Predictable Clinical Benefits without Evidence of Synergy in Trials of Combination Therapies with Immune-Checkpoint Inhibitors

Purpose: Combinations of immune-checkpoint inhibitors (ICI) with other cancer therapies have been approved for advanced cancers in multiple indications, and numerous trials are under way to test new combinations. However, the mechanisms that account for the superiority of approved ICI combinations relative to their constituent monotherapies remain unknown. Experimental Design: We analyzed 13 phase III clinical trials testing combinations of ICIs with each other or other drugs in patients with advanced melanoma and lung, breast, gastric, kidney, and head and neck cancers. The clinical activity of the individual constituent therapies, measured in the same or a closely matched trial cohort, was used to compute progression-free survival (PFS) curves expected under a model of independent drug action. To identify additive or synergistic efficacy, PFS expected under this null model was compared with observed PFS by Cox regression. Results: PFS elicited by approved combination therapies with ICIs could be accurately predicted from monotherapy data using the independent drug action model (Pearson r = 0.98, P < 5 x 10(-9), N = 4,173 patients, 8 types of cancer). We found no evidence of drug additivity or synergy except in one trial in which such interactions might have extended median PFS by 9 days. Conclusions: Combining ICIs with other cancer therapies affords predictable and clinically meaningful benefit by providing patients with multiple chances of response to a single agent. Conversely, there exists no evidence in phase III trials that other therapies interact with and enhance the activity of ICIs. These findings can inform the design and testing of new ICI combination therapies while emphasizing the importance of developing better predictors (biomarkers) of ICI response.