Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer

Abstract

Purpose: To evaluate the safety and efficacy of gemcitabine and cisplatin in combination with the immune checkpoint inhibitor pembrolizumab as neoadjuvant therapy before radical cystectomy (RC) in muscle-invasive bladder cancer.

Methods: Patients with clinical T2-4aN0/XM0 muscle-invasive bladder cancer eligible for RC were enrolled. The initial six patients received lead-in pembrolizumab 200 mg once 2 weeks prior to pembrolizumab 200 mg once on day 1, cisplatin 70 mg/m² once on day 1, and gemcitabine 1,000 mg/m² once on days 1 and 8 every 21 days for four cycles. This schedule was discontinued for toxicity and subsequent patients received cisplatin 35 mg/m² once on days 1 and 8 without lead-in pembrolizumab. The primary end point was pathologic downstaging (< pT2N0) with null and alternative hypothesis rates of 35% and 55%, respectively. Secondary end points were toxicity including patient-reported outcomes, complete pathologic response (pT0N0), event-free survival, and overall survival. Association of pathologic downstaging with programmed cell death ligand 1 staining was explored.

Results: Thirty-nine patients were enrolled between June 2016 and March 2020 (72% cT2, 23% cT3, and 5% cT4a). Patients received a median of four cycles of therapy. All patients underwent RC except one who declined. Twenty-two of 39 patients (56% [95% CI, 40 to 72]) achieved < pT2N0 and 14 of 39 (36% [95% CI, 21 to 53]) achieved pT0N0. Most common adverse events (AEs) of any grade were thrombocytopenia (74%), anemia (69%), neutropenia (67%), and hypomagnesemia (67%). One patient had new-onset type 1 diabetes mellitus with ketoacidosis related to pembrolizumab and no patients required steroids for immune-related AEs. Clinicians consistently under-reported AEs when compared with patients.

Conclusion: Neoadjuvant gemcitabine and cisplatin plus pembrolizumab met its primary end point for improved pathologic downstaging and was generally safe. A global study of perioperative chemotherapy plus pembrolizumab or placebo is ongoing.

Trial registration: ClinicalTrials.gov NCT02690558.

FIG 1.

(A) Pathologic response and (B) pathologic downstaging at the time of cystectomy (pathologic stage compared with pretreatment clinical stage).

FIG 2.

Recurrence-free survival after cystectomy for (A) all patients and (B) stratified by pathologic response.

FIG 3.

Direct comparison of clinician-reported and patient-reported AEs. CTCAE clinician-reported maximum grade and PRO-CTCAE patient-reported maximum composite score were compared for each AE for every patient. The difference between maximum AE grade reported by clinicians and patients was calculated. The number of patient-AE pairs for each possible difference value are shown for each AE, demonstrating a consistent under-reporting of AE grade by clinicians. AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; PRO-CTCAE, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events.

FIG A1.

Flow diagram of the trial. AE, adverse event; IV, intravenous.

FIG A2.

Distribution of composite PRO-CTCAE scores at each protocol timepoint for (A) fatigue and (B) nausea. PRO-CTCAE, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events.