Expanding access to cancer immunotherapy: A systematic review of low-dose PD-(L)1 inhibitor strategies

Abstract

Background: Anti-PD-(L)1 inhibitors have transformed cancer treatment. However, their high costs severely restrict their accessibility, especially in low- and middle-income countries (LMIC). Low-dose regimens, inferior to weigh-based or flat dosings, may help address this barrier. Our aim is to evaluate their dosing strategies, clinical outcomes, and potential cost savings.

Methods: WebOfScience, ASCO and ESMO conference databases were systematically searched until January 31st, 2025, for post- commercialization use of anti-PD-(L)1 agents at reduced doses compared to FDA- and/or EMA- approved weight-based regimens.

Results: Five clinical trials and 27 observational studies, including 2055 patients, met the review criteria. Two studies had non-inferiority designs, and 26 grouped patients across various treatment lines in the metastatic setting among them. Most studies originated from LMIC (53 %), focusing on head and neck (30 %) and lung cancers (15 %). Low-dose anti-PD-(L)1 use reported radiological responses in 16 (ranging 5-100 %), observing similar responses than pivotal trials in refractory Hodgkin lymphoma, lung and kidney cancers. Risk of bias was serious in 56 % of the studies, while rest was moderate. Nivolumab was the anti-PD-(L)1 most frequently investigated (k = 27). Nivo40mg Q2W (k = 8) and Nivo20mg Q3W (k = 6) were the most assessed doses. More than two-thirds of the studies achieved estimated savings of ≥ 80 % compared to list prices.

Conclusion: Low-dose anti-PD-(L)1 regimens show promising radiological responses, including as monotherapy, especially in lymphoma, lung and kidney cancers. However, the high risk of bias in available studies limits definitive conclusions. Prudent use may be considered in resource-limited settings. Ongoing non-inferiority trials or near-equivalence are essential to confirm clinical validity.

Keywords: Anti-PD1; Anti-PDL1; Cost-effectiveness; Financial toxicity; ICI; Immune-checkpoint inhibitor; Immunotherapy; Low-dose; Reduced dose; Ultra-low dose; Underdosing.