Abstract B003: Landscape of chemoradiation plus immunotherapy trials across multiple locally advanced cancer types: The more, the better?
Authors: Gui Bin , Parashar Bhupesh 
Published: January 2025

Purpose: Checkpoint inhibitors (ICIs) are being added to standard-of-care chemoradiotherapy in multiple clinical trials. The optimal sequencing of immunotherapy and chemoradiotherapy remains widely debated. Therefore, we compiled available trials and reviewed various aspects that may be associated with outcomes. Methods: We conducted a systematic literature review of randomized controlled Phase 3 trials (RCTs) in PubMed, ClinicalTrials.gov and Google scholar from 1/1/2018 to 11/8/2024. We included all available seminal randomized controlled trials with matured data, encompassing locally advanced non–small and small cell lung carcinomas, head and neck, endometrial and cervical cancers treated with chemoradiotherapy plus ICI. Performance of these trials with different ICI timing was analyzed in a high level and stratified by radiation treatment sites, oncovirus driven histology, anti PD1/PD-L1 agents and treatment discontinuation rate. Results: Eleven seminal randomized clinical trials across 6 different cancer types with 7891 patients were included. Among 5 trials with thoracic RT, 2 trials(PACIFIC and ADRIATIC) with only consolidative design proved PFS superiority over placebo, while PACIFIC-2 and LU-005 with concurrent and maintenance design did not. Moreover, CheckMate-73L failed to prove the superiority of concurrent and maintenance ICI over consolidative ICI. Among 3 head & neck trials all with induction + concurrent + maintenance design, only CONTINUUM trial treating nasopharyngeal cancer with 3 cycles of induction ICI proved EFS superiority. Among 3 gynecological trials all with concurrent + maintenance design, only anti PD-1 agent showed PFS superiority in cervical cancer (KEYNOTE-A18) and dMMR endometrial cancer (KEYNOTE-B21) in pre-planned analysis. The trials with concurrent ICI approaches failed in all non-viral driven cancers (NSCLC, SCLC and overall endometrial), but succeeded in EBV-rich Asian nasopharyngeal cancer (CONTINUUM) and HPV-driven cervical cancer (KEYNOTE-A18 and CALLA post hoc analysis of PD-L1 TAP ≥20%). However, this success was not found in HPV-driven head & neck squamous cell cancer (HPV subgroup of either KEYNOTE-412 or JAVELIN). For consolidative ICI trials in thorax, the treatment discontinuation rate was significantly lower in experimental arm compared to control arm (population weighted p=0.0003), mainly due to less tumor progression. For the trials with concurrent ICI, the treatment discontinuation rate was significantly higher in experimental arm (population weighted p=0.001), mainly due to more adverse events. Conclusion: Despite multifactorial heterogeneity, this review provides insights for designing future trials in locally advanced cancers. Consolidative ICI approaches generally showed superiority in thoracic cancers, while concurrent ICI approaches often failed in non-viral-driven cancers likely due to higher adverse events and discontinuation rates but showed efficacy in EBV-rich nasopharyngeal and HPV-driven cervical cancers. As more trial data matures, the existing trends will be further tested.

Citation Format: Bin Gui, Bhupesh Parashar. Landscape of chemoradiation plus immunotherapy trials across multiple locally advanced cancer types: The more, the better? [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B003.