The oral multikinase inhibitor regorafenib improves overall survival in patients with chemo-refractory metastatic colorectal cancer (mCRC). However regorafenib induces various adverse events (AEs) which often impair patients' quality of life. Therefore the identification of early predictive markers for the efficacy of regorafenib is warranted.
We retrospectively examined 146 consecutive mCRC patients who received regorafenib in two institutions from May 2013 to March 2015. Clinical parameters including patients' backgrounds, AEs and changes in the value of biochemical parameters (LDH, CEA, and CA 19-9) from the initiation of regorafenib until day 28 were evaluated to identify predictors for progression-free survival (PFS).
Patient characteristics: median age (range), 64 (37-87) years; ECOG performance status 0/1/2, 28/63/9%; KRAS status wild/mutant/unknown, 55/44/1%; prior chemotherapy fluoroprymidine/oxaliplatin/irinotecan/bevacizumab/anti-EGFR antibodies (only for KRAS wild type)/TAS-102, 100/100/99/95/94/6%. Response rate and disease control rate were 0.7%, 31.9%, respectively. Median PFS was 2.1 months, and median overall survival was 6.6 months with the median follow-up time of 5.4 months. Major AEs in all courses (all garde/ ≥ grade3) were hand foot skin reaction 71/21%, hypertension 47/9% and proteinuria 50/6%. The results of univariate and multivariate analyses of PFS are shown in the table. The patients whose serum CA19-9 decreased after regorafenib had a significantly better PFS (median 15.7 vs. 8.7 weeks, p= 0.004) compared to patients whose CA19-9 level did not decrease. The early CA19-9 decrease remained an independent predictive factor (HR 0.408, 95%CI: 0.199-0.836, p = 0.014) from the results of multivariate analysis.
|Univariate analysis||Multivariate analysis|
|HR (95% CI)||p-value||HR (95% CI)||p-value|
|Age (≥70years)||1.199 (0.776-1.852)||0.413||-||-|
|KRAS (mutant)||0.901 (0.623-1.303)||0.579||-||-|
|Primary site(+)||1.761 (1.093-2.835)||0.020||1.141 (0.657-1.981)||0.639|
|No of metastatic sites(≥2)||1.742 (1.069-2.839)||0.026||1.879 (0.910-3.877)||0.088|
|Time from the first line (≥18months)||0.637 (0.408-0.995)||0.048||0.297 (0.151-0.586)||0.001|
|Hand foot skin reaction (≥Grade2)||0.743 (0.516-1.073)||0.114||-||-|
|Hypertension (≥Grade2)||0.903 (0.617-1.322)||0.600||-||-|
|CEA decreased (≥10%)||0.538 (0.344-0.841)||0.007||0.800 (0.426-1.503)||0.488|
|CA19-9 decreased (≥10%)||0.462 (0.269-0.792)||0.005||0.408 (0.199-0.836)||0.014|
Early response of CA19-9 may predict the efficacy of regorafenib. Further studies are needed for external validation.
Clinical trial identification
T. Ura, K. Muro, K. Yamazaki: lecture fee: Bayer HealthCare Pharmaceuticals. All other authors have declared no conflicts of interest.