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: Raychaudhuri Ruben , Khaki Ali Raza , Redman Mary Weber , Baker Kelsey K. , Lin Aaron , Woo Brianna , Hannochka Andrii , Conrad Nathan , Vakar-Lopez Funda , Yezefski Todd , Schweizer Michael Thomas , Montgomery Robert Bruce , Yu Evan Y. , Dash Atreya , Psutka Sarah P. , Lin Daniel W. , Schade George R. , Gore John L. , Wright Jonathan L. , Grivas Petros 
Published: February 2025

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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.