Phase I trial of hypofractionated radiotherapy and pembrolizumab in the treatment of muscle invasive/metastatic bladder cancer: Results of the PLUMMB trial.

756 Background: The objective of the PLUMMB trial (NCT02560636) was to assess the safety, tolerability and efficacy of the addition of the anti-PD1 antibody Pembrolizumab with hypofractionated weekly bladder radiotherapy (RT) in patients with advanced/metastatic bladder cancer. We present the final results, subject to database lock and statistical QC. Methods: The trial aimed to recruit 28 patients planned for RT to the bladder with a dose escalation phase (modified 3+3) of 7 dose cohorts to determine the primary endpoint maximum tolerated dose (MTD), and a dose expansion phase to answer the secondary endpoints: acute toxicity (up to 6 weeks post RT); late toxicity (until 28 days post Pembrolizumab (CTCAE - Common Terminology Criteria for Adverse Events) or 2 years post RT (RTOG - Radiation Therapy Oncology Group)); progression free survival (PFS); overall survival (OS); and local control of bladder cancer. Exploratory endpoint was control of bladder related symptoms. Results: Between Sep 2016 and Nov 2023, 28 patients were recruited: median age 75 (IQR 69-85), white, majority male (79%), ever-smokers (75%). Three (11%) had locally advanced (T2a-T2b N0 M0) and 25 (89%) had nodal/metastatic bladder cancer (T1b-T4 N0-N3 M0-M1b). Two patients did not receive any Pembrolizumab or RT so were excluded from endpoint analyses. Three patients remain on Pembrolizumab (all ≥6 months post RT). Five patients experienced dose limiting toxicity (DLT) (see table) and the MTD was confirmed at 24Gy in 6 fractions (f) and Pembrolizumab 200mg, which was the expansion cohort. The rates of worst acute toxicity in patients who had ≥2 doses of Pembrolizumab, ≥4f of RT and had a toxicity assessment 6 weeks post RT were: 4/20 (20%) grade 1; 12 (60%) grade 2; and 4 (20%) grade 3. For late toxicity in patients who had ≥1 dose of Pembrolizumab, 1f of RT and survived to 6 weeks post RT: 15/24 (63%) reported grade 2+ and 8 (33%) grade 3+ using CTCAE; and 5 (21%) reported grade 2 using RTOG not within 3 months of disease progression (0 grade 3+). For patients who had ≥1 dose of Pembrolizumab and 1f of RT: 13/26 (50%) had a response as per RECIST 1.1 (7 CR, 6 PR, 6 SD, 6 PD - best response). PFS and OS was 31% (95%CI: 15-49) and 62% (95%CI: 40-77) at 1 year, and 16% (95%CI: 5-34) and 33% (95%CI: 15-51) at 2 years, respectively. Finally, 12/24 (50%) patients were free of grade 2+ bladder symptoms at 3 months post RT, and 8 (33%) at 6 months. Conclusions: DLT is seen when combining 6Gy fractions of radiotherapy and Pembrolizumab 100-200mg, but 24Gy in 6f radiotherapy with Pembrolizumab is safe and effective in the treatment of advanced bladder cancer with 50% of patients having a favourable response. Clinical trial information: NCT02560636 . Dose Cohort Radiotherapy Pembrolizumab Number registered (%) Number with DLT A-1 36Gy in 6f 100 6 (21) 3 A-2 36Gy in 6f 200 B-1a 24Gy in 6f 100 1 (4) B-1b 24Gy in 6f 200 12 (43) B-2a 24Gy in 4f 100 4 (14) B-2b 24Gy in 4f 200 5 (18) 2 B-3a 30Gy in 5f 200