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.
Competing Interest Statement
PKS is a member of the SAB or Board of Directors of Glencoe Software, Applied Biomath and RareCyte Inc and has equity in these companies. In the last five years the Sorger lab has received research funding from Novartis and Merck. Sorger declares that none of these relationships are directly or indirectly related to the content of this manuscript. BI is a consultant for Merck and Volastra.
Funding Statement
This work was funded by NCI grants U54-CA225088 to PKS and K08-CA222663 to BI. BI is supported by the Burroughs Wellcome Fund Career Award for Medical Scientists.
Author Declarations
All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.
Yes
All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.
Yes
Data Availability
All source data is from published clinical trials cited in references and Supplementary Tables 1-3.
