PD-1 checkpoint blockade alone or combined PD-1 and CTLA-4 blockade as immunotherapy for lung cancer?

ABSTRACT

Introduction: Signaling through T-cell surface, an immune checkpoint protein such as PD-1 or CTLA-4 helps dampen or terminate unwanted immune responses. Blocking a single immune checkpoint or multiple checkpoints simultaneously can generate anti-tumor activity against a variety of cancers including lung cancer.

Area covered: This review highlights the results of recent clinical studies of single or combination checkpoint inhibitor immunotherapy in non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). The authors discuss pembrolizumab and pembrolizumab plus ipilimumab, durvalumab and durvalumab plus tremelimumab, nivolumab and nivolumab plus ipilimumab for NSCLC as well as nivolumab and nivolumab plus ipilimumab for SCLC.

Expert opinion: Available data suggest that, in both metastatic NSCLC and SCLC, combined PD-1 and CTLA-4 blockade may produce a higher tumor response rate than PD-1 blockade alone. Nevertheless, combination therapy is associated with an increased toxicity. Several larger-scale studies are currently ongoing. For checkpoint inhibitor immunotherapy in SCLC and NSCLC, combination therapy is associated with a higher incidence of toxicities than single therapy; however, it appears to help increase tumor response rate. The increased response rate, if confirmed in larger scale studies, will likely make combination therapy another useful therapeutic approach for lung cancer.

KEYWORDS:

• Lung neoplasm
• immunotherapy
• PD-1
• checkpoint inhibitor
• nivolumab
• pembrolizumab

Article highlights

• To date, no results from randomized study directly comparing single agent anti PD-1 vs. anti PD-1 plus anti CTLA-4 checkpoint in lung cancer are available for review.

• In a small study of metastatic NSCLC, pembrolizumab plus ipilimumab produced 25% objective response rate (ORR), while historically single-agent pembrolizumab was associated with 18% ORR.

• In a phase-Ib study of metastatic NSCLC, durvalumab plus tremelimumab produced 18% ORR, while historically single-agent durvalumab was associated with 16% ORR.

• In a study of treatment-naïve metastatic NSCLC, nivolumab plus ipilimumab produced 43% ORR, while in another cohort of the same study nivolumab alone produced 23% ORR.

• In a phase 1/2 study of advanced SCLC, nivolumab plus ipilimumab produced 21% ORR, while nivolumab alone produced 10% ORR.

• Overall, treatment with a combined checkpoint inhibitor blockade was associated with greater toxicity than what would be expected with single-agent PD-1 blockade.

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Declaration of interest

J Gray has received research funding from Merck & Co and has received support for acting as a speaker and as a member of the advisory board of Genentech. SJ Antonia has also acted as a consultant for Bristol-Myers Squibb, AstraZeneca, Medimmune, Merck & Co and Cellular Biomedicine Group Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This manuscript has not been funded.