Abstract B011: Predictable successes: drug additivity explains the efficacy of combination therapies for metastatic urothelial cancer
Authors: Schlachter Noah M. , Miller Eric J. , Anker Jonathan F. , Galsky Matthew D. , Palmer Adam C. 
Published: May 2024

Abstract
Objective: Combination drug regimens have changed the treatment landscape of metastatic urothelial cancer (mUC) and other cancers and are integrated into routine clinical practice. Combination drug regimens may impact cancer outcomes via three major pharmacologic principles: less-than-additive, additive, or more-than-additive efficacy (i.e., synergy). Despite the profound implications of these types of interactions on future drug and biomarker development, as well as on treatment sequencing, these principles have been underexplored in contemporary clinical trials. Here we analyze recent phase 3 trials in locally advanced or metastatic UC to assess whether progression-free survival (PFS) distributions of combination therapies with immune checkpoint inhibitors (ICIs) are lesser than, greater than, or equal to the additive effect expected based on single-agent efficacies. Methods: We analyzed phase 3 trials in locally advanced or metastatic UC including EV302, CheckMate 901, KEYNOTE-361, DANUBE, and IMvigor130. When one monotherapy was not included as an arm in the phase 3 trial, we utilized monotherapy PFS distributions from trials in patients with metastatic UC including EV103, KEYNOTE-045, CheckMate 275, and HCRN-GU17-294. The expected additive effect of a drug combination was calculated by adding the PFS durations of individual drugs, sampled from monotherapy distributions, as recently described for other approved oncology drug combinations (Hwangbo et al, Nature Cancer, 2023). Results: Combination therapies with ICIs were as clinically effective as predicted by additivity, or less so in one case. Specifically, Pembrolizumab plus Enfortumab vedotin (EV302), Nivolumab plus Gemcitabine/Cisplatin (CheckMate 901), Pembrolizumab plus chemotherapy (KEYNOTE-361), and Durvalumab plus Tremelimumab (DANUBE) each exhibited PFS distributions that were statistically indistinguishable from PFS predicted by the additivity model (Cox Proportional Hazards). Atezolizumab plus chemotherapy (IMvigor130) was inferior to additivity. Subgroup analyses by PD-L1 expression and by cisplatin versus carboplatin will be presented. Conclusions: Life-prolonging treatments for mUC have been the result of additive combination therapies, wherein the efficacy of the drug combination is quantitatively explained by the individual efficacies of the component drugs. Additivity in this setting has several potential implications: (1) when a single-agent is principally active in a biomarker-defined subpopulation, the use of that agent in a combination will also principally improve outcomes in that subpopulation; (2) net duration of disease control may be similar between up-front combination and sequential use of the same drugs; assuming that the biology of disease at progression does not preclude the ability to receive subsequent lines of therapy, and (3) future drug development should prioritize combinations based on highly active single agents rather than solely based on hypothesized mechanistic rationale.
Citation Format: Noah M. Schlachter, Eric J. Miller, Jonathan F. Anker, Matthew D. Galsky, Adam C. Palmer. Predictable successes: drug additivity explains the efficacy of combination therapies for metastatic urothelial cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B011.