Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance)

Abstract

Purpose: The combination of gemcitabine and cisplatin (GC) is a standard therapy for metastatic urothelial carcinoma. Based on data that angiogenesis plays a role in urothelial carcinoma growth and progression, a randomized placebo-controlled trial was performed with the primary objective of testing whether patients treated with GC and bevacizumab (GCB) have superior overall survival (OS) than patients treated with GC and placebo (GCP).

Patients and methods: Between July 2009 and December 2014, 506 patients with metastatic urothelial carcinoma without prior chemotherapy for metastatic disease and no neoadjuvant or adjuvant chemotherapy within 12 months were randomly assigned to receive either GCB or GCP. The primary end point was OS, with secondary end points of progression-free survival, objective response, and toxicity.

Results: With a median follow-up of 76.3 months among alive patients, the median OS was 14.5 months for patients treated with GCB and 14.3 months for patients treated with GCP (hazard ratio for death = 0.87; 95% CI, 0.72 to 1.05; two-sided stratified log-rank P = .14). The median progression-free survival was 8.0 months for GCB and 6.7 months for GCP (hazard ratio = 0.77; 95% CI, 0.63 to 0.95; P = .016). The proportion of patients with grade 3 or greater adverse events did not differ significantly between both arms, although increased bevacizumab-related toxicities such as hypertension and proteinuria occurred in the bevacizumab-treated arm.

Conclusion: The addition of bevacizumab to GC did not result in improved OS. The observed median OS of about 14 months is consistent with prior phase III trials of cisplatin-based chemotherapy.

Trial registration: ClinicalTrials.gov NCT00942331.

Conflict of interest statement

Jonathan E. RosenbergStock and Other Ownership Interests: IlluminaHonoraria: UpToDate, Medscape, Peerview, Research To Practice, Intellisphere, Clinical Care Options, ClinicalMind, Physicans' Education ResourceConsulting or Advisory Role: Lilly, Merck, Roche/Genentech, AstraZeneca/MedImmune, Bristol Myers Squibb, Seattle Genetics, Bayer, BioClin Therapeutics, QED Therapeutics, Adicet Bio, Fortress Biotech, Pharmacyclics, Western Oncolytics, GlaxoSmithKline, Janssen Oncology, Astellas Pharma, Boehringer Ingelheim, Pfizer/EMD Serono, Mirati Therapeutics, ImmunomedicsResearch Funding: Genentech/Roche, Seattle Genetics, Bayer, AstraZeneca, QED Therapeutics, Astellas PharmaPatents, Royalties, Other Intellectual Property: Predictor of platinum sensitivity Karla A. BallmanConsulting or Advisory Role: ARIAD, Medtronic, Takeda, AgenusPatents, Royalties, Other Intellectual Property: Prostate cancer signature patentExpert Testimony: Janssen Oncology, Lilly, Sanofi Susan HalabiEmployment: ASCO Amir MortazaviHonoraria: Motive Medical IntelligenceConsulting or Advisory Role: Seattle Genetics, Debiopharm Group, PfizerResearch Funding: Acerta Pharma, Genentech/Roche, Merck, Novartis, Seattle Genetics, Mirati Therapeutics, Bristol Myers Squibb, Roche, Astellas Pharma, Debiopharm Group Christopher SweeneyStock and Other Ownership Interests: LeuchemixConsulting or Advisory Role: Sanofi, Janssen Biotech, Astellas Pharma, Bayer, Genentech/Roche, AstraZeneca, Pfizer, Amgen, LillyResearch Funding: Janssen Biotech, Astellas Pharma, Sanofi, Bayer, Dendreon, PfizerPatents, Royalties, Other Intellectual Property: Leuchemix, Parthenolide, Dimethylaminoparthenolide. Exelixis: Abiraterone plus cabozantinib combination Walter M. StadlerConsulting or Advisory Role: CVS Caremark, Sotio, AstraZeneca, Eisai, Bayer, Pfizer, Merck, Treadwell TherapeuticsResearch Funding: Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Exelixis, Novartis, Genentech/Roche, GlaxoSmithKline, Medivation, Pfizer, Merck, Millennium, Janssen, Johnson & Johnson, AstraZeneca, AbbVie, X4 Pharma, Calithera Biosciences, Clovis Oncology, Eisai, Seattle Genetics, Tesaro, Corvus Pharmaceuticals, Astellas MedivationExpert Testimony: TevaOther Relationship: UpToDate, American Cancer Society Benjamin A. TeplyConsulting or Advisory Role: Janssen, AstraZenecaResearch Funding: AstraZeneca, Inovio Pharmaceuticals, Bristol Myers SquibbPatents, Royalties, Other Intellectual Property: Receive royalties from patents related to health/medicine, held by MIT Joel PicusConsulting or Advisory Role: Novo Nordisk, PfizerResearch Funding: BioClin Therapeutics, Mirati Therapeutics, Rexahn Pharmaceuticals, Seattle Genetics, TRACON Pharma, eFFECTOR Therapeutics Scott T. TagawaConsulting or Advisory Role: Medivation, Astellas Pharma, Dendreon, Janssen, Bayer, Genentech, Endocyte, Immunomedics, Karyopharm Therapeutics, AbbVie, Tolmar, QED Therapeutics, Amgen, Sanofi, Pfizer, Clovis Oncology, Novartis, Genomic Health, POINT Biopharma, Blue Earth Diagnostics, Seattle Genetics, AIkido Pharma, 4D PharmaResearch Funding: Lilly, Sanofi, Janssen, Astellas Pharma, Progenics, Millennium, Amgen, Bristol Myers Squibb, Dendreon, Rexahn Pharmaceuticals, Bayer, Genentech, Newlink Genetics, Inovio Pharmaceuticals, AstraZeneca, Immunomedics, Novartis, AVEO, Boehringer Ingelheim, Merck, Stem CentRx, Karyopharm Therapeutics, AbbVie, Medivation, Endocyte, Exelixis, Clovis Oncology, POINT BiopharmaTravel, Accommodations, Expenses: Sanofi, Immunomedics, AmgenUncompensated Relationships: Telix Pharmaceuticals, ATLAB Pharma, Phosplatin Therapeutics Sreedhar KatragaddaConsulting or Advisory Role: Curio ScienceTravel, Accommodations, Expenses: Xcenda Daniel VaenaHonoraria: HMPConsulting or Advisory Role: Bristol Myers Squibb, Bayer, Genomic Health, Natera, Seattle Genetics, Exelixis, EMD Serono, Immunomedics, Bristol Myers Squibb/Celgene, EisaiResearch Funding: Bristol Myers Squibb, Novartis, AstraZeneca, Peloton Therapeutics, BioClin Therapeutics, Aeglea Biotherapeutics, Nektar, Calithera Biosciences, Tizona Therapeutics Inc, Compugen, TG Therapeutics, Merck, OBI Pharma, Incyte, Seattle Genetics, Roche/Genentech, Blueprint Medicines Christopher HoimesHonoraria: Seattle GeneticsConsulting or Advisory Role: Bristol Myers Squibb, Eisai, Prometheus, Seattle Genetics, Genentech/Roche, Merck Sharp & Dohme, 2bPreciseSpeakers' Bureau: Bristol Myers Squibb, Genentech/Roche, Astellas Pharma, Seattle Genetics, EisaiResearch Funding: Merck Sharp & DohmeUncompensated Relationships: 2bPrecise Elizabeth R. PlimackConsulting or Advisory Role: Bristol Myers Squibb, Genentech/Roche, Janssen, Merck, Flatiron Health, Seattle Genetics, Pfizer, AstraZeneca, Infinity Pharmaceuticals, MEI PharmaResearch Funding: Bristol Myers Squibb, AstraZeneca, Pfizer, Merck Sharp & Dohme, Astellas Pharma, Genentech/RochePatents, Royalties, Other Intellectual Property: US patent no.: 14/588,503, Filed January 2, 2015Open Payments Link: https://openpaymentsdata.cms.gov/physician/66377 Thomas W. FlaigLeadership: Aurora OncologyStock and Other Ownership Interests: Aurora OncologyConsulting or Advisory Role: Seattle Genetics, Janssen OncologyResearch Funding: Novartis, Bavarian Nordic, Dendreon, GTx, Janssen Oncology, Medivation, Sanofi, Pfizer, Bristol Myers Squibb, Roche/Genentech, Exelixis, Aragon Pharmaceuticals, Sotio, Tokai Pharmaceuticals, AstraZeneca/MedImmune, Lilly, Astellas Pharma, Agensys, Seattle Genetics, La Roche-Posay, Merck, SeagenPatents, Royalties, Other Intellectual Property: The University of Colorado has filed two patents related in which I am an inventor. These are related to early-stage bladder cancer treatment and detection. Neither is commercialized or licensed at this time Robert DreicerConsulting or Advisory Role: Astellas Pharma, Pfizer, Eisai, Merck, EMD Serono, Propella Therapeutics, Myovant Sciences, Bayer, Tavanta Therapeutics, Veru, Infinity Pharmaceuticals, Pfizer/AstellasResearch Funding: Seattle Genetics, Bristol Myers Squibb, Exelixis, Novartis Dean BajorinConsulting or Advisory Role: Merck, Dragonfly Therapeutics, Fidia Farmaceutici SpA, Bristol Myers Squibb FoundationResearch Funding: Novartis, Merck, Bristol Myers Squibb, AstraZeneca, Astellas Pharma, Seattle Genetics/AstellasTravel, Accommodations, Expenses: Merck Olwen HahnLeadership: Via OncologyStock and Other Ownership Interests: Teleflex MedicalHonoraria: Cardinal HealthConsulting or Advisory Role: PfizerTravel, Accommodations, Expenses: Cardinal Health Eric J. SmallStock and Other Ownership Interests: Fortis, Harpoon TherapeuticsHonoraria: Janssen, Johnson & JohnsonConsulting or Advisory Role: Fortis, Janssen Oncology, Beigene, Tolero Pharmaceuticals, Teon Therapeutics, Ultragenyx PharmaceuticalsResearch Funding: JanssenTravel, Accommodations, Expenses: JanssenOpen Payments Link: https://openpaymentsdata.cms.gov/physician/660367/summary Michael J. MorrisConsulting or Advisory Role: Bayer, Endocyte, Advanced Accelerator Applications, ORIC Pharmaceuticals, Johnson & Johnson, Curium Pharma, AthenexResearch Funding: Bayer, Sanofi, Endocyte, Progenics, Corcept Therapeutics, Roche/Genentech, JanssenTravel, Accommodations, Expenses: Endocyte, FujifilmNo other potential conflicts of interest were reported.

Figures

FIG 1.

CONSORT diagram. All randomly assigned patients were included in the OS and PFS analyses. Only patients with measurable disease were included in the objective response analysis. GCB, gemcitabine, cisplatin, and bevacizumab; GCP, gemcitabine, cisplatin, and placebo; OS, overall survival; PFS, progression-free survival.

FIG 2.

(A) Kaplan-Meier curves showing overall survival of patients treated with GCB or GCP. (B) Kaplan-Meier curves showing progression-free survival of patients treated with GCB or GCP. aKaplan-Meier method, bCox model, cWald chi-square test, and dLog-rank test. GCB, gemcitabine, cisplatin, and bevacizumab; GCP, gemcitabine, cisplatin, and placebo; HR, hazard ratio.

FIG 3.

Subgroup analyses of (A) overall survival and (B) progression-free survival. HR, hazard ratio.