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Abstract

Introduction: Bevacizumab in combination with fluoropyrimidine-based chemotherapy is a standard treatment for patients with metastatic colorectal cancer (mCRC) in the first-line and bevacizumab-naive second-line settings. This randomised study evaluated the benefit of continuing bevacizumab with standard chemotherapy as second-line treatment for patients with mCRC who progressed after receiving a standard bevacizumab-containing regimen in the first-line setting. The study included a broad biomarker collection as an exploratory objective. We present here analysis of outcomes according to tumour KRAS status. Methods: Patients with unresectable, histologically confirmed mCRC who progressed within 3 months after discontinuation of first-line bevacizumab + chemotherapy were randomised to second-line fluoropyrimidine-based chemotherapy +/- bevacizumab (2.5 mg/kg/wk equivalent). The choice of oxaliplatin- or irinotecan-based second-line chemotherapy was based on the regimen used in the first-line setting (crossover) and was included in the stratification variables. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), response rate and safety. Subgroup analysis according to KRAS status was performed for both OS and PFS; no adjustment was made for multiplicity. Results: Conclusive tumour KRAS mutation data were available for 616 of the 820 patients (75%). Baseline characteristics were similar in the biomarker and randomised populations. Overall, 300 (49%) patients had mutant-type (MT) KRAS tumours and 316 (51%) had wild-type (WT) KRAS tumours. Median OS in the KRAS WT group was 15.4 months for bevacizumab + chemotherapy vs 11.1 months for chemotherapy alone (p = 0.0052; HR = 0.69) and 10.4 months for bevacizumab + chemotherapy vs 10.0 months for chemotherapy alone in the KRAS MT group (p = 0.4969; HR = 0.91). Median PFS in the KRAS WT group was 6.4 months for bevacizumab + chemotherapy vs 4.5 months for chemotherapy alone (p < 0.0001; HR = 0.61) and 5.5 months for bevacizumab + chemotherapy vs 4.1 months for chemotherapy alone in the KRAS MT group (p = 0.0027; HR = 0.70). No treatment interaction by KRAS status was observed for either OS (p = 0.1266) or PFS (p = 0.4436). More patients with KRAS WT tumours received later lines of treatment with EGFR inhibitors than those with KRAS MT tumours; however, treatment arms were balanced in both KRAS WT (69.9% for bevacizumab + chemotherapy vs 68.7% for chemotherapy alone) and MT groups (7.4% for bevacizumab + chemotherapy vs 8.9% for chemotherapy alone). Similarly, more patients with KRAS MT tumours received later lines of treatment with bevacizumab than those with KRAS WT tumours; treatment arms were also balanced in both KRAS WT (8.1% for bevacizumab + chemotherapy vs 8.4% for chemotherapy alone) and MT groups (22.2% for bevacizumab + chemotherapy vs 17.3% for chemotherapy alone). Conclusion: This is the first randomized study evaluating the benefit of continuing bevacizumab in combination with standard chemotherapy as second-line treatment for patients with mCRC who progressed after receiving a standard bevacizumab-containing regimen in the first-line setting. The biomarker findings from this study suggest that patients with both WT and MT KRAS tumours are likely to benefit from bevacizumab treatment.

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APA

Van Cutsem, E., Maria Vieitez, J., Bouche, O., Osterlund, P., Bennouna, J., Andre, T., … Arnold, D. (2012). Randomised phase III study of bevacizumab + chemotherapy beyond progression in bevacizumab-treated patients with metastatic colorectal cancer: TML study KRAS subgroup findings. Annals of Oncology, 23, iv15. Retrieved from http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=emed14&AN=71716512 http://oxfordsfx.hosted.exlibrisgroup.com/oxford?sid=OVID:embase&id=pmid:&id=doi:10.1093%2Fannonc%2Fmds151&issn=0923-7534&isbn=&volume=23&issue=4&spage=iv5&pages=&date

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