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