Association of Bevacizumab Plus Oxaliplatin-Based Chemotherapy With Disease-Free Survival and Overall Survival in Patients With Stage II Colon Cancer: A Secondary Analysis of the AVANT Trial

Abstract

Importance: In the pivotal Bevacizumab-Avastin Adjuvant (AVANT) trial, patients with high-risk stage II colon cancer (CC) had 5-year and 10-year overall survival (OS) rates of 88% and 75%, respectively, with adjuvant fluorouracil and oxaliplatin-based chemotherapy; however, the trial did not demonstrate a disease-free survival (DFS) benefit of adding bevacizumab to oxaliplatin-based chemotherapy in stage III CC and suggested a detrimental effect on OS. The Long-term Survival AVANT (S-AVANT) study was designed to collect extended follow-up for patients in the AVANT trial.

Objective: To explore the efficacy of adjuvant bevacizumab combined with oxaliplatin-based chemotherapy in patients with high-risk, stage II CC.

Design, setting, and participants: This prespecified secondary end point analysis of the AVANT and S-AVANT studies included 573 patients with curatively resected high-risk stage II CC and at least 1 of the following criteria: stage T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age younger than 50 years, or fewer than 12 nodes analyzed. The AVANT study was a multicenter randomized stage 3 clinical trial. Data were collected from December 2004 to February 2019, and data for this study were analyzed from March to September 2019.

Intervention: Patients were randomly assigned to receive 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4), FOLFOX4 with bevacizumab, or capecitabine and oxaliplatin (XELOX) with bevacizumab.

Main outcomes and measures: The primary end points of this secondary analysis were DFS and OS in patients with high-risk stage II CC.

Results: The AVANT study included 3451 patients, of whom 573 (16.6%) had high-risk stage II CC (192 [33.5%] randomized to FOLFOX4 group; 194 [33.9%] randomized to FOLFOX4 with bevacizumab group; 187 [32.6%] randomized to XELOX with bevacizumab group). With a median (interquartile range) age of 57.0 (47.2-65.7) years, the study population comprised 325 men (56.7%) and 248 women (43.3%). After a median (interquartile range) follow-up of 6.9 (6.1-11.3) years, the 3-year DFS and 5-year OS rates were 88.2% (95% CI, 83.7%-93.0%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 group, 86.6% (95% CI, 81.8%-91.6%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 with bevacizumab group, and 86.7% (95% CI, 81.8%-91.8%) and 93.2% (95% CI, 89.6%-97.0%) in the XELOX with bevacizumab group, respectively. The DFS hazard ratio was 0.94 (95% CI, 0.59-1.48; P = .78) for FOLFOX4 with bevacizumab vs FOLFOX4 and 1.07 (95% CI, 0.69-1.67; P = .76) for XELOX with bevacizumab vs FOLFOX4. The OS hazard ratio was 0.92 (95% CI, 0.55-1.55; P = .76) for FOLFOX4 with bevacizumab vs FOLFOX4 and 0.85 (95% CI, 0.50-1.44; P = .55) for XELOX with bevacizumab vs FOLFOX4.

Conclusions and relevance: In this secondary analysis of data from the AVANT trial, adding bevacizumab to oxaliplatin-based chemotherapy was not associated with longer DFS or OS in patients with high-risk stage II CC. The findings suggest that the definition of high-risk stage II CC needs to be revisited.

Trial registration: ClinicalTrial.gov Identifiers: AVANT (NCT00112918); S-AVANT (NCT02228668).

Conflict of interest statement

Conflict of Interest Disclosures: Dr Chibaudel reported receiving grants from Roche during the conduct of the study and personal fees from Roche, Bayer, Eli Lilly and Co, Pfizer, Sanofi, Servier, and Beigine outside the submitted work. Dr Gallego-Plazas reported receiving grants from Roche during the conduct of the study; receiving personal fees from Roche, Amgen, Merck, Servier, Bayer, and Eli Lilly and Co; receiving travel fees from Novartis; and serving on the congress of Ipsen outside the submitted work. Dr Cervantes reported receiving grants from and belonging to the speakers bureau of Roche during the conduct of the study. Dr Mineur reported receiving grants from Roche outside the submitted work. Dr Moehler reported receiving grants from MerckSerono during the conduct of the study and receiving personal fees from MerckSerono and Roche outside the submitted work. Dr Aranda reported receiving personal fees for consulting with Amgen, Bayer, Celgene, Merck, Roche, and Sanofi outside the submitted work. Dr Van Cutsem reported receiving grants from Roche outside the submitted work; participating on advisory boards for Array, AstraZeneca, Bayer, Biocartis, Bristol-Myers Squibb, Celgene, Daiichi, GlaxoSmithKline, Pierre-Fabre, Incyte, Ipsen, Eli Lilly and Co, Merck Sharp and Dohme, Merck, Novartis, Roche, Servier, Sirtex, and Taiho; and having research grants from Bayer, Boehringer Ingelheim, Celgene, Ipsen, Eli Lilly and Co, Roche, Merck Sharp and Dohme, Merck , Novartis, Roche, and Servier paid to his institution. Dr Tabernero reported serving as a scientific consultant for Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Eli Lilly and Co, Merck Sharp and Dohme, Menarini, MerckSerono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign, Rafael Pharmaceuticals, F. Hoffmann-La Roche, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS, and Roche Diagnostics outside the submitted work. Dr Hoff reported receiving grants from Roche during the conduct of the study. Dr André reported receiving grants from Gercor during the conduct of the study; receiving personal fees from Roche/Ventana, Bristol Myers Squibb, Amgen, AstraZeneca, Merck Sharp and Dohme Oncology, Halliodx, Servier, Sanofi, Pierre Fabre, and Tesaro/GlaxoSmithKline outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Flowchart of Participants in Bevacizumab-Avastin Adjuvant (AVANT) and Long-term Survival Bevacizumab-Avastin Adjuvant (S-AVANT) Studies

FOLFOX4 indicates 5-fluorouracil, leucovorin, and oxaliplatin; and XELOX, capecitabine and oxaliplatin.

Figure 2.. Disease-Free Survival and Overall Survival, According to Treatment Group, in 318 Patients With High-Risk Stage II Colon Cancer

FOLFOX4 indicates 5-fluorouracil, leucovorin, and oxaliplatin; XELOX, capecitabine and oxaliplatin.

Figure 3.. Overall Survival According to High-Risk Stage II Criteria and to Favorable, Single Unfavorable, or Multiple Unfavorable Criteria in Patients With High-Risk Stage II Colon Cancer

Favorable high-risk factors included being younger than 50 years and/or having vascular or perineural invasion. Single unfavorable high-risk factors were having fewer than 12 examined nodes, having stage T4 disease, or having perforation or obstruction. Multiple high-risk factors included all other high-risk factor combinations.