Neoadjuvant Durvalumab ± Tremelimumab in Combination With Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Muscle-Invasive Bladder Carcinoma: Results of the Phase I/II NEMIO Study.

PURPOSE: To evaluate the efficacy and safety of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) combined with durvalumab ± tremelimumab in patients with muscle-invasive bladder cancer (MIBC).

METHODS

NEMIO (ClinicalTrials.gov identifier: NCT03549715) is a multicenter, randomized, noncomparative phase II trial in cT2-T4a N0-1 cisplatin-eligible MIBC planned for radical cystectomy (RC). Patients received ddMVAC (cisplatin 70 mg/m2, methotrexate 30 mg/m2, doxorubicin 30 mg/m2, and vinblastine 3 mg/m2 on days 1, and pegfilgrastim 6 mg on days 2) once every 2 weeks × four cycles plus durvalumab ± tremelimumab (durvalumab 1,500 mg and tremelimumab 75 mg) once every 4 weeks × two doses (C1D1 and C3D1) before RC. Coprimary end points (local assessment) were pathologic complete response (pCR; ypT0N0) and grade ≥3 treatment-related adverse events (TRAEs). The study was considered positive if the pCR rate was ≥45% and the rate of grade ≥3 TRAEs was ≤30%.

RESULTS

From 2018 to 2022, 119 patients received ddMVAC + durvalumab (n = 60) or ddMVAC + durvalumab + tremelimumab (n = 59); 113 underwent RC. The overall Bayesian posterior mean pCR rate was 48.70% (95% CI, 35.93 to 61.56) with doublet and 46.27% (95% CI, 33.92 to 58.85) with triplet. Among 103 patients with PD-L1 data (exploratory), Bayesian posterior mean pCR was 68.25% (95% CI, 54.57 to 80.49) in PD-L1-high tumors versus 33.49% (95% CI, 22.13 to 45.91) in PD-L1-low/negative tumors. Bayesian posterior mean grade ≥3 TRAEs occurred in 40.95% (95% CI, 32.50 to 49.69) overall (30.48% [95% CI, 20.00 to 42.08] doublet; 49.63% [95% CI, 37.55 to 61.73] triplet); immune-related adverse events occurred in 26.9% (grade ≥3 4.2%). Two-year event-free survival and overall survival rates were 75% and 85% in the doublet arm, and 77% and 88% in the triplet arm, respectively.

CONCLUSION

Neoadjuvant ddMVAC plus durvalumab demonstrated encouraging pCR rates, favorable early survival outcomes, and manageable safety profile. Adding tremelimumab provides similar pCR but worse toxicity. These results support further study of ddMVAC plus durvalumab as a neoadjuvant chemoimmunotherapy strategy for localized MIBC, to be evaluated in comparative trials within an evolving perioperative treatment landscape.