Abstract
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.