5681 - A Phase Ib/2 study of neoadjuvant pembrolizumab (pembro) and chemotherapy for locally advanced Urothelial Cancer (UC)

Background

Pembro is FDA and EMA approved for metastatic UC and may improve response rates in the locally advanced setting when combined with gemcitabine (G) and cisplatin (C) neoadjuvant chemotherapy (NAC). Cohort I of the multicenter phase 1b/2 chemo-immunomodulation trial evaluated NAC GC and pembro in C-eligible patients (pts).

Methods

Pts with cT2-4aN0M0 UC or mixed histology are eligible on cohort I (C-eligible) or II (C-ineligible). Phase 1b and 2 treatments were the same: pembro 200mg q3wks on day 8 for 5 doses; with C (70mg/m2) day 1, and G (1000mg/m2) days 1 and 8 of a 21 day cycle, for 4 cycles; followed by radical cystectomy with node dissection (RC). Minimum criteria for evaluation of safety is one dose pembro and for efficacy is two doses and RC. The primary endpoint is pathologic non-muscle invasive rate (PaIR, ≤pT1N0M0) of ≥48%.

Results

Cohort I completed accrual on phase 1b/2 and safety & efficacy analysis for 40 evaluable pts are presented. Median age 65 yrs, 75% male, 10% had mixed UC histology, and PD-L1 combined positive score ≥10 was 52%. No DLTs in 6 pts on phase 1b. There was 1 death on post-RC day 9 due to mesenteric ischemia (ileal conduit). One pt did not have RC due to AE (gr4 thrombocytopenic purpura); UC in remission at 14mo. One pt with presumed gr3 MI during cycle 4 had a negative inpatient cardiac workup and completed therapy and RC without further gr3/4 AE. One gr4 hyponatremia and ten gr3 events did not preclude RC (2-each thromboembolism, elevated creatinine, hyponatremia;1-each: dehydration, emesis, neutropenic fever, infection). Gr 3/4 cytopenias occurred in 57% of pts. Median number of doses given for pembro=5, C=4, G=8. Of 35 pts who had RC (4 refused, 1AE) the median time to surgery was 18.5wks from registration, and 5.3wks from last dose. Baseline stage was cT2 51%, cT3 44%, cT4a 5%. The PaIR was 60% (95% CI: 42, 74) and did not correlate with baseline PD-L1 score. At 14 months (1.6 – 33.3) median follow up, the estimated 12mo relapse free-, overall-, and disease specific survival, is 80%, 94%, and 97%, respectively.

Conclusions

Neoadjuvant GC with pembro in locally advanced UC has manageable toxicity, a comparable time to surgery as NAC, and is associated with robust disease downstage and control rate that warrants further study.

Clinical trial identification

Clinicaltrials.gov: NCT02365766

Editorial Acknowledgement