Final Overall Survival of a Randomized Trial of Bevacizumab for Primary Treatment of Ovarian Cancer

Abstract

Purpose: We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma.

Methods: A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m²) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry.

Results: Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non-BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2, HRR, and CD31 were not predictive of bevacizumab activity.

Conclusion: No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.

Trial registration: ClinicalTrials.gov NCT00262847.

FIG 1.

CONSORT diagram of the enrollment, randomization, and intention-to-treat analysis. The overall survival median follow-up for the entire study population was 102.9 months (95% CI, 100.7 to 105.9 months). As of January 17, 2018, 204 patients were alive with a progression event, and 178 patients were alive without progression; 1,491 patients died. AUC, area under the concentration v time curve.

FIG 2.

Kaplan-Meier curves that compare overall survival (OS) of the various treatment arms studied in GOG-0218. Database lock was January 17, 2018. (A) Final protocol-specified OS according to treatment arm. Overall median follow-up was 102.9 months (95% CI, 100.7 to 105.9 months). In the 1,873 patients who comprised the entire study population, 1,491 died, 204 were alive with a progression event, and 178 were alive without progression. Median follow-up for the control cohort (carboplatin and paclitaxel plus placebo followed by placebo [CT + P → P]) was 103.4 months (95% CI, 100.4 to 107.9 months). In 625 patients, 565 experienced a progression event, and 493 died; 72 were alive with a progression event, and 60 were alive without progression. Median follow-up for the bevacizumab-concurrent cohort (carboplatin and paclitaxel plus bevacizumab followed by placebo [CT + B → P]) was 102.3 months (95% CI, 98.8 to 106.5 months). In 625 patients, 563 experienced a progression event, and 506 died; 57 were alive with a progression event, and 62 were alive without progression. The hazard ratio (HR) for bevacizumab-concurrent v control stratified by stage and Gynecologic Oncology Group (GOG) performance status was 1.06 (95% CI, 0.94 to 1.20; P = .34). Median follow-up for the bevacizumab-concurrent plus maintenance cohort (carboplatin and paclitaxel plus bevacizumab followed by bevacizumab [CT + B → B]) was 101.9 months (95% CI, 98.7 to 107.4 months). In 623 patients, 567 experienced a progression event, and 492 died; 75 were alive with a progression event, and 56 were alive without progression. The HR for death for bevacizumab-concurrent plus maintenance v control stratified by stage and GOG performance status was 0.96 (95% CI, 0.85 to 1.09; P = .53). (B) Disease-specific OS according to treatment arm. Patients who died as a result of causes other than disease or treatment-related causes were censored. Overall, the number of deaths reduced from 1,491 to 1,387 (change of 104; 7.0%). In the control arm, the number of deaths reduced from 493 to 462 (change of 31; 6.3%). In the bevacizumab-concurrent arm, the number of deaths reduced from 506 to 474 (change of 32; 6.3%). In the bevacizumab-concurrent plus maintenance arm, the number of deaths reduced from 492 to 451 (change of 41; 8.3%). The HR for bevacizumab-concurrent v control stratified by stage and GOG performance status was 1.06 (95% CI, 0.93 to 1.20; P = .39). The HR for death for bevacizumab-concurrent plus maintenance v control stratified by stage and GOG performance status was 0.94 (95% CI, 0.82 to 1.07; P = .33). (C) Final OS according to treatment arm after censoring those who received bevacizumab as a second line of therapy. Overall, 184 patients received bevacizumab as a second-line therapy after progression. When measuring OS since the time patients initiated treatment (n = 205), the HR for bevacizumab-concurrent v control stratified by stage and GOG performance status and after censoring those who received bevacizumab postprogression was 1.05 (95% CI, 0.92 to 1.20; P = .49). The HR for death for bevacizumab-concurrent plus maintenance v control stratified by stage and GOG performance status and after censoring those who received bevacizumab postprogression was 0.96 (95% CI, 0.84 to 1.09; P = .52). (D) Final OS according to treatment arm and stratified by International Federation of Gynecology and Obstetrics stage III. Survival of patients with stage III disease was similar in all three treatment arms. Relative to control, the HR for death for bevacizumab-concurrent was 1.08 (95% CI, 0.93 to 1.25), and that of bevacizumab-concurrent plus maintenance was 1.05 (95% CI, 0.91 to 1.22). (E) Final OS according to treatment arm and stratified by International Federation of Gynecology and Obstetrics stage IV. Relative to control, the HR for death of bevacizumab-concurrent was 0.99 (95% CI, 0.78 to 1.26), whereas that of bevacizumab-concurrent plus maintenance was 0.75 (95% CI, 0.59 to 0.95). Note that in this exploratory analysis, the survival of patients with stage IV disease treated in the bevacizumab-concurrent plus maintenance arm (box) approximated that observed for patients with stage III disease (as in panel D).

FIG 3.

Analysis of prognostic factors. (A) Forest plot of clinical and pathologic prognostic factors (N = 1,873). (B) Forest plot of molecular prognostic biomarkers. The sample size for the genetic category analysis was 1,195 blood and tumor samples. Patients were categorized into three genetic categories: BRCA1/2, homologous recombination repair mutations, or wild type (no mutation). For the forest plots, BRCA1/2 and homologous recombination repair mutations were depicted as separate categories. The sample size for the CD31 analysis was 1,438 blood and tumor samples. HR, hazard ratio; HRD, homologous repair deficiency; Q3, quartile 3.

FIG 4.

Analyses of BRCA1/2 and homologous recombination deficiency (HRD) according to final overall survival. (A) Kaplan-Meier survival curves demonstrate the prognostic impact of mutations in genes involved in homologous recombination. Of the 1,873 patients studied in GOG-0218, 1,195 provided blood or tumor samples to be sequenced and were able to be categorized into three genetic categories: breast cancer susceptibility gene 1/2 (BRCA1/2), homologous recombination repair (HRR) mutations, or wild type (no mutation). Using wild type as the reference, the hazard ratio (HR) for death for BRCA1/2 was 0.62 (95% CI, 0.52 to 0.73) and for death for HRR mutations, 0.65 (95% CI, 0.51 to 0.85). (B) Kaplan-Meier survival curves that demonstrate the effect of treatment allocation on overall survival stratified by genetic category. Although BRCA1/2 and HRR mutations were associated with improved prognosis, their occurrence did not predict bevacizumab activity. For graphic purposes, BRCA1/2 and HRR were combined into one category. For the patients who were BRCA/HRR negative (ie, wild type), the HR for death in those treated with bevacizumab-concurrent plus maintenance (carboplatin and paclitaxel plus bevacizumab followed by bevacizumab [CT + B → B]) relative to control (carboplatin and paclitaxel plus placebo followed by placebo [CT + P → P]) and stratified by stage and Gynecologic Oncology Group (GOG) performance status was 0.89 (95% CI, 0.74 to 1.07); the HR for death in those treated with bevacizumab-concurrent (carboplatin and paclitaxel plus bevacizumab followed by placebo [CT + B → P]) relative to control and stratified by stage and GOG performance status was 0.96 (95% CI, 0.80 to 1.15). For the patients who had BRCA/HRR mutations, the HR for death in those treated with bevacizumab-concurrent plus maintenance relative to control and stratified by stage and GOG performance status was 1.18 (95% CI, 0.86 to 1.63); the HR for death in those treated with bevacizumab-concurrent relative to control and stratified by stage and GOG performance status was 1.44 (95% CI, 1.02 to 2.02). (*) Germline wild type: BRCA1/2; ataxia-telangiectasia mutated (ATM); ataxia telangiectasia and Rad3 related (ATR); BRCA1-associated RING domain 1 (BARD1); Bloom DNA helicase (BLM); BRCA1 interacting protein C-terminal helicase 1 (BRIP1); checkpoint kinase 2 (CHEK2); MRE11 meiotic recombination 11 homolog A (MRE11A; Saccharomyces cerevisiae); nibrin (NBN); partner and localizer of BRCA2 (PALB2); RAD51 homolog C (RAD51C; S cerevisiae); RAD51 homolog D (RAD51D); RB binding protein 8, endonuclease (RBBP8); structure-specific endonuclease subunit homolog (SLX4; S cerevisiae); and x-ray repair cross complementing 2 (XRCC2).