of patients (8/27) had a complete or major pathological response to pembrolizumab and remained in remission after a median follow-up duration of 25 months. Analyses of immune kinetics in the blood identified CD8+ immune responses as early as 7 days after administration of pembrolizumab. Investigations of tumour material from the 20 patients with paired samples available revealed brisk lymphocyte infiltration among responders. Furthermore, tumour infiltrates from responding patients were enriched with CD8+ T cells expressing PD-1, CD39 and eomesodermin, suggesting an exhausted phenotype. T cells of this phenotype were detectable before treatment, indicating that pre-existing intratumoural T cells drive the early responsiveness to pembrolizumab observed in this study. Conversely, patients with high levels of regulatory T cell proliferation were more likely to have disease recurrence. Transcriptomic analyses revealed robust associations between a neoadjuvant response signature and response to pembrolizumab.

Senior author Tara Mitchell summarizes: “Patients can have complete tumour responses after a single dose of PD-1 blockade. These early responses are predictive of recurrence-free survival; no patients with complete or near complete responses have developed recurrent or metastatic melanoma.” These findings await further validation in a larger cohort of patients.

References

Original article

  1. Huang, A. C. et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat. Med. https://doi.org/10.1038/s41591-019-0357-y (2019)

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Correspondence to Peter Sidaway.

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Sidaway, P. Early responses indicate remission. Nat Rev Clin Oncol 16, 272 (2019). https://doi.org/10.1038/s41571-019-0196-2

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