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.
INTRODUCTION
The treatment of metastatic urothelial (transitional cell) carcinoma has undergone major shifts since 2016, when the first immune checkpoint inhibitor was approved.1 Since then, seven new drugs have been approved for metastatic disease. However, cisplatin-based combination chemotherapy remains the standard first-line therapy for patients who are fit to receive it. Gemcitabine and cisplatin (GC) doublet chemotherapy has become the de facto standard-of-care treatment based on its improved tolerability profile and similar anticancer activity as the combination of methotrexate, vinblastine, doxorubicin, and cisplatin.2
CONTEXT
Key Objective
Does angiogenesis inhibition with bevacizumab improve survival in patients with metastatic urothelial cancer treated with gemcitabine and cisplatin (GC) chemotherapy?
Knowledge Generated
Cisplatin-based therapy is the standard treatment for patients with metastatic urothelial cancer. Angiogenesis has been shown to be associated with stage and aggressiveness in urothelial cancer. Phase II trials suggested that the addition of bevacizumab to chemotherapy would prolong survival compared with historical controls.
Relevance
In this trial, the addition of bevacizumab to GC chemotherapy, compared with GC and placebo, did not improve overall survival. The progression-free survival was longer by 1.3 months, but was not felt to be clinically relevant. Data from recent phase III trials show that platinum-based chemotherapy remains the standard of care for most patients, followed by immunotherapy either as maintenance for patients with a response or stable disease or as treatment for disease progression on platinum-based chemotherapy. Further work is needed to identify those patients where angiogenesis inhibition might be critical.
Angiogenesis is a fundamental process underlying cancer growth and progression, and vascular endothelial growth factor A (VEGF-A) is the primary mediator of this process in urothelial carcinoma. Higher VEGF and hypoxia-inducible factor 1α levels are associated with increased risk of cancer progression and poor prognosis.3-5 Targeting angiogenesis in advanced urothelial carcinoma has shown signs of antitumor activity in early-stage clinical trials,6-9 although the results have been inconsistent.10 Single-agent VEGF-targeted tyrosine kinase inhibitors show low rates of objective responses in refractory disease. Treatment with ramucirumab, an anti-VEGFR2 antibody, improved progression-free survival (PFS) in platinum-refractory urothelial carcinoma in phase II and III testing, but no significant overall survival (OS) benefit was observed.11-13 Although approved by the US Food and Drug Administration in several other malignancies, ramucirumab is not approved for urothelial carcinoma.
Bevacizumab, a humanized monoclonal antibody targeting VEGFA, has shown efficacy in several cancer types in combination with chemotherapy.14-17 The role of VEGF pathway inhibition in untreated metastatic urothelial carcinoma was explored in two phase II trials using bevacizumab in combination with cytotoxic chemotherapy. A single-arm phase II study of bevacizumab in combination with GC in metastatic urothelial carcinoma demonstrated a longer than expected OS compared with historical controls (19.1 months v expected 14 months).18 A similar single-arm phase II trial of gemcitabine, carboplatin, and bevacizumab also showed longer than expected OS compared with historical controls.19
Cancer and Leukemia Group B (CALGB) 90601 was designed as a randomized, double-blind, placebo-controlled phase III trial to determine whether the addition of bevacizumab to standard GC chemotherapy improved OS in patients with metastatic urothelial carcinoma. CALGB is now part of the Alliance for Clinical Trials in Oncology.
PATIENTS AND METHODS
Eligibility
Adult patients having an Eastern Cooperative Oncology Group performance score of 0 or 1 were enrolled on this study if they had histologically or cytologically documented metastatic or locally advanced or unresectable urothelial carcinoma. Patients with prior combination chemotherapy for metastatic disease or prior treatment with bevacizumab or other angiogenesis inhibitors were not eligible. Prior neoadjuvant or adjuvant chemotherapy was permissible, provided that the interval from the end of therapy to diagnosis of metastatic disease was at least 1 year. All patients were required to have adequate organ function for cisplatin-based chemotherapy, including a measured or calculated creatinine clearance ≥ 50 mL/min and, for bevacizumab-placebo treatment, proteinuria ≤ grade 1. Patients were excluded if they had current New York Heart Association class II-IV congestive heart failure; significant bleeding or arterial thrombotic events within 6 months; history of brain metastasis; clinically significant peripheral arterial disease; GI perforation within 12 months; nonhealing wounds, ulcers, or bone fractures; grade 2 or greater peripheral neuropathy; or peritoneal carcinomatosis. Each participant signed an institutional review board–approved, protocol-specific informed consent document in accordance with federal and institutional guidelines.
Study Design
This was a randomized, double-blind phase III trial in which patients were randomly assigned with equal probability to one of the two treatment regimens: gemcitabine, cisplatin, and placebo (GCP) or gemcitabine, cisplatin, and bevacizumab (GCB). Random assignment was stratified by the presence of visceral metastases (lung, liver, bone, splenic, or intra-abdominal) and prior administration of neoadjuvant, adjuvant, or radiosensitizing systemic chemotherapy for urothelial cancer (yes or no).
End Points
The primary end point was OS, which was determined from the date of random assignment to date of death because of any cause. Patients who were alive were censored at the time of their last follow-up. Secondary end points were PFS, objective response (defined as confirmed complete and partial responses), and adverse events. PFS was defined from the date of random assignment to date of progression or death because of any cause, whichever occurred first. Progression was defined using the RECIST 1.0 criteria. Patients without disease progression or death at the time of analysis were censored at the time of the last disease status assessment (or, if no disease assessments were performed after the baseline visit, at the time of random assignment plus 1 day). Patients who received nonprotocol-specified anticancer therapy before experiencing documented disease progression were censored at the time of receiving the nonprotocol-specified therapy. Objective response was defined as either confirmed complete response or partial response using RECIST 1.0 criteria. Imaging scans of the disease were performed at baseline and then every three cycles until disease progression, relapse, or initiation of nonprotocol therapy.
Treatment
Patients received gemcitabine 1,000 mg/m2 intravenously on days 1 and 8 and cisplatin 70 mg/m2 intravenously on day 1 every 21 days. For patients with creatinine clearance between 50 and 59 mL/min, the cisplatin dose could be divided into 35 mg/m2 each on days 1 and 8. Patients could receive up to six cycles of chemotherapy. Bevacizumab or placebo was administered at a dose of 15 mg/kg every 21 days starting from day 1 of chemotherapy. Patients continued maintenance bevacizumab or placebo upon completion of planned chemotherapy until cancer progression or unacceptable toxicity. Patients received appropriate supportive care per institutional guidelines.
Statistical Analyses
The primary end point was OS. The target sample size was 500 randomly assigned patients with 454 deaths at final analysis. The log-rank test had 87% power to detect a hazard ratio (HR) of death of 0.74 (equivalent to a difference in the median OS from 13.8 months in the GCP arm to 18.6 months in the GCB arm), assuming a two-sided type I error rate of 0.05, a monthly accrual rate of almost 14 patients/mo accrued over a 36-month enrollment period, a follow-up period of 36 months after study closure, and that the OS followed an exponential distribution. There were planned interim analyses for superiority and futility. The Lan-Demets analog of the O'Brien-Fleming sequential boundary was used to maintain the overall significance level of α = .05 while conducting interim analyses on OS. None of the stopping boundaries were crossed for the planned interim analyses.
The trial was monitored by the Alliance Data and Safety Monitoring Board (DSMB) for efficacy and safety. The time needed to reach the study-specified number of deaths was longer than anticipated; thus, the study team requested the release of the data from Alliance DSMB when 419 deaths were observed. The analysis performed on the data at this time did not cross the efficacy boundary. A sensitivity analysis was performed in which the remaining number of needed deaths was assigned to the GCP arm, but the efficacy boundary was still not crossed. Based on this, the Alliance DSMB released the data for final analysis.
An intent-to-treat approach was used in the analysis for all the clinical end points with the exception of adverse events and objective response (which was evaluable only in patients with measurable disease at study entry). The primary analysis of OS and PFS end points was based on a two-sided stratified log-rank test for treatment effect, with stratification factors of visceral metastases (yes or no) and prior chemotherapy (yes or no). The proportional hazards model was used to generate HRs for OS and PFS (comparing the GCB arm with the GCP arm) and corresponding 95% CIs. These hazards models included the stratification factors. In addition, exploratory interaction tests were conducted to determine whether the effect of treatment varied by subgroups (stratification factors, performance status, sex, and primary tumor site). A forest plot displayed the 95% CIs for the subgroups of interest. The Kaplan-Meier method was used to estimate the OS and PFS distributions by treatment arms. An inverse Kaplan-Meier estimate was used to estimate the follow-up duration. The Cochran-Mantel-Haenszel test was used to compare the proportion of patients who experienced an objective response between the two treatment arms, adjusting for the stratification factor variables. All-cause adverse events were tabulated as frequency and relative frequency according to the maximum grade of the event experienced by the patient.
All reported P values are two-sided. The date of the locked database was September 15, 2020. All analyses were conducted using SAS (version 9.4M6). Data collection and statistical analyses were conducted by the Alliance Statistics and Data Center. Data quality was ensured by review of data by the Alliance Statistics and Data Center and by the study chairperson following Alliance policies.
RESULTS
Patient Characteristics
Between July 15, 2009, and December 2, 2014, 506 patients were randomly assigned to GCB or GCP. The CONSORT diagram is shown in Figure 1. All patients who were randomly assigned were included in the primary analysis for OS and PFS. Overall, the arms were well-balanced for known prognostic factors (Table 1). More than two thirds (69%) of patients had visceral metastasis. Numerically, more patients in the GCB arm had good performance status than in the GCP arm (58% v 51%). Most patients had not received prior perioperative chemotherapy. As expected, most patients had tumors of bladder origin.
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.
TABLE 1.
Patient Characteristics and Stratification Factors
Efficacy
The primary end point analysis for OS includes 425 deaths (209 for GCB and 216 for GCP) with a median follow-up time of 76.3 months (95% CI, 69.1 to 83.0) for those who are alive. The median OS was 14.5 months (95% CI, 13.5 to 16.2) for patients treated with GCB and 14.3 months (95% CI, 12.2 to 16.2) for patients treated with GCP (two-sided stratified log rank P = .15; Fig 2A). The corresponding HR was 0.87 (95% CI, 0.72 to 1.05). Subgroup analyses did not reveal any subsets of patients with a significant improvement in OS compared with placebo (Fig 3A). All the relevant subgroup by treatment interaction tests were not statistically significant.
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.
The median follow-up time for PFS was 46.0 months (95% CI, 29.2 to 68.1) for those without progression or death, and there were 370 PFS events (185 for GCB and 185 for GCP). The median number of follow-up tumor scans performed for GCB patients was 3 (95% CI, 0 to 13) and for GCP was 2 (95% CI, 0 to 11). Within the GCB arm, 53 patients were censored at the time of nonprotocol treatment and two patients had 0 follow-up assessments compared with 54 patients and one patient, respectively, in the GCP arm. Subgroup analyses did not reveal any subsets of patients with a significant improvement in PFS compared with placebo (Fig 3B). PFS was statistically significantly longer in patients treated with GCB than in patients treated with GCP (8.0 months [95% CI, 7.1 to 8.5] for GCB and 6.7 months [95% CI, 6.3 to 7.4] for GCP; HR = 0.77; 95% CI, 0.63 to 0.95; two-sided log rank P = .015; Fig 2B), although the absolute difference in the median PFS of 1.3 months is not considered clinically meaningful.
There was no significant difference in objective response rate (ORR) between the two arms (two-sided P = .56; Table 2); patients treated with GCB had a confirmed ORR of 40.4% (95% CI, 33.8 to 47.0), and patients treated with GCP had a confirmed ORR of 36.4% (95% CI, 29.8 to 42.9). Eight percent of patients in both arms had complete responses. Unconfirmed best responses did not differ significantly between both arms (Appendix Table A1, online only).
TABLE 2.
Objective Responses
Safety
The safety population for this trial consisted of the 469 (237 GCB and 232 GCP) patients who received at least one dose of protocol treatment. The median number of chemotherapy cycles was six in both arms. Chemotherapy dose reductions occurred in 90 (38%) patients treated with GCB and 90 (39%) patients treated with GCP. The reasons for chemotherapy dose reductions and delays are shown in Appendix Tables A2 and A3 (online only). Chemotherapy discontinuations for adverse events occurred in 41 (16%) patients treated with GCB and 35 (14%) patients treated with GCP (Appendix Table A4, online only). Reasons for discontinuation of bevacizumab or placebo are found in Appendix Table A5 (online only).
Maintenance therapy after chemotherapy was initiated in 113 patients on GCB and 105 on GCP. Of these, the median number of bevacizumab or placebo cycles was six and four, respectively. Maintenance therapy was discontinued because of adverse events in 17 GCB patients (15%) and eight GCP patients (8%) and because of progression in 74 GCB patients (65%) and 74 GCP patients (70%).
Grade 3-4 thrombocytopenia was more frequent in patients treated with GCB than in patients treated with GCP (27% v 18%), although rates of anemia and febrile neutropenia were similar (Table 3). Hypertension and proteinuria, both expected bevacizumab-related side effects, were more frequent in patients treated with GCB (Table 4). There was no increase in thrombosis overall. Twelve treatment-related grade 5 events were reported: seven in the GCB arm and five in the GCP arm (Appendix Table A6, online only). There were 84 (35.4%) patients with a serious adverse event in the GCB arm compared with 73 (31.5%) patients in the GCP arm.
TABLE 3.
Hematologic Adverse Events
TABLE 4.
Nonhematologic Adverse Events
DISCUSSION
The addition of bevacizumab to standard first-line chemotherapy for locally advanced or metastatic urothelial carcinoma did not improve OS, the primary end point of this trial. PFS was improved, but the 1.3-month difference between arms was not clinically meaningful. The standard of care for first-line therapy remained unchanged during the 5 years it took to accrue the 506 patients for this trial. Even today, cisplatin-based chemotherapy without the addition of biologic agents remains the standard of care as first-line therapy in patients with adequate organ function.
When this trial was designed, phase II data from two single-arm trials suggested that the addition of bevacizumab to gemcitabine and platinum chemotherapy yielded longer than expected median survival compared with historical controls.18,19 Interestingly, neither of those trials suggested a significant improvement in PFS. Conversely, the anti-VEGFR2 antibody ramucirumab improved PFS but not OS in phase II and III testing.11-13 Collectively, these trials affirm the importance of phase III randomized trials testing the addition of novel agents, particularly when adding them to active cytotoxic regimens.
Although treatment was overall tolerable and toxicity was not dramatically different between the arms, typical bevacizumab on-target toxicities such as proteinuria and hypertension were increased in the GCB arm. In addition, bevacizumab led to modest increases in thrombocytopenia, although dose reductions were similar between the two arms. The rates of thrombotic events were similar overall, although there were numerically more strokes and myocardial infarctions in the GCB arm than in the GCP arm.
Despite preclinical and clinical data suggesting a benefit for targeting angiogenesis in bladder cancer, bevacizumab did not improve survival in this trial. The results in this study with a PFS but not OS advantage appear similar to those using bevacizumab in combination with chemotherapy in many other solid tumors.20-22 Recent data suggest that a proportion of patients have angiogenesis-driven tumors,23 and the expectation is that those patients are more likely to benefit from angiogenesis inhibition. However, although angiogenesis RNA expression signatures have been associated with benefit to VEGF-targeted tyrosine kinase inhibitors in clear cell kidney cancer,24,25 clinically validated angiogenesis biomarkers for use in patient selection are not yet defined in any other solid tumor. Archival specimens from patients enrolled on this trial have been collected to evaluate whether angiogenesis signatures identified in other tumor types might identify a subset of patients who benefit from antiangiogenic therapy.
Much work remains to be done to improve outcomes of patients with metastatic urothelial carcinoma. The recent US Food and Drug Administration26 approval of avelumab as maintenance therapy was based on a 7.1-month improvement in OS in patients who have had stable disease or response to platinum-based chemotherapy. The approvals of enfortumab vedotin and erdafitinib provide new options for patients with progressive disease after platinum chemotherapy and/or immunotherapy. In the coming years, improved understanding of the association of molecular biomarkers and response to chemotherapy may allow for optimal patient selection for treatment; these studies are ongoing and use specimens from this and other trials.
In conclusion, the addition of bevacizumab did not improve OS over GC chemotherapy alone. Although there was a modest improvement in PFS, these results do not change the standard of care, which remains initiation of first-line therapy with cisplatin-based combination chemotherapy for medically eligible patients.
ACKNOWLEDGMENT
The authors would like to acknowledge Elizabeth Harlos, Cecilia Mitchell, and Misty Bova-Solem for their work on biostatistics and data management and Sara DiNapoli and Margaret McPartland for editorial assistance.
Appendix
TABLE A1.
Unconfirmed Best Objective Responses
TABLE A2.
Reasons for Chemotherapy Dose Reduction by Drug and by Arm
TABLE A3.
Reasons for Chemotherapy Delay by Drug and by Arm
TABLE A4.
Reasons for Chemotherapy Discontinuation
TABLE A5.
Reasons for Bevacizumab or Placebo Discontinuation
TABLE A6.
Grade 5 Noncancer Treatment–Related Deaths
Jonathan E. Rosenberg
Stock and Other Ownership Interests: Illumina
Honoraria: UpToDate, Medscape, Peerview, Research To Practice, Intellisphere, Clinical Care Options, ClinicalMind, Physicans' Education Resource
Consulting 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, Immunomedics
Research Funding: Genentech/Roche, Seattle Genetics, Bayer, AstraZeneca, QED Therapeutics, Astellas Pharma
Patents, Royalties, Other Intellectual Property: Predictor of platinum sensitivity
Karla A. Ballman
Consulting or Advisory Role: ARIAD, Medtronic, Takeda, Agenus
Patents, Royalties, Other Intellectual Property: Prostate cancer signature patent
Expert Testimony: Janssen Oncology, Lilly, Sanofi
Susan Halabi
Employment: ASCO
Amir Mortazavi
Honoraria: Motive Medical Intelligence
Consulting or Advisory Role: Seattle Genetics, Debiopharm Group, Pfizer
Research Funding: Acerta Pharma, Genentech/Roche, Merck, Novartis, Seattle Genetics, Mirati Therapeutics, Bristol Myers Squibb, Roche, Astellas Pharma, Debiopharm Group
Christopher Sweeney
Stock and Other Ownership Interests: Leuchemix
Consulting or Advisory Role: Sanofi, Janssen Biotech, Astellas Pharma, Bayer, Genentech/Roche, AstraZeneca, Pfizer, Amgen, Lilly
Research Funding: Janssen Biotech, Astellas Pharma, Sanofi, Bayer, Dendreon, Pfizer
Patents, Royalties, Other Intellectual Property: Leuchemix, Parthenolide, Dimethylaminoparthenolide. Exelixis: Abiraterone plus cabozantinib combination
Walter M. Stadler
Consulting or Advisory Role: CVS Caremark, Sotio, AstraZeneca, Eisai, Bayer, Pfizer, Merck, Treadwell Therapeutics
Research 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 Medivation
Expert Testimony: Teva
Other Relationship: UpToDate, American Cancer Society
Benjamin A. Teply
Consulting or Advisory Role: Janssen, AstraZeneca
Research Funding: AstraZeneca, Inovio Pharmaceuticals, Bristol Myers Squibb
Patents, Royalties, Other Intellectual Property: Receive royalties from patents related to health/medicine, held by MIT
Joel Picus
Consulting or Advisory Role: Novo Nordisk, Pfizer
Research Funding: BioClin Therapeutics, Mirati Therapeutics, Rexahn Pharmaceuticals, Seattle Genetics, TRACON Pharma, eFFECTOR Therapeutics
Scott T. Tagawa
Consulting 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 Pharma
Research 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 Biopharma
Travel, Accommodations, Expenses: Sanofi, Immunomedics, Amgen
Uncompensated Relationships: Telix Pharmaceuticals, ATLAB Pharma, Phosplatin Therapeutics
Sreedhar Katragadda
Consulting or Advisory Role: Curio Science
Travel, Accommodations, Expenses: Xcenda
Daniel Vaena
Honoraria: HMP
Consulting or Advisory Role: Bristol Myers Squibb, Bayer, Genomic Health, Natera, Seattle Genetics, Exelixis, EMD Serono, Immunomedics, Bristol Myers Squibb/Celgene, Eisai
Research 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 Hoimes
Honoraria: Seattle Genetics
Consulting or Advisory Role: Bristol Myers Squibb, Eisai, Prometheus, Seattle Genetics, Genentech/Roche, Merck Sharp & Dohme, 2bPrecise
Speakers' Bureau: Bristol Myers Squibb, Genentech/Roche, Astellas Pharma, Seattle Genetics, Eisai
Research Funding: Merck Sharp & Dohme
Uncompensated Relationships: 2bPrecise
Elizabeth R. Plimack
Consulting or Advisory Role: Bristol Myers Squibb, Genentech/Roche, Janssen, Merck, Flatiron Health, Seattle Genetics, Pfizer, AstraZeneca, Infinity Pharmaceuticals, MEI Pharma
Research Funding: Bristol Myers Squibb, AstraZeneca, Pfizer, Merck Sharp & Dohme, Astellas Pharma, Genentech/Roche
Patents, Royalties, Other Intellectual Property: US patent no.: 14/588,503, Filed January 2, 2015
Open Payments Link: https://openpaymentsdata.cms.gov/physician/66377
Thomas W. Flaig
Leadership: Aurora Oncology
Stock and Other Ownership Interests: Aurora Oncology
Consulting or Advisory Role: Seattle Genetics, Janssen Oncology
Research 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, Seagen
Patents, 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 Dreicer
Consulting or Advisory Role: Astellas Pharma, Pfizer, Eisai, Merck, EMD Serono, Propella Therapeutics, Myovant Sciences, Bayer, Tavanta Therapeutics, Veru, Infinity Pharmaceuticals, Pfizer/Astellas
Research Funding: Seattle Genetics, Bristol Myers Squibb, Exelixis, Novartis
Dean Bajorin
Consulting or Advisory Role: Merck, Dragonfly Therapeutics, Fidia Farmaceutici SpA, Bristol Myers Squibb Foundation
Research Funding: Novartis, Merck, Bristol Myers Squibb, AstraZeneca, Astellas Pharma, Seattle Genetics/Astellas
Travel, Accommodations, Expenses: Merck
Olwen Hahn
Leadership: Via Oncology
Stock and Other Ownership Interests: Teleflex Medical
Honoraria: Cardinal Health
Consulting or Advisory Role: Pfizer
Travel, Accommodations, Expenses: Cardinal Health
Eric J. Small
Stock and Other Ownership Interests: Fortis, Harpoon Therapeutics
Honoraria: Janssen, Johnson & Johnson
Consulting or Advisory Role: Fortis, Janssen Oncology, Beigene, Tolero Pharmaceuticals, Teon Therapeutics, Ultragenyx Pharmaceuticals
Research Funding: Janssen
Travel, Accommodations, Expenses: Janssen
Open Payments Link: https://openpaymentsdata.cms.gov/physician/660367/summary
Michael J. Morris
Consulting or Advisory Role: Bayer, Endocyte, Advanced Accelerator Applications, ORIC Pharmaceuticals, Johnson & Johnson, Curium Pharma, Athenex
Research Funding: Bayer, Sanofi, Endocyte, Progenics, Corcept Therapeutics, Roche/Genentech, Janssen
Travel, Accommodations, Expenses: Endocyte, Fujifilm
No other potential conflicts of interest were reported.
DISCLAIMER
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
PRIOR PRESENTATION
Presented at ASCO Annual Meeting, May 31-June 4, 2019, Chicago, IL.
SUPPORT
Supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 to the Alliance for Clinical Trials in Oncology, UG1CA233180 to Dana-Farber Cancer Institute, UG1CA233290 and P30CA008748 to Memorial Sloan Kettering Cancer Center, UG1CA233234 to Case Western Reserve University, UG1CA233324 to University of Colorado-Denver, UG1CA233327 to University of Chicago, UG1CA233331 to The Ohio State University, UG1CA233339 to Washington University, UG1CA189819 to Christiana Care Health Services, Inc, UG1CA189858 to Southeast Clinical Oncology Research Consortium, U10CA180820 to ECOG-ACRIN Medical Research Foundation, U10CA180819 to SWOG/Fred Hutchinson Cancer Research Center, and P50CA221745. The research was also supported in part by Genentech and by support for the Alliance for Clinical Trials for Oncology (https://acknowledgments.alliancefound.org).
CLINICAL TRIAL INFORMATION
DATA SHARING STATEMENT
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO.21.00286.
AUTHOR CONTRIBUTIONS
Conception and design: Jonathan E. Rosenberg, Susan Halabi, Christopher Sweeney, Walter M. Stadler, Robert Dreicer, Dean Bajorin, Olwen Hahn, Eric J. Small, Michael J. Morris
Administrative support: Walter M. Stadler, Michael J. Morris
Provision of study materials or patients: Amir Mortazavi, Christopher Sweeney, Walter M. Stadler, Joel Picus, Scott T. Tagawa, Sreedhar Katragadda, Daniel Vaena, Elizabeth R. Plimack, Robert Dreicer
Collection and assembly of data: Jonathan E. Rosenberg, Karla A. Ballman, Susan Halabi, Pamela J. Atherton, Amir Mortazavi, Christopher Sweeney, Walter M. Stadler, Joel Picus, Scott T. Tagawa, Sreedhar Katragadda, Daniel Vaena, Christopher Hoimes, Elizabeth R. Plimack, Olwen Hahn, Eric J. Small, Michael J. Morris
Data analysis and interpretation: Jonathan E. Rosenberg, Karla A. Ballman, Susan Halabi, Pamela J. Atherton, Amir Mortazavi, Christopher Sweeney, Walter M. Stadler, Benjamin A. Teply, Joel Picus, Daniel Vaena, Jamal Misleh, Thomas W. Flaig, Dean Bajorin, Eric J. Small, Michael J. Morris
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance)
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
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Jonathan E. Rosenberg
Stock and Other Ownership Interests: Illumina
Honoraria: UpToDate, Medscape, Peerview, Research To Practice, Intellisphere, Clinical Care Options, ClinicalMind, Physicans' Education Resource
Consulting 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, Immunomedics
Research Funding: Genentech/Roche, Seattle Genetics, Bayer, AstraZeneca, QED Therapeutics, Astellas Pharma
Patents, Royalties, Other Intellectual Property: Predictor of platinum sensitivity
Karla A. Ballman
Consulting or Advisory Role: ARIAD, Medtronic, Takeda, Agenus
Patents, Royalties, Other Intellectual Property: Prostate cancer signature patent
Expert Testimony: Janssen Oncology, Lilly, Sanofi
Susan Halabi
Employment: ASCO
Amir Mortazavi
Honoraria: Motive Medical Intelligence
Consulting or Advisory Role: Seattle Genetics, Debiopharm Group, Pfizer
Research Funding: Acerta Pharma, Genentech/Roche, Merck, Novartis, Seattle Genetics, Mirati Therapeutics, Bristol Myers Squibb, Roche, Astellas Pharma, Debiopharm Group
Christopher Sweeney
Stock and Other Ownership Interests: Leuchemix
Consulting or Advisory Role: Sanofi, Janssen Biotech, Astellas Pharma, Bayer, Genentech/Roche, AstraZeneca, Pfizer, Amgen, Lilly
Research Funding: Janssen Biotech, Astellas Pharma, Sanofi, Bayer, Dendreon, Pfizer
Patents, Royalties, Other Intellectual Property: Leuchemix, Parthenolide, Dimethylaminoparthenolide. Exelixis: Abiraterone plus cabozantinib combination
Walter M. Stadler
Consulting or Advisory Role: CVS Caremark, Sotio, AstraZeneca, Eisai, Bayer, Pfizer, Merck, Treadwell Therapeutics
Research 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 Medivation
Expert Testimony: Teva
Other Relationship: UpToDate, American Cancer Society
Benjamin A. Teply
Consulting or Advisory Role: Janssen, AstraZeneca
Research Funding: AstraZeneca, Inovio Pharmaceuticals, Bristol Myers Squibb
Patents, Royalties, Other Intellectual Property: Receive royalties from patents related to health/medicine, held by MIT
Joel Picus
Consulting or Advisory Role: Novo Nordisk, Pfizer
Research Funding: BioClin Therapeutics, Mirati Therapeutics, Rexahn Pharmaceuticals, Seattle Genetics, TRACON Pharma, eFFECTOR Therapeutics
Scott T. Tagawa
Consulting 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 Pharma
Research 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 Biopharma
Travel, Accommodations, Expenses: Sanofi, Immunomedics, Amgen
Uncompensated Relationships: Telix Pharmaceuticals, ATLAB Pharma, Phosplatin Therapeutics
Sreedhar Katragadda
Consulting or Advisory Role: Curio Science
Travel, Accommodations, Expenses: Xcenda
Daniel Vaena
Honoraria: HMP
Consulting or Advisory Role: Bristol Myers Squibb, Bayer, Genomic Health, Natera, Seattle Genetics, Exelixis, EMD Serono, Immunomedics, Bristol Myers Squibb/Celgene, Eisai
Research 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 Hoimes
Honoraria: Seattle Genetics
Consulting or Advisory Role: Bristol Myers Squibb, Eisai, Prometheus, Seattle Genetics, Genentech/Roche, Merck Sharp & Dohme, 2bPrecise
Speakers' Bureau: Bristol Myers Squibb, Genentech/Roche, Astellas Pharma, Seattle Genetics, Eisai
Research Funding: Merck Sharp & Dohme
Uncompensated Relationships: 2bPrecise
Elizabeth R. Plimack
Consulting or Advisory Role: Bristol Myers Squibb, Genentech/Roche, Janssen, Merck, Flatiron Health, Seattle Genetics, Pfizer, AstraZeneca, Infinity Pharmaceuticals, MEI Pharma
Research Funding: Bristol Myers Squibb, AstraZeneca, Pfizer, Merck Sharp & Dohme, Astellas Pharma, Genentech/Roche
Patents, Royalties, Other Intellectual Property: US patent no.: 14/588,503, Filed January 2, 2015
Open Payments Link: https://openpaymentsdata.cms.gov/physician/66377
Thomas W. Flaig
Leadership: Aurora Oncology
Stock and Other Ownership Interests: Aurora Oncology
Consulting or Advisory Role: Seattle Genetics, Janssen Oncology
Research 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, Seagen
Patents, 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 Dreicer
Consulting or Advisory Role: Astellas Pharma, Pfizer, Eisai, Merck, EMD Serono, Propella Therapeutics, Myovant Sciences, Bayer, Tavanta Therapeutics, Veru, Infinity Pharmaceuticals, Pfizer/Astellas
Research Funding: Seattle Genetics, Bristol Myers Squibb, Exelixis, Novartis
Dean Bajorin
Consulting or Advisory Role: Merck, Dragonfly Therapeutics, Fidia Farmaceutici SpA, Bristol Myers Squibb Foundation
Research Funding: Novartis, Merck, Bristol Myers Squibb, AstraZeneca, Astellas Pharma, Seattle Genetics/Astellas
Travel, Accommodations, Expenses: Merck
Olwen Hahn
Leadership: Via Oncology
Stock and Other Ownership Interests: Teleflex Medical
Honoraria: Cardinal Health
Consulting or Advisory Role: Pfizer
Travel, Accommodations, Expenses: Cardinal Health
Eric J. Small
Stock and Other Ownership Interests: Fortis, Harpoon Therapeutics
Honoraria: Janssen, Johnson & Johnson
Consulting or Advisory Role: Fortis, Janssen Oncology, Beigene, Tolero Pharmaceuticals, Teon Therapeutics, Ultragenyx Pharmaceuticals
Research Funding: Janssen
Travel, Accommodations, Expenses: Janssen
Open Payments Link: https://openpaymentsdata.cms.gov/physician/660367/summary
Michael J. Morris
Consulting or Advisory Role: Bayer, Endocyte, Advanced Accelerator Applications, ORIC Pharmaceuticals, Johnson & Johnson, Curium Pharma, Athenex
Research Funding: Bayer, Sanofi, Endocyte, Progenics, Corcept Therapeutics, Roche/Genentech, Janssen
Travel, Accommodations, Expenses: Endocyte, Fujifilm
No other potential conflicts of interest were reported.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO.21.00286.