Next-Generation Checkpoint Combinations: Optimizing PD-(L)1-Based Therapy Across the Advanced, Adjuvant, and Neoadjuvant Settings.

Authors

Fausto Petrelli, Lara Colombo Zefinetti, Andrea D'Alessio, Lorenzo Dottorini, Antonio Ghidini

Published in

Current oncology reports. Volume 28. Issue 1. Jul 06, 2026. Epub Jul 06, 2026.

Abstract

Programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors are foundational components of therapy across many solid tumors, yet primary and acquired resistance limit durable benefit for a substantial proportion of patients. Rather than attempting a broad survey of every disease area, this review deliberately focuses on three tumor types in which PD-(L)1-based combinations have generated the most mature, practice-relevant evidence and in which the field is evolving most rapidly: renal cell carcinoma (RCC), urothelial (bladder) cancer, and non-small cell lung cancer (NSCLC). For each, we examine how combinations are being developed and positioned across the advanced, adjuvant, and neoadjuvant/perioperative settings, and we place selected cross-cutting strategies (dual checkpoint blockade, antibody-drug conjugates, hypoxia-inducible factor [HIF]-2α inhibition, and other partners) in that disease-specific context.
In RCC, immune checkpoint inhibitor (ICI) plus vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) doublets are established first-line standards, adjuvant pembrolizumab is the first agent to improve both disease-free and overall survival after nephrectomy, and the HIF-2α inhibitor belzutifan has become a post-ICI/TKI option while being tested earlier in disease. In bladder cancer, the antibody-drug conjugate enfortumab vedotin combined with pembrolizumab has displaced platinum chemotherapy as first-line therapy for advanced disease, and perioperative durvalumab added to neoadjuvant chemotherapy improves event-free and overall survival in muscle-invasive disease. In NSCLC, neoadjuvant and perioperative chemoimmunotherapy regimens now demonstrate overall survival benefit, complementing established advanced-disease and adjuvant strategies. We also summarize combinations that have failed-most notably concurrent PD-(L)1 blockade with EGFR or ALK TKIs in oncogene-driven NSCLC, and anti-TIGIT antibodies in phase III-because these negative results are as instructive as the successes. Within RCC, bladder cancer, and NSCLC, next-generation PD-(L)1 combinations are reshaping treatment across all disease stages. The magnitude of benefit, the relevant biomarkers, and the toxicity trade-offs differ substantially by tumor type and by setting. Successful development depends on a sound biologic rationale, biomarker-informed patient selection, and careful toxicity management, and the evidence base remains uneven-ranging from mature phase III data to early signals-which we make explicit throughout.

PMID:
42406187
Bibliographic data and abstract were imported from PubMed on 06 Jul 2026.

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