K K H Goey1, S G Elias2, H van Tinteren3, M M Laclé4, S M Willems4, G J A Offerhaus4, W W J de Leng4, E Strengman4, A J Ten Tije5, G-J M Creemers6, A van der Velden7, F E de Jongh8, F L G Erdkamp9, B C Tanis10, C J A Punt11, M Koopman1. 1. Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht. 2. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht. 3. Department of Biometrics, Netherlands Cancer Institute Amsterdam - Antoni van Leeuwenhoek Hospital, Amsterdam. 4. Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht. 5. Department of Medical Oncology, Amphia Hospital, Breda. 6. Department of Medical Oncology, Catharina Hospital, Eindhoven. 7. Department of Medical Oncology, Tergooi Hospital, Hilversum. 8. Department of Medical Oncology, Ikazia Hospital, Rotterdam. 9. Department of Medical Oncology, Zuyderland MC, Heerlen-Sittard. 10. Department of Medical Oncology, Groene Hart Hospital, Gouda. 11. Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Abstract
BACKGROUND: The phase 3 CAIRO3 study showed that capecitabine plus bevacizumab (CAP-B) maintenance treatment after six cycles capecitabine, oxaliplatin, and bevacizumab (CAPOX-B) in metastatic colorectal cancer (mCRC) patients is effective, without compromising quality of life. In this post hoc analysis with updated follow-up and data regarding sidedness, we defined subgroups according to RAS/BRAF mutation status and mismatch repair (MMR) status, and investigated their influence on treatment efficacy. PATIENTS AND METHODS: A total of 558 patients with previously untreated mCRC and stable disease or better after six cycles CAPOX-B induction treatment were randomised to either CAP-B maintenance treatment (n = 279) or observation (n = 279). Upon first progression, patients were to receive CAPOX-B reintroduction until second progression (PFS2, primary end point). We centrally assessed RAS/BRAF mutation status and MMR status, or used local results if central assessment was not possible. Intention-to-treat stratified Cox models adjusted for baseline covariables were used to examine whether treatment efficacy was modified by RAS/BRAF mutation status. RESULTS: RAS, BRAF mutations, and MMR deficiency were detected in 240/420 (58%), 36/381 (9%), and 4/279 (1%) patients, respectively. At a median follow-up of 87 months (IQR 69-97), all mutational subgroups showed significant improvement from maintenance treatment for the primary end point PFS2 [RAS/BRAF wild-type: hazard ratio (HR) 0.57 (95% CI 0.39-0.84); RAS-mutant: HR 0.74 (0.55-0.98); V600EBRAF-mutant: HR 0.28 (0.12-0.64)] and secondary end points, except for the RAS-mutant subgroup regarding overall survival. Adjustment for sidedness instead of primary tumour location yielded comparable results. Although right-sided tumours were associated with inferior prognosis, both patients with right- and left-sided tumours showed significant benefit from maintenance treatment. CONCLUSIONS: CAP-B maintenance treatment after six cycles CAPOX-B is effective in first-line treatment of mCRC across all mutational subgroups. The benefit of maintenance treatment was most pronounced in patients with RAS/BRAF wild-type and V600EBRAF-mutant tumours. CLINICALTRIALS.GOV NUMBER: NCT00442637.
BACKGROUND: The phase 3 CAIRO3 study showed that capecitabine plus bevacizumab (CAP-B) maintenance treatment after six cycles capecitabine, oxaliplatin, and bevacizumab (CAPOX-B) in metastatic colorectal cancer (mCRC) patients is effective, without compromising quality of life. In this post hoc analysis with updated follow-up and data regarding sidedness, we defined subgroups according to RAS/BRAF mutation status and mismatch repair (MMR) status, and investigated their influence on treatment efficacy. PATIENTS AND METHODS: A total of 558 patients with previously untreated mCRC and stable disease or better after six cycles CAPOX-B induction treatment were randomised to either CAP-B maintenance treatment (n = 279) or observation (n = 279). Upon first progression, patients were to receive CAPOX-B reintroduction until second progression (PFS2, primary end point). We centrally assessed RAS/BRAF mutation status and MMR status, or used local results if central assessment was not possible. Intention-to-treat stratified Cox models adjusted for baseline covariables were used to examine whether treatment efficacy was modified by RAS/BRAF mutation status. RESULTS: RAS, BRAF mutations, and MMR deficiency were detected in 240/420 (58%), 36/381 (9%), and 4/279 (1%) patients, respectively. At a median follow-up of 87 months (IQR 69-97), all mutational subgroups showed significant improvement from maintenance treatment for the primary end point PFS2 [RAS/BRAF wild-type: hazard ratio (HR) 0.57 (95% CI 0.39-0.84); RAS-mutant: HR 0.74 (0.55-0.98); V600EBRAF-mutant: HR 0.28 (0.12-0.64)] and secondary end points, except for the RAS-mutant subgroup regarding overall survival. Adjustment for sidedness instead of primary tumour location yielded comparable results. Although right-sided tumours were associated with inferior prognosis, both patients with right- and left-sided tumours showed significant benefit from maintenance treatment. CONCLUSIONS: CAP-B maintenance treatment after six cycles CAPOX-B is effective in first-line treatment of mCRC across all mutational subgroups. The benefit of maintenance treatment was most pronounced in patients with RAS/BRAF wild-type and V600EBRAF-mutant tumours. CLINICALTRIALS.GOV NUMBER: NCT00442637.
Authors: Utku Oflazoglu; Ahmet Alacacioglu; Umut Varol; Yuksel Kucukzeybek; Tarik Salman; Halil Taskaynatan; Yasar Yildiz; Seray Saray; M Oktay Tarhan Journal: Support Care Cancer Date: 2019-11-22 Impact factor: 3.603
Authors: Letizia Procaccio; Vera Damuzzo; Francesca Di Sarra; Alberto Russi; Federica Todino; Vincenzo Dadduzio; Francesca Bergamo; Alessandra Anna Prete; Sara Lonardi; Hans Prenen; Angelo Claudio Palozzo; Fotios Loupakis Journal: Drug Saf Date: 2019-02 Impact factor: 5.228