Lisa Salvatore1, Emilio Bria2, Isabella Sperduti3, Axel Hinke4, Susanna Hegewisch-Becker5, Thomas Aparicio6, Karine Le Malicot7, Valérie Boige8, Dieter Koeberle9, Daniela Baertschi10, Daniel Dietrich10, Giampaolo Tortora2, Dirk Arnold11. 1. Medical Oncology Unit, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Universita' Cattolica del Sacro Cuore, Rome, Italy. Electronic address: lisa.salvatore@policlinicogemelli.it. 2. Medical Oncology Unit, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Universita' Cattolica del Sacro Cuore, Rome, Italy. 3. Biostatistics, IRCCS Regina Elena National Cancer Institute, Rome, Italy. 4. CCRC, Düsseldorf, Germany. 5. HOPE -Hämatologisch-Onkologische Praxis Eppendorf, Hamburg, Germany. 6. Department of Gastroenterology, Saint Louis Hospital, APHP, Université de Paris, Paris, France. 7. Fédération Francophone de Cancérologie Digestive, EPICAD INSERM UMR LNC 1231, Dijon, France. 8. Department of Oncologic Medicine, Gustave Roussy, Villejuif, France. 9. Claraspital, Basel, University Bern, Switzerland. 10. Swiss Group for Clinical Cancer Research, Bern, Switzerland. 11. Asklepios Tumorzentrum Hamburg AK Altona, Hamburg, Germany.
Abstract
BACKGROUND: The real impact of bevacizumab maintenance as single agent in metastatic colorectal cancer (mCRC) remains unclear. SAKK-41/06 and PRODIGE-9 failed to demonstrate the non-inferiority and superiority of bevacizumab versus no maintenance, respectively, while AIO-KRK-0207 showed the non-inferiority of maintenance bevacizumab versus bevacizumab and fluoropyrimidines for time to strategy failure. METHODS: Bibliography electronic databases (PubMed, MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials) were searched for English published clinical trials prospectively randomizing mCRC patients to receive bevacizumab maintenance or not after first-line chemotherapy plus bevacizumab. Individual patients' data (IPD) were provided by investigators for all included trials. Primary end-points were progression-free survival (PFS) and overall survival (OS), both from the start of induction and maintenance. Univariate and multivariate analyses for PFS and OS were performed. RESULTS: Three phase III studies - PRODIGE-9, AIO-KRK-0207 and SAKK-41/06 - were included. Considering the different timing of randomization, IPD of patients not progressed during induction and starting maintenance phase entered the analysis. 909 patients were included, 457 (50%) received bevacizumab maintenance. Median PFS from induction start was 9.6 and 8.9 months in bevacizumab group versus no maintenance group, respectively (HR 0.78; 95%CI: 0.68-0.89; p < 0.0001). Subgroups analysis for PFS showed a significant interaction according for RAS status (p = 0.048), with a maintenance benefit limited to RAS wild-type patients. No difference in terms of OS was observed. CONCLUSIONS: Despite the statistically significant PFS improvement for bevacizumab maintenance, the absolute benefit appears limited. Subgroup analysis shows a differential effect of bevacizumab maintenance in favor of RAS wild-type patients. Considering these results, maintenance therapy with fluoropyrimidine with or without bevacizumab remains the first option. Single agent bevacizumab maintenance can be considered in selected cases, such as cumulative toxicity or patient's refusal, in particular for RAS wild-type patients.
BACKGROUND: The real impact of bevacizumab maintenance as single agent in metastatic colorectal cancer (mCRC) remains unclear. SAKK-41/06 and PRODIGE-9 failed to demonstrate the non-inferiority and superiority of bevacizumab versus no maintenance, respectively, while AIO-KRK-0207 showed the non-inferiority of maintenance bevacizumab versus bevacizumab and fluoropyrimidines for time to strategy failure. METHODS: Bibliography electronic databases (PubMed, MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials) were searched for English published clinical trials prospectively randomizing mCRC patients to receive bevacizumab maintenance or not after first-line chemotherapy plus bevacizumab. Individual patients' data (IPD) were provided by investigators for all included trials. Primary end-points were progression-free survival (PFS) and overall survival (OS), both from the start of induction and maintenance. Univariate and multivariate analyses for PFS and OS were performed. RESULTS: Three phase III studies - PRODIGE-9, AIO-KRK-0207 and SAKK-41/06 - were included. Considering the different timing of randomization, IPD of patients not progressed during induction and starting maintenance phase entered the analysis. 909 patients were included, 457 (50%) received bevacizumab maintenance. Median PFS from induction start was 9.6 and 8.9 months in bevacizumab group versus no maintenance group, respectively (HR 0.78; 95%CI: 0.68-0.89; p < 0.0001). Subgroups analysis for PFS showed a significant interaction according for RAS status (p = 0.048), with a maintenance benefit limited to RAS wild-type patients. No difference in terms of OS was observed. CONCLUSIONS: Despite the statistically significant PFS improvement for bevacizumab maintenance, the absolute benefit appears limited. Subgroup analysis shows a differential effect of bevacizumab maintenance in favor of RAS wild-type patients. Considering these results, maintenance therapy with fluoropyrimidine with or without bevacizumab remains the first option. Single agent bevacizumab maintenance can be considered in selected cases, such as cumulative toxicity or patient's refusal, in particular for RAS wild-type patients.
Authors: Erik van Dijk; Erik van Werkhoven; Rebecca Asher; Jennifer K Mooi; David Espinoza; Hendrik F van Essen; Harm van Tinteren; Nicole C T van Grieken; Cornelis J A Punt; Niall C Tebbutt; Bauke Ylstra Journal: Int J Cancer Date: 2022-05-23 Impact factor: 7.316