Combinatorial benefit without synergy in recent clinical trials of immune checkpoint inhibitors

ABSTRACT Hundreds of clinical trials are testing combinations of Immune Checkpoint Inhibitors (ICIs) with other cancer therapies in the hope that they will have additive or synergistic efficacy involving mechanisms such as immune priming. However we find that the clinically observed benefits of recently reported and approved combination therapies with ICIs are fully and accurately accounted for by increasing the chance of a single-agent response in individual patients (drug independence), with no requirement for additive or synergistic efficacy (correlation between observed and expected Progression Free Survival: Pearson r = 0.98, P = 5×10 −9 , n = 4173 patients in 14 trials). Thus, the likely anti-tumor efficacy of new ICI combinations can be predicted if monotherapy data are available; predicting adverse effects remain challenging. Realizing the promise of drug additivity or synergy is likely to require better response biomarkers that identify patients in whom multiple constituents of a combination therapy are active.