Quantitative Evaluation of Pharmacologic Synergy for Neoadjuvant Enfortumab Vedotin Plus Pembrolizumab in Muscle-Invasive Bladder Cancer: A Copula-Based Secondary Analysis

Abstract

Objectives

Perioperative treatment with enfortumab vedotin (EV) plus pembrolizumab has demonstrated a high pathological complete response (pCR) rate in patients with cisplatin-ineligible muscle-invasive bladder cancer (MIBC). However, whether this therapeutic benefit reflects true pharmacologic synergy or can be explained by independent drug action (IDA) remains uncertain.

Methods

We analyzed data from EV-103 cohort H (EV monotherapy), the cisplatin-ineligible subset of PURE-01 (pembrolizumab monotherapy), and KEYNOTE-905/EV-303 (EV plus pembrolizumab). An IDA model incorporating a Gaussian copula was applied to estimate the predicted pCR rate of the combination therapy. The primary analysis assumed weak positive dependence between drug responses (correlation coefficient ρ = 0.24). Sensitivity analyses evaluated the observed-minus-IDA-predicted pCR difference across a continuous range of dependence assumptions (ρ = 0.00–0.99).

Results

The predicted pCR rate for EV plus pembrolizumab was 53.5%, consisting of 21.4% EV-only responders, 17.1% pembrolizumab-only responders, and 15.0% dual responders. The observed pCR rate in the KEYNOTE-905/EV-303 trial was 57.1%, corresponding to an absolute difference of 3.6 percentage points compared with the model prediction. In sensitivity analyses, the posterior median observed-minus-predicted difference increased with stronger positive dependence, but the 95% credible intervals were wide and included zero across a broad range of dependence assumptions.

Conclusions

Although modest pharmacologic synergy cannot be excluded given the uncertainty in the available data, substantial population-level pharmacologic synergy is not required to explain the high pCR observed with the combination.