Neoadjuvant nivolumab (N) +/- ipilimumab (I) in cisplatin-ineligible patients (pts) with muscle-invasive bladder cancer (MIBC).
Authors: Guercio Brendan John , Pietzak Eugene J. , Brown Samantha , Chen Jie-Fu , Peters Vanessa , Regazzi Ashley Marie , Aggen David Henry , Donahue Timothy F. , Goh Alvin C. , Cha Eugene K. , Donat S. Machele , Dalbagni Guido , Bochner Bernard H. , Funt Samuel Aaron , Bajorin Dean F. , Iyer Gopa , Ostrovnaya Irina , Al-Ahmadie Hikmat A. , Rosenberg Jonathan E. , Teo Min Yuen 
Published: February 2022

498 Background: Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy (RC) confers survival benefit but a substantial subset of MIBC pts are cisplatin-ineligible. We conducted a phase II trial of N±I neoadjuvant therapy for cisplatin-ineligible MIBC. Methods: Cisplatin-ineligible pts with MIBC (cT2-T4aN0M0) were enrolled into 2 consecutive cohorts of 15 pts each (C1: N 3 mg/kg q 2 weeks (wk) x 5; C2: I (3mg/kg) + N (1mg/kg) wk 0 and 6, with N (3mg/kg) wk 3 and 9). A 3rd cohort was planned (C3: I (3mg/kg) + N (1mg/kg) q 3 wk x 3). Primary endpoint (EP) was eligibility for planned RC within 60 days without delay from treatment-related adverse events (TRAEs) or progressive disease (PD). Secondary EPs included pathologic downstaging (PaDo, <ypT2pN0) and complete response (pCR, ypT0pN0) rates, recurrence-free survival (RFS), and safety. Exploratory EP was event-free survival (EFS). Results: From 8/2018-5/2021, 15 pts were enrolled onto C1 and C2 (N = 30). Median age 76 (range 53-87), 80% male, with median Charlson comorbidity score of 1 (range 0-5). In C1 and C2, 14/15 and 6/15 pts received all planned treatment, respectively. In C2, 7/15 received ≤ 50% of planned doses. In C1, 11 pts underwent RC, 2 had PD before RC, 1 did not undergo RC due to TRAE, and 1 declined RC. Overall, 12/15 met the primary EP. For C2, 9 pts underwent RC, 3 had PD before RC, 2 did not undergo RC due to AE (1 of which was TRAE), and 1 opted for radiation, with 8/15 meeting the primary EP. C3 was dropped due to C2’s failure to meet the primary EP. In C1, 4 pts had PaDo (26%), with 2 pCRs (13%). In C2, 3 pts had PaDo (20%), with 1 pCR (7%). In C1, 1 pt who did not undergo RC due to TRAE had clinical CR of 13.2 months (mos) but died of sepsis at 16.1 mos; 2 pts in C2 who did not undergo RC have ongoing clinical CR at 16.1 and 10.8 mos follow-up (f/u). For time-to-event EPs, see Table. In C1, the only observed grade 3-4 TRAE was myocarditis (n=1, 7%). In C2, 4 pts (27%) had grade 3-4 TRAE, including elevated lipase (20%), pneumonitis (13%), fatigue (13%), and elevated AST + ALT(13%). Median tumor mutation burden was 8.8/megabase; DNA damage response genes were altered in 31% of pts and FGFR3 in 14%, with no genomic correlation with PaDo. For C1, 4/10 had baseline PD-L1 expression on ≥1% of tumor cells; 1 had PD-L1 ≥5%. Conclusions: In this cohort of cisplatin-ineligible pts with MIBC and comorbidities, neoadjuvant N was well tolerated. N+I was associated with greater toxicity resulting in RC delays. Pathologic response rates were low in both cohorts, raising questions about utility of treatment intensification in cisplatin-ineligible patients. Some pts who did not undergo RC due to TRAEs had sustained clinical CR. Clinical trial information: NCT03520491. Clinical trial information: NCT03520491. [Table: see text]