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.

Conflict of interest statement

Tracy L. RoseResearch Funding: Roche/Genentech, GeneCentric, Bristol Myers Squibb, Merck, AstraZeneca Michael R. HarrisonConsulting or Advisory Role: Bayer, Exelixis, Genentech, Fujifilm, Janssen Oncology, AstraZeneca, Pfizer, Bristol Myers SquibbSpeakers' Bureau: Genentech, ExelixisResearch Funding: Bristol Myers Squibb, Genentech, Pfizer, Merck, Clovis Oncology, Acerta Pharma, AstraZeneca, Astellas Pharma, Bayer, Exelixis, Seattle Genetics Sundhar RamalingamHonoraria: Bayer Young E. WhangResearch Funding: Astellas Pharma, Clovis Oncology, Constellation Pharmaceuticals, Amgen, Regeneron, Arvinas Blaine BrowerConsulting or Advisory Role: Seattle Genetics/AstellasTravel, Accommodations, Expenses: Seattle Genetics/Astellas Marc A. BjurlinHonoraria: Intuitive Surgical Angela B. SmithConsulting or Advisory Role: Merck, Photocure, Urogen Pharma, Fergene, Ambu Matthew E. NielsenStock and Other Ownership Interests: Grand Rounds Health Eric WallenStock and Other Ownership Interests: MDxHealth Daniel GeorgeLeadership: Capio BioSciencesHonoraria: Sanofi, Bayer, Exelixis, EMD Serono, OncLive, Pfizer, UroToday, Acceleron Pharma, American Association for Cancer Research, Axess Oncology, Janssen Oncology, Millennium Medical PublishingConsulting or Advisory Role: Bayer, Exelixis, Pfizer, Sanofi, Astellas Pharma, Innocrin Pharma, Bristol Myers Squibb, Genentech, Janssen, Merck Sharp & Dohme, Myovant Sciences, AstraZeneca, Michael J. Hennessy Associates, Constellation Pharmaceuticals, Physicans' Education Resource, Propella Therapeutics, RevHealth LLCSpeakers' Bureau: Sanofi, Bayer, ExelixisResearch Funding: Exelixis, Janssen Oncology, Novartis, Pfizer, Astellas Pharma, Bristol Myers Squibb, Acerta Pharma, Bayer, Dendreon, Innocrin Pharma, Calithera Biosciences, Sanofi/AventisTravel, Accommodations, Expenses: Bayer, Exelixis, Merck, Pfizer, Sanofi, Janssen Oncology, UroToday Tian ZhangLeadership: Capio BioSciences, Archimmune TherapeuticsStock and Other Ownership Interests: Capio Biosciences, Archimmune Therapeutics, NanoroboticsHonoraria: Exelixis, Genentech/Roche, MJH Life Sciences, Pacific GenuityConsulting or Advisory Role: Janssen, Genentech/Roche, Sanofi, Exelixis, AstraZeneca, Pfizer, Bristol Myers Squibb, Foundation Medicine, Pharmacyclics, Amgen, Merck, Seattle Genetics, Dendreon, Calithera BiosciencesSpeakers' Bureau: Exelixis, Genentech/Roche, Genomic Health, Sanofi/AventisResearch Funding: Janssen, Acerta Pharma, Pfizer, Merrimack, Stem CentRx, Novartis, OmniSeq, Personal Genome Diagnostics, Regeneron, Merck, Mirati Therapeutics, Astellas PharmaPatents, Royalties, Other Intellectual Property: Circulating tumor cell novel capture by c-MET technology, Prochelators as Targeted Prodrugs for Prostate CancerTravel, Accommodations, Expenses: Acerta Pharma, Genomic Health, AstraZeneca Anthony DrierEmployment: Docs Global William Y. KimLeadership: Advanced Chemotherapy TechnologiesStock and Other Ownership Interests: Johnson & Johnson, Bristol Myers Squibb, Kura Oncology, BeiGene, FibroGen, Amgen, AbbVie, G1 Therapeutics, Spectrum Pharmaceuticals, Illumina, Arvinas, Fibrogen, NantWorks, Oramed, Natera, ZentalisHonoraria: Takeda, H3 BiomedicineConsulting or Advisory Role: GeneCentric, Foundation MedicineResearch Funding: Merck, GeneCentric, Foundation MedicinePatents, Royalties, Other Intellectual Property: BASE47 bladder cancer subtype classifier, PurIST (Purity Independent Subtyping of Tumors)Travel, Accommodations, Expenses: Takeda, H3 Biomedicine Matthew I. MilowskyResearch Funding: Merck, Roche/Genentech, Bristol Myers Squibb, Astellas Pharma, Clovis Oncology, Inovio Pharmaceuticals, Mirati Therapeutics, Constellation Pharmaceuticals, Syndax, Incyte, Amgen, Regeneron, Arvinas, Seagen, Pfizer, Johnson & Johnson/JanssenNo other potential conflicts of interest were reported.

Figures

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.