A Phase I Study to Assess the Safety and Tolerability of Intravesical Pembrolizumab in Recurrent Non-Muscle Invasive Bladder Cancer (NMIBC).

406 Background: Intravesical BCG has been the mainstay of therapy following TURBT for intermediate risk NMIBC for many years and is thought to act through activation of non-specific local immunity. With the recent success of checkpoint inhibitor treatment in metastatic bladder cancer, we sought to investigate the anti-PD1 inhibitor pembrolizumab as a potential agent for use in patients with intermediate risk NMIBC in a phase I/II study. The primary aim of the phase I safety run-in was to assess the safety and tolerability of intravesical pembrolizumab after TURBT in patients with intermediate risk NMIBC. Methods: Eligible patients had recurrent NMIBC for which adjuvant treatment post TURBT was a reasonable treatment option, ECOG PS 0-1 and adequate end organ function. Pembrolizumab was administered by intravesical instillation once weekly for a total of 6 doses. Intra-patient dose escalation was performed in three paired patient cohorts with doses starting at 50mg and increasing through 100mg to a maximum of 200mg. Adverse events (AEs) were assessed using CTCAE v4.03 with dose limiting toxicity (DLT) defined as a clinically significant, drug related, grade 4 haematological or ≥ grade 3 non-haematological toxicity occurring within 7 days of administration of the first treatment at a given dose for that patient. Results: In the first 4 patients treated, no DLTs were seen during dose escalation. Drug-related AEs included Grade 1 dysuria, fatigue and nausea. Grade 1-2 urinary tract infections, Grade 1 cystitis and Grade 3 urosepsis (SAE) were observed but assessed as probably not related to pembrolizumab. Recruitment of a final cohort of two patients at repeated doses of 200mg is ongoing to confirm safety and tolerability of this dose. Conclusions: Administration of intravesical pembrolizumab was safe and well tolerated in patients with NMIBC following TURBT. A randomised, parallel group, phase II marker-lesion study to assess the safety, efficacy and tolerability of either intravesical pembrolizumab or intravenous pembrolizumab in a larger cohort of patients with intermediate risk recurrent NMIBC is planned. Clinical trial information: NCT03167151.