A Phase 1 Trial of Durvalumab in Combination with Bacillus Calmette-Guerin (BCG) or External Beam Radiation Therapy in Patients with BCG-unresponsive Non-muscle-Invasive Bladder Cancer: The Hoosier Cancer Research Network GU16-243 ADAPT-BLADDER Study.
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Hahn Noah M, O'Donnell Michael A, Efstathiou Jason A, Zahurak Marianna, Rosner Gary L, Smith Jeff, Kates Max R, Bivalacqua Trinity J, Tran Phuoc T, Song Daniel Y, Baras Alex S, Matoso Andres, Choi Woonyoung, Smith Kellie N, Pardoll Drew M, Marchionni Luigi, McGuire Bridget, Grace Phelan Mary, Johnson Burles A, O'Neal Tanya, McConkey David J, Rose Tracy L, Bjurlin Marc, Lim Emerson A, Drake Charles G, McKiernan James M, Deutsch Israel, Anderson Christopher B, Lamm Donald L, Geynisman Daniel M, Plimack Elizabeth R, Hallman Mark A, Horwitz Eric M, Al-Saleem Essel, Chen David Y T, Greenberg Richard E, Kutikov Alexander, Guo Gordon, Masterson Timothy A, Adra Nabil, Kaimakliotis Hristos Z
Аннотация
OBJECTIVE: To evaluate the safety and preliminary efficacy of anti-PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT).
DESIGN, SETTING, AND PARTICIPANTS: A multicenter phase 1 trial was conducted at community and academic sites.
INTERVENTION: Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only).
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Post-treatment cystoscopy and urine cytology were performed at 3 and 6 -mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates.
RESULTS AND LIMITATIONS: Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients.
CONCLUSIONS: D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches.
PATIENT SUMMARY: Durvalumab combination therapy can be safely administered to non-muscle-invasive bladder cancer patients with the goal of increasing durable response rates.