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Purpose of review <p>The advent of anti-PD-1 therapy has transformed the treatment paradigm of advanced melanoma, enabling durable responses in a proportion of patients. However, the impact of both primary and acquired resistance remains a significant barrier to sustained disease control. This review explores the biological rationale and clinical progress of anti-PD-1 based combination strategies, with a particular emphasis on emerging triplet regimens and next-generation immunotherapeutic approaches designed to extend survival and overcome resistance.</p> Recent Findings <p>While dual checkpoint inhibition (anti-PD-1 plus anti-CTLA-4 or anti-LAG-3) has improved clinical outcomes, further therapeutic advances are needed to expand the depth and durability of responses. Triplet combinations have shown promising activity in early-phase trials, with acceptable safety profiles. Promising triplet strategies currently under investigation include combinations of BRAF and MEK inhibitors with anti-PD-1 agents in BRAF-mutant melanoma, as well as regimens pairing anti-PD-1 therapy with emerging immunomodulatory agents. Biomarkers and disease control prior to infusion appear to be key determinants of outcome.</p> Summary <p>Anti-PD-1-based triplet therapies represent a promising frontier in melanoma treatment. Future trials should define optimal combinations, patient selection, and therapeutic sequencing to maximize benefit and minimize toxicity.</p>

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Anti-PD-1 Combinations: Triplets and Beyond

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月29日

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  • Claudia Trojaniello,
  • Antonella Lucia Marretta,
  • Bianca Arianna Facchini,
  • Paolo Antonio Ascierto

摘要

Purpose of review

The advent of anti-PD-1 therapy has transformed the treatment paradigm of advanced melanoma, enabling durable responses in a proportion of patients. However, the impact of both primary and acquired resistance remains a significant barrier to sustained disease control. This review explores the biological rationale and clinical progress of anti-PD-1 based combination strategies, with a particular emphasis on emerging triplet regimens and next-generation immunotherapeutic approaches designed to extend survival and overcome resistance.

Recent Findings

While dual checkpoint inhibition (anti-PD-1 plus anti-CTLA-4 or anti-LAG-3) has improved clinical outcomes, further therapeutic advances are needed to expand the depth and durability of responses. Triplet combinations have shown promising activity in early-phase trials, with acceptable safety profiles. Promising triplet strategies currently under investigation include combinations of BRAF and MEK inhibitors with anti-PD-1 agents in BRAF-mutant melanoma, as well as regimens pairing anti-PD-1 therapy with emerging immunomodulatory agents. Biomarkers and disease control prior to infusion appear to be key determinants of outcome.

Summary

Anti-PD-1-based triplet therapies represent a promising frontier in melanoma treatment. Future trials should define optimal combinations, patient selection, and therapeutic sequencing to maximize benefit and minimize toxicity.