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.

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 (<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) <4 cycles 4 (24) Pembro Cycles 3 cycles 15 (88) <3 cycles 2 (12) * 1 patient with cN1 (T4a); + 1 patient had dose reduction.