Supplementary appendix

Transcription

1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Tewari KS, Sill MW, Penson RT, et al. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet 2017; published online July 27.

2 1 ONLINE SUPPLEMENT Final Overall Survival of the Phase III Randomized Trial of Chemotherapy with and without Bevacizumab for Advanced Cervical Cancer: An NRG Oncology/Gynecologic Oncology Group Study Krishnansu S. Tewari, MD 1, Michael W. Sill, PhD 2, Richard T. Penson, MD 3, Helen Huang, MS 2, Lois M. Ramondetta, MD 4, Lisa M. Landrum, MD 5, Ana Oaknin, MD 6, Thomas J. Reid, MD 7, Mario M. Leitao, MD 8, Helen E. Michael, MD 9, Philip J. DiSaia, MD 1, Larry J. Copeland, MD 10, William T. Creasman, MD 11, Frederick B. Stehman, MD 9, Mark F. Brady, PhD 2, Robert A. Burger, MD 12, J. Tate Thigpen, MD 13, Michael J. Birrer, MD 3, Steven E. Waggoner, MD 14, David H. Moore, MD 15, Wui-Jin Koh, MD 16, Bradley J. Monk, MD 17 1) University of California, Irvine Medical Center, 101 The City Drive South, Orange, CA 92868; 2) Roswell Park Cancer Institute, SUNY at Buffalo, Elm & Carlton Streets, Buffalo, NY 14263; 3) Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114; 4) MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; 5) University of Oklahoma, Oklahoma City, OK; 6) Vall d'hebron University Hospital, Passeig de la Vall d Hebron, , Barcelona, Spain; 7) University of Cincinnati College of Medicine/Women's Cancer Center at Kettering, 3230 Eden Avenue, Cincinnati, OH 45267; 8) Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065; 9) Indiana University School of Medicine, 340 W 10 th Street #6200, Indianapolis, IN 46202; 10) The Ohio State University Medical Center, 410 W 10 th Avenue, Columbus OH 43210; 11) Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 28425; 12) University of Pennsylvania, 3400 Civic Center Blvd, Suite 3, Philadelphia, PA 19104; 13) University of Mississippi Medical Center, 2500 N State Street, Jackson, MS 39216; 14) Case Western Reserve University, Euclid Avenue, Cleveland, OH 44106; 15) Franciscan St. Francis Health, 8111 S Emerson Avenue, Indianapolis, IN 46237; 16) University of Washington, 1959 NE Pacific St #B509, Seattle, WA 98195; 17) Arizona Oncology (US Oncology Network), Univeristy of Arizona College of Medicine, Creighton University School of Medicine at St Joseph s Hospital, 2222 E. Highland Avenue #400, Phoenix, AZ Corresponding Author: Krishnansu S. Tewari, MD, FACOG, FACS Professor & Director of Research The Division of Gynecologic Oncology University of California, Irvine Medical Center 101 The City Drive South, Bldg 56 Orange, CA Telephone: ; Fax: ktewari@uci.edu

3 2 ONLINE SUPPLEMENT Contents Reiteration of the 2012 Interim Analysis Report 3 Reiteration of the 2013 Interim Analysis Report 3 Comment on the GOG 240 Overall Survival Curves 4 Verification of the Proportional Hazards Model Assumption 4 Determination of Relative Risks of Adverse Events of Interest 4 Global impact of GOG Online Supplement Table 1 6 Online Supplement Figure Legends and Figures 7 Online Supplement References 12 Acknowledgements 13

4 ONLINE SUPPLEMENT Reiteration of the 2012 Interim Analysis Report The non-platinum chemotherapy doublet of topotecan plus paclitaxel was selected for study based on laboratory data demonstrating synergy between topotecan and microtubule-interfering agents and a phase II study in which the regimen was active in heavily pre-treated women with recurrent, previously irradiated, cervical cancer. 1,2 With the occurrence of 174 events, the pre-planned interim analysis was triggered and following a review of the results, the GOG DSMB concluded that topotecan was not a superior substitute for cisplatin when combined with paclitaxel by OS in the GOG 240 study population (HR 1. 20; 99% CI, ; p=0. 88). The DSMB recommended that this information be communicated to the physicians and patients participating in the study via Dear Investigator and Dear Patient letters prepared by the Study Chair and reviewed by the DSMB. The analysis did not indicate that the topotecan regimens (with and without bevacizumab) performed worse than the cisplatin regimens by overall survival. Given these results, patients who were receiving therapy with any of the four arms of GOG 240 could remain on their current treatment assignment unless progression, unacceptable toxicity, or complete response manifested. It was noted that the results concerning the topotecan regimens in GOG 240 were independent of the tolerability and efficacy of anti-angiogenesis therapy using bevacizumab in this study population. At the time of dissemination of the interim analysis results, GOG 240 had closed to accrual only and the bevacizumab question was ongoing as of April Reiteration of the 2013 Second Interim Analysis Report At the request of the DSMB, the database was frozen for a second time on 12 December 2012 at a median follow-up of months during which time 271 deaths had occurred. Following the second analysis, the NCI determined that the trial had met its primary endpoint concerning anti-vegf therapy (HR 0. 71; 98% CI, ; p=0. 004). These results were communicated to participating physicians and patients via Dear Investigator and Dear Patient letters and issued as a Press Release by the NCI on 7 February Arrangements were made by the NCI and Genentech, Inc. for provision of bevacizumab for study participants who had been assigned to the chemotherapy-alone arms. Although the American Society of Clinical Oncology (ASCO) accepted the abstract containing the second interim analysis results for their General Plenary, the program committee granted a rare exception to its embargo policy and released the abstract into the public domain in early March 2013, fully three

5 months ahead of the Annual Meeting. These data represent a proof-of-concept and confirmation of the efficacy of anti-angiogenesis therapy in advanced cervical cancer. 3 Comment on the GOG 240 Overall Survival Curves The initial OS curves of GOG 240 generated from the 2 nd interim analysis and released into the public domain by the National Cancer Institute appear in the Online Supplement Figure 2. Having occurred prior to the protocol-specified 348 events required at final OS analysis, alpha-spending mandated a broader confidence interval of 98% ( ) in which the integration of anti-angiogenesis therapy reduced the hazard of death by 29%, leading directly to US FDA approval. Interestingly, the database transferred to the FDA was notable for a 3. 9 month improvement in OS resulting from acquisition by Genentech of delinquent data not initially available to the NCI at the time of the second interim analysis (Online Supplement Figure 3). For this reason, the section in the package insert detailing the expansion of the label to include bevacizumab contains Kaplan Meier survival curves depicting median OS of mos (chemotherapy plus bevacizumab) vs mos (chemotherapy alone) rather than the vs mos reported in the NCI Press Release. Verification of the Proportional Hazards (PH) Model Assumption The PH model assumption was verified by examining the magnitude of the Spearman correlation coefficiants (and their significance) using Schoenfeld s residuals against survival, the logarithm of survival, and the survival squared. We also used SAS PH model checking routine called assess in proc phreg which also indicated no issues with the PH model assumption. Determination of Relative Risks of Adverse Events of Interest Table 3 of the principle manuscript captures the patients worst grade of toxicities during the course of therapy for specific adverse events. The risk ratio that appears in each row of Table 3 is the probabiliity (P) of the specific adverse event (AE) in the chemotherapy plus bevacizumab arms (C+B) divided by the probability of that specific adverse event in the chemotherapy alone arms (C): P(AE/C+B) / P(AE/C). The confidence interal for the risk ratio was provided by SAS RELRISK statement and used asymptotic results. It uses the Wald Method for determining the confidence interval. Fisher s Exact Test was used to obtain the p-value. These methods can be examined in SAS procedures manual under PROC FREQ - Details

6 Global Impact of GOG 240 Although the approvals of bevacizumab with chemotherapy for advanced cervical cancer by the United Kingdom s Cancer Drug Fund and the United States FDA were granted following public disclosure of the 2 nd interim analysis, it was not until the presentation of the final OS analysis at the 2014 Annual Meeting of the European Society of Medical Oncology that a label was granted throughout the world, beginning with SwissMedic approval on 22 December Following a 27 February 2015 Positive Opinion issued by the Committee for Medicinal Products for Human Use, on 8 April 2015 the European Medicines Agency approved bevacizumab for women suffering from advanced cervical cancer in the 28-member countries of the European Union. GOG 240 is beyond a proof of concept concerning the therapeutic benefit of anti-angiogenesis therapy in this population. On the basis of this one phase III randomized clincial trial, bevacizumab has been granted a label in many countries. As of January 2017, these include not only the United States, Switzerland, the United Kingdom and the 27 other members of the European Union, but also Canada, Mexico, Costa Rica, Panama, Brasil, Chile, Peru, Ecuador, Argentina, Venezuela, Colombia, Uroguay, South Africa, Morocco, Australia, Israel, Turkey, Lebanon, United Arab Emirates, Oman, Qatar, Bahrain, Kuwait, India, Korea, Hong Kong, Malaysia, Japan, Singapore, and Vietnam. 78

7 ONLINE SUPPLEMENT TABLE 1. Association of Median OS at Final Analysis with Selected Toxicities Adverse Event Occurrence Median OS (mos) 95% CI Neutropenia G2 + Absent , Present , Fistula G3 + Absent , Present TE G3 + Absent , Present , Htn G2 + Absent , Present , Proteinuria G1 + Absent , Present G: grade; TE: thromboembolism; Htn: hypertension

8 FIGURE LEGENDS FOR ONLINE SUPPLEMENT: Online Supplement Figure 1. Kaplan-Meier curves depicting the intent-to-treat updated progression-free survival comparing chemotherapy alone (both backbones) to chemotherapy plus bevacizumab. Proportion Progression-Free No Bev (n=225) Events, n (%) 206 (92) Median PFS, months Months on Study Bev No Bev Bevacizumab (n=227) 199 (88) HR=0 68 (95% CI, ) P= RR, % P= September 2014, Madrid, Spain esmo.org 8 2 PFS: progression-free survival RR: response rate HR: hazard ratio CI: confidence interval Bev: bevacizumab

9 Online Supplement Figure 2. Kaplan-Meier curves depicting the intent-to-treat final protocol-specified overall survival among patients not previously treated with pelvic radiation with and without bevacizumab. HR 0.64; 95% CI ; p=0.11 HR: hazard ratio CI: confidence interval

10 Online Supplement Figure 3: OS among patients who manifested grade 2 or higher neutropenia as compared to patients who did not develop grade 2 or higher neutropenia (bevacizumab-containing arms only) September 2014, Madrid, Spain esmo.org HR 0. 75; 95% CI ; p= HR: hazard ratio CI: confidence interval

11 Online Supplement Figure 4: OS curves comparing chemotherapy alone to chemotherapy plus bevacizumab at the time of the 2 nd interim analysis (ie, 271 events). Proportion Surviving Chemotherapy (n=225) Events, n (%) 140 (62) Median OS, months 13 3 Chemotherapy + Bev (n=227) 131 (58) ChemoRx alone September , Madrid, 167 Spain esmo.org ChemoRx + Bev HR=0 71 (97% CI, ) P= Median follow-up Months on Study 20 8 months OS: overall survival HR: hazard ratio CI: confidence interval ChemoRx: chemotherapy Bev: bevacizumab

12 11 Online Supplement Figure 5: U.S. Food and Drug Administration Registration OS curves comparing chemotherapy alone to chemotherapy plus bevacizumab at the time of the 2nd interim analysis (ie., 271 events). Proportion Surviving Chemotherapy plus bevacizumab (n=227) Chemotherapy alone (n=22) Median OS: 16 8 mos vs 12 9 mos HR 0 74; 95% CI, ; p= OS: overall survival HR: hazard ratio CI: confidence interval ChemoRx: chemotherapy Bev: bevacizumab Months on Study ChemoRx alone ChemoRx + Bev September 2014, Madrid, Spain esmo.org

13 Online Supplement References: 1. Bahadori HR, Green MR, Catapano CV. Synergistic interaction between topotecan and microtubuleinterfering agents. Cancer Chemother Pharmacol 2001;48: Tiersten AD, Selleck MJ, Hershman DL, et al. Phase II study of topotecan and paclitaxel for recurrent, persistent, or metastatic cervicasl carcinoma. Gynecol Oncol 2004;92: Krill LS, Adelson JW, Randall LM, Bristow RE. Clinical commentary: Medical ethics and the ramifications of equipoise in clinical research. Is a confirmatory trial using a non-bevacizumab containing arm feasible in patients with recurrent cervical cancer. Gynecol Oncol 2014;134:

14 ACKNOWLEDGEMENTS The authors would like to recognize the significant contributions made on this study by Dr. Harry J. Long III (deceased) of the Mayo Clinic, Rochester, Minnesota. This work was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469), the Gynecologic Oncology Group Statistical and Data Center (CA 37517), the NRG Oncology SDMC grant U10 CA and the NRG Oncology Operations grant U10CA The following Gynecologic Oncology Group member institutions participated in the primary treatment studies: Roswell Park Cancer Institute, University of Alabama at Birmingham, Duke University Medical Center, Abington Memorial Hospital, Walter Reed Army Medical Center, Wayne State University, University of Minnesota Medical School, Northwestern Memorial Hospital, University of Mississippi Medical Center, Colorado Gynecologic Oncology Group P.C., University of Washington, University of Pennsylvania Cancer Center, Milton S. Hershey Medical Center, University of Cincinnati, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, Indiana University School of Medicine, Wake Forest University School of Medicine, University of California Medical Center at Irvine, Rush- Presbyterian-St. Luke's Medical Center, Magee Women's Hospital, SUNY Downstate Medical Center, University of Kentucky, University of New Mexico, The Cleveland Clinic Foundation, State University of New York at Stony Brook, Washington University School of Medicine, Memorial Sloan-Kettering Cancer Center, Cooper Hospital/University Medical Center, Columbus Cancer Council, MD Anderson Cancer Center, University of Massachusetts Medical School, Fox Chase Cancer Center, Women's Cancer Center, University of Oklahoma, University of Virginia Health Sciences Center, University of Chicago, Mayo Clinic, Case Western Reserve University, Tampa Bay Cancer Consortium, Yale University, University of Wisconsin Hospital, Cancer Trials Support Unit, University of Texas - Galveston, Women and Infants Hospital, The Hospital of Central Connecticut, Georgia Core, Aurora Women's Pavilion of West Allis Memorial Hospital, Grupo Espanol de Investigacion en Cancer de Ovario, University of California, San Francisco-Mt. Zion, St. Joseph s Hospital and Medical Center (Arizona), and Community Clinical Oncology Program. The authors would like to acknowledge Juliet Wolford, MD for her assistance with editing the survival curve figures so that the legends and color schemes remained consistent across Figures 2, 3, and Online Supplement Figures 1-3.