Dose-limiting Urinary Toxicity With Pembrolizumab Combined With Weekly Hypofractionated Radiation Therapy in Bladder Cancer

Abstract

There is currently significant interest in the potential benefits of combining radiation and immune checkpoint blockade (ICB) to stimulate both regional and distant abscopal immune responses. In melanoma and lung cancer, patients who have received radiation therapy during ICB appear to have prolonged survival. The PLUMMB trial (Pembrolizumab in Muscle-invasive/Metastatic Bladder cancer) (NCT02560636) is a phase I study to test the tolerability of a combination of weekly radiation therapy with pembrolizumab in patients with metastatic or locally advanced urothelial cancer of the bladder. In the first dose-cohort, patients received pembrolizumab 100 mg 3-weekly, starting 2 weeks before commencing weekly adaptive bladder radiation therapy to a dose of 36 Gy in 6 fractions. The first dose-cohort was stopped after 5 patients, having met the predefined definition of dose-limiting toxicity. Three patients experienced grade 3 urinary toxicities, 2 of which were attributable to therapy. One patient experienced a grade 4 rectal perforation. In view of these findings, the trial has been paused and the protocol will be amended to reduce radiation therapy dose per fraction. The authors advise caution to those combining radiation therapy and ICB, particularly when radiation therapy is given at high dose per fraction for pelvic tumours. The PLUMMB trial met the protocol-defined definition of dose-limiting toxicity and will be amended to reduce radiation therapy dose.

Recent Progress of Potentiating Immune Checkpoint Blockade with External Stimuli—an Industry Perspective

“…In fact, in patients with bladder cancer, dose‐limiting urinary toxicity was reported when anti‐PD‐L1 antibodies were combined with radiotherapy. [ 69 ]…”

Review: Brain Metastases in Bladder Cancer

“…One explanation for LC improvement with hypofractionated WBRT is UC radioresistance responding favorably to higher RT doses per fraction [90]. Several trials demonstrated improved LC with hypofractionated RT for unresectable BC; however, combining hypofractionated RT with ICB may exacerbate treatment toxicity [91][92][93]. In the absence of larger, more robust data showing a consistent benefit for hypofractionated WBRT, we favor 30 Gy/10 fraction WBRT for multiple unresectable lesions, with consideration of hippocampal avoidance WBRT and concurrent and adjuvant memantine for eligible patients.…”

Photodynamic Therapy and Immune Checkpoint Blockade†

“…There is a 5% incidence rate of pneumonitis in conjunction with PD-1/PD-L1 blockade (17), and this approximately doubles when given in combination with CTLA-4 inhibition (18). Toxicity profiles of immune checkpoint inhibitors also vary as a function of combination with chemotherapies (19) and ionizing radiation (20,21). For example, a phase I study to test the tolerability of pembrolizumab and radiation therapy in patients with metastatic or locally advanced urothelial cancer of the bladder was paused due to grade 3 bladder toxicities although the radiation dosing schedule is normally well-tolerated alone.…”

“…For example, a phase I study to test the tolerability of pembrolizumab and radiation therapy in patients with metastatic or locally advanced urothelial cancer of the bladder was paused due to grade 3 bladder toxicities although the radiation dosing schedule is normally well-tolerated alone. The investigators plan to mitigate these in field toxicities by de-escalating the radiation dose (20).…”