Durvalumab (PD-L1) + tremelimumab (CTLA-4) neoadjuvant combo hits 44% pCR—but higher CTLA-4 dose triggers serious irAEs in cisplatin-ineligible MIBC

Durvalumab (anti–PD-L1) plus tremelimumab (anti–CTLA-4) was evaluated in a pilot neoadjuvant study for cisplatin-ineligible, high-risk muscle-invasive urothelial carcinoma (NCT02812420), with cystectomy planned 4–6 weeks after therapy. In the higher-dose tremelimumab cohort (D 1500mg + T 300mg; n=13), 9 patients underwent cystectomy; among those, pCR was 44% (4/9) with 1-year RFS 67% (SE 16%) and 1-year OS 62% (SE 14%), but 3 grade ≥3 irAEs (colitis, hepatitis, and myositis/myocarditis) led to early cohort termination and 2 patients became unable to proceed to surgery due to toxicity (both later died). With longer follow-up in the lower-dose cohort (D 1500mg + T 75mg; n=28), 5-year OS was 82% (SE 7%) and 5-year RFS was 74% (SE 9%); as a benchmark, single-agent neoadjuvant atezolizumab in cisplatin-ineligible/refusing MIBC (ABACUS) delivered pCR 31% and 1-year RFS 79%, suggesting the pCR signal here is in-range-to-higher while the higher-dose CTLA-4 toxicity looks less tolerable for a curative-intent setting. Baseline tertiary lymphoid structures (TLS) associated with downstaging/response (TLS-high responders 69% vs 29% TLS-low; OR 0.18, 95% CI 0.04–0.75) and trended toward improved RFS/OS (RFS HR 0.24, p=0.047; OS HR 0.32, p=0.068).