A phase II clinical trial of neoadjuvant sasanlimab and stereotactic body radiation therapy as an in situ vaccine for cisplatin-ineligible muscle invasive bladder cancer: The RAD VACCINE MIBC clinical trial.

Abstract

750 Background: Up to 50% of patients with muscle invasive bladder cancer (MIBC) are ineligible for cisplatin-based neoadjuvant chemotherapy (CNAC) posing a significant unmet need. Immune checkpoint inhibition (ICI) is an alternative strategy and has been combined with other systemic or local therapies to improve the pathologic complete response (pCR) rate, a surrogate for durable disease control. Stereotactic body radiation therapy (SBRT) at 8 Gy × 3 can induce immune activation and immunogenic cell death, potentially synergizing with ICI as an in situ vaccine generating tumor specific responses. Methods: We conducted a phase II prospective trial in patients with cT2–4aN0M0 MIBC who were ineligible or declined CNAC, evaluating the safety and efficacy of Sasanlimab (PF-06801591; two 300 mg SC doses, 28 days apart) with SBRT to the tumor (8 Gy x 3 fractions at 48-hourly intervals starting on the 2 nd ICI cycle) prior to radical cystectomy (RC). Using Simon’s 2-stage design, 15 patients were enrolled in a safety lead-in, targeting 33 total with the primary endpoint of pCR. Secondary endpoints included adverse events, health-related quality of life (EORTC QLQ C30), and recurrence free survival. Exploratory endpoints assessed germline/somatic sequencing, immunogenic cell death (Serum DAMP/iDAMP ratio), and spatial immune profiling. Results: From March 2022–April 2025, 33 patients were enrolled (predominantly urothelial, 73% ≥ cT3). Four withdrew due to progression after intervention before RC. The trial met its primary endpoint - 44.8% pCR (pT0) rate and 75.9% down-staged to pT0/Ta/T1. Two-year metastasis free survival was 72.2% overall, 92.3% for pCR, and 56.3% for non-pCR patients (p = 0.02). CTCAE grade ≥3 treatment-related AEs occurred in 9.1%: adrenal insufficiency (6.1%) and nephritis (3.0%, resolved with steroids). Grade ≥3 Clavien Dindo 30-day surgical AEs occurred in 13.8% of patients without any mortality. No significant deterioration in EORTC QOL C30 was observed from baseline through ICI therapy, SBRT or RC. Integrated single nuclei RNA sequencing, spatial transcriptomics, and multiplex flow cytometry revealed divergent response mechanisms. One patient subset presented mature tertiary lymphoid structures (TLS) and elevated T follicular helper cell frequency that associated with a germinal center TLS B cell response. Another patient subset exhibited robust dendritic cell expansion associated with an activated CD4+ T cell response. Conclusions: In situ vaccination (SBRT with ICI) achieved a meaningful pCR rate with acceptable toxicity in CNAC ineligible MIBC. These promising clinical and mechanistic findings support this strategy in future trials with other systemic agents to improve pCR with the potential for improved distant control, and organ preservation. Clinical trial information: NCT05241340 .