Neoadjuvant pembrolizumab (pembro) and accelerated methotrexate, vinblastine, doxorubicin, cisplatin (aMVAC) in non-urothelial (non-UC) histologic subtype muscle invasive bladder cancer (MIBC): A phase 2 trial.
Authors: Ruben Raychaudhuri, Ali Raza Khaki, Mary Weber Redman, Kelsey K. Baker, Aaron Lin, Brianna Woo, Andrii Hannochka, Nathan Conrad, Funda Vakar-Lopez, Todd Yezefski, Michael Thomas Schweizer, Robert Bruce Montgomery, Evan Y. Yu, Atreya Dash, Sarah P. Psutka, Daniel W. Lin, George R. Schade, John L. Gore, Jonathan L. Wright, Petros Grivas
Journal: Journal of Clinical Oncology (2025)

769 Background: Cisplatin-based chemotherapy (CT) prior to radical cystectomy (RC) + perioperative anti-PDL1 improves pathologic complete response rates (pCR) and survival in MIBC with predominant UC. Outcomes are poorer in the 5-10% of MIBC with pure/predominant non-UC histology. Thus, optimizing neoadjuvant therapy for these patients (pts) is critical. Pembro monotherapy has induced promising pCR rates in histologic subtypes (PURE-01 trial). We hypothesized that aMVAC + pembro would be safe and effective for non-UC MIBC and conducted a single-center trial testing this combination in pts with pure/predominant non-UC MIBC. Methods: Pts with resectable MIBC (cT2-4a/N0-1) with pure/predominant non-UC histology and fit for CT and RC were treated with neoadjuvant pembro (200mg q3 weeks x 3) + aMVAC (q2 weeks x 4) with G-CSF. Primary endpoint was pCR rate. Secondary endpoints included toxicity, pathologic downstaging (&lt;ypT2N0), and event-free and overall survival (EFS, OS) from initiation of neoadjuvant therapy. EFS/OS were estimated using Kaplan-Meier method. A single arm phase II trial with 91% exact power to rule out 8% pCR rate at 1-sided 4% level, if true pCR rate was 36%, required 17 pts. If ≥4/17 had pCR, then an 8% pCR rate was rejected. Results: 17 pts were enrolled from 3/2020 to 3/2024 (Table). Median age was 60 (range 39-74); 12 were male, 5 female. Predominant histologies at TURBT were squamous (5), plasmacytoid (3), micropapillary (3), poorly differentiated (3), glandular (2), and sarcomatoid (1). 4 pts discontinued treatment (2 toxicity, 1 patient choice, 1 unrelated illness), of whom 2 completed 3 planned pembro doses. Median time to RC from completing neoadjuvant therapy was 6 weeks (range 4-24); 2/17 pts did not proceed to RC, 1 (squamous) due to clinical status (achieved clinical CR and remained recurrence-free) and 1 (micropapillary) deemed to have unresectable MIBC. 9/17 patients (53%) achieved pCR; 1 patient achieved ypTisN0 (downstaging 59%). With median follow-up of 29 months the estimated 2-year OS was 75% (95%CI: 40-91) and estimated 2-year EFS was 69% (95%CI: 36-88). Median OS was not reached; estimated median EFS was 38 months (95%CI: 12, NR). Conclusions: The primary endpoint was met: pCR and downstaging rates with neoadjuvant aMVAC + pembro were significantly higher than reported historically in pts with pure/predominant non-UC MIBC. EFS/OS were also encouraging. No new safety signal was noted; all but 2 pts underwent RC. Correlative analysis for putative biomarkers, using tissue, blood and urine biospecimens, is ongoing. Clinical trial information: NCT04383743 . Baseline and Treatment Characteristics N(%) Clinical T-Stage at diagnosis T2 10 (59) T3-4 * 7 (41) aMVAC Cycles 4 cycles + 13 (76) &lt;4 cycles 4 (24) Pembro Cycles 3 cycles 15 (88) &lt;3 cycles 2 (12) * 1 patient with cN1 (T4a); + 1 patient had dose reduction.