Combination of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of cancer - a brief update

Our plain-English summary of Combination of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of cancer - a brief update, by J. Park, B.S. Skålhegg (Frontiers in Immunology, 2025).

The study

• Authors: J. Park, B.S. Skålhegg
• Journal: Frontiers in Immunology
• Published: 2025;16:1680838
• Type of article: Review
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The introduction of immune checkpoint inhibitors (ICIs) has revolutionized cancer therapy, offering durable responses in multiple malignancies by targeting regulatory pathways such as programmed cell death protein 1 (PD-1), its ligand (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These pathways, which normally maintain immune tolerance and homeostasis, can be exploited by tumors to evade immune surveillance. Dual blockade using monoclonal antibodies (mAbs) targeting PD-1/PD-L1 and CTLA-4 has shown synergistic effects, improving response rates, overall survival, and progression-free survival in several cancer types. The U.S. Food and Drug Administration (FDA) has approved two such combinations: nivolumab plus ipilimumab and durvalumab plus tremelimumab, based on demonstrated clinical benefit in melanoma, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer, pleural mesothelioma, and esophageal squamous cell carcinoma. However, clinical benefit has not been consistent across all tumor types, with limited efficacy observed in cancers such as glioblastoma, head and neck squamous cell carcinoma, and Merkel cell carcinoma. Additionally, combination therapy is associated with a higher incidence of immune-related adverse events, affecting multiple organ systems and necessitating careful dosing strategies to balance efficacy and toxicity. This review summarizes the current landscape of FDA-approved PD-1/PD-L1 and CTLA-4 combinations, their therapeutic achievements, clinical limitations, and supports future research in combination immunotherapy.

Copyright © 2025 Park and Skålhegg.

In plain English

This article is a review, not an original study; it does not examine asbestos exposure. The authors summarized published clinical trials of drugs blocking PD-1 or PD-L1 combined with drugs blocking CTLA-4. These were mainly the FDA-approved nivolumab plus ipilimumab and durvalumab plus tremelimumab, including unapproved uses, plus some trials of pembrolizumab plus ipilimumab. For mesothelioma, the review reported the CheckMate 743 phase 3 trial in unresectable malignant pleural mesothelioma. In that trial, median overall survival was 18.1 months with nivolumab plus ipilimumab versus 14.1 months with platinum-based chemotherapy, which led to FDA approval in 2020. A phase 2 trial of durvalumab plus tremelimumab in unresectable pleural or peritoneal mesothelioma reported a 25% response rate and median overall survival of 16.6 months. The article lists that combination as FDA-approved for hepatocellular carcinoma, and with added chemotherapy for non-small cell lung cancer, but not for mesothelioma. Across cancers, the review noted more frequent and severe treatment-related side effects with combinations than with single drugs. It also noted limited benefit in glioblastoma, head and neck squamous cell carcinoma and Merkel cell carcinoma. The authors concluded that the combinations improved clinical outcomes across multiple cancer types but carry a higher incidence of adverse events.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of published clinical trials of PD-1/PD-L1 plus CTLA-4 inhibitor combinations. It focused on the FDA-approved combinations but also covered trials in unapproved uses and trials of pembrolizumab plus ipilimumab.
• Who was studied: No population of its own. The review summarized clinical trials in many cancer types, including melanoma, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, lung cancer, mesothelioma and esophageal squamous cell carcinoma.
• Exposure: Not an asbestos exposure. The treatments reviewed were immune checkpoint inhibitor drug combinations, chiefly nivolumab plus ipilimumab and durvalumab plus tremelimumab, with some trials of pembrolizumab plus ipilimumab.
• Main results:
  • In the CheckMate 743 phase 3 trial in unresectable malignant pleural mesothelioma, nivolumab plus ipilimumab was compared with platinum-based chemotherapy. Median overall survival was 18.1 vs 14.1 months (HR 0.74, 96.6% CI 0.60 to 0.91; p=0.0020). Two-year overall survival was 41% vs 27%. Grade 3–4 adverse events occurred in 30%.
  • These CheckMate 743 results led to FDA approval of nivolumab plus ipilimumab in 2020 as first-line treatment for unresectable malignant pleural mesothelioma.
  • In the 3-year follow-up of CheckMate 743 (combination versus chemotherapy), the 3-year overall survival rate was 23% versus 15% and the progression-free survival rate was 14% versus 1%.
  • In a single-arm phase 2 trial in relapsed malignant pleural mesothelioma after platinum-based chemotherapy, nivolumab plus ipilimumab gave an ORR of 38%, median PFS of 6.2 months and 12-month overall survival of 64%.
  • In a randomized, non-comparative phase 2 trial in relapsed malignant pleural mesothelioma, the combination arm had an ORR of 27.8%, median overall survival of 15.9 months and a 12-month overall survival rate of 58.1%.
  • In a phase 2 trial of durvalumab plus tremelimumab in unresectable pleural or peritoneal mesothelioma, ORR was 25%, median PFS 8.0 months and median overall survival 16.6 months. Grade 3–4 adverse events occurred in 18%.
  • Table 1 lists tremelimumab as FDA-approved for hepatocellular carcinoma with durvalumab, and for NSCLC with durvalumab plus chemotherapy. It lists no mesothelioma indication.
  • In a neoadjuvant phase 2 study in resectable malignant pleural mesothelioma, median overall survival was not reached at 34.1 months of follow-up with durvalumab plus tremelimumab. With durvalumab alone it was 14 months.
  • Other combinations, such as pembrolizumab plus ipilimumab, were evaluated in a limited number of trials.
  • Across cancers, combination therapy was associated with increased frequency and severity of treatment-related adverse events compared with monotherapy.
  • Limited clinical benefit from nivolumab plus ipilimumab was observed in glioblastoma, head and neck squamous cell carcinoma and Merkel cell carcinoma.
• The authors' conclusion: The authors concluded that PD-1/PD-L1 plus CTLA-4 combinations led to significant improvements in clinical outcomes across multiple cancer types, but with a higher incidence of adverse events. They added that the best dosing varies by cancer type and that reliable biomarkers are needed to select patients.
• Limitations the authors state:
  • The authors stated that the review focused on combinations that have received FDA approval. Investigational agents and drugs approved by other agencies were outside its scope.

Topics

Medical terms in this study, explained in our Lexicon: PD-1/PD-L1, CTLA-4, checkpoint inhibitors, PD-L1, Monoclonal Antibody, Synergistic Effect, Overall Survival, Progression-Free Survival.

Related studies

• Efficacy and safety of PD-1/PD-L1 and CTLA-4 immune checkpoint inhibitors in the treatment of diffuse pleural mesothelioma: a systematic review and meta-analysis — P. Sun, D. Song, et al. (2025)
• JAK Inhibitor Upadacitinib Induces Remission in Refractory Immune-Related Colitis Triggered by CTLA-4 and PD-1 Inhibitor Combination Therapy in Malignant Pleural Mesothelioma: A Case Report — M. Kono, Y. Komeda, et al. (2024)
• Genetic variability of immune checkpoints in asbestos-related diseases — I. Zeljkovic, K. Goricar, et al. (2026)
• Safety and efficacy of PD-1/PD-L1 immune checkpoint inhibitors in patients with pre-treated advanced stage malignant mesothelioma: a systematic review and meta-analysis — A. Zafar, A.A. Rashid, et al. (2024)
• CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study — R.E. Sanborn, O. Hamid, et al. (2021)
• The combination of soluble forms of PD-1 and PD-L1 as a predictive marker of PD-1 blockade in patients with advanced cancers: a multicenter retrospective study — T. Kurosaki, K. Chamoto, et al. (2023)

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