In Denmark, regorafenib has not been approved by the National Health Authorities. Therefore no standard therapy is available for patients with refractory KRAS wildtype (KRASwt) metastatic colorectal cancer (mCRC). Pre-clinical studies have demonstrated activity of temozolomide (TMZ) in mCRC cell lines (Inno et al, World J Clin Cases 2014), and clinical phase 2 data indicate effect of TMZ in heavily pre-treated mCRC patients (Scacham-Shmueli et al, JCO 2011; Pietrantonio et al, Ann of Oncol 2014, Pietrantonio et al, Targ Oncol, 2015). The combination of TMZ and capecitabine (TMZ-Cap) have synergetic schedule-depend effect (Fine et al, ASCO 2005). Therefore we initiated and completed two parallel phase II studies on the combination of TMZ-Cap in heavily pre-treated mCRC patients with KRASwt and KRASmut mCRC, respectively. Data on the combination of TMZ-Cap in KRASmut patients was recently presented (Qvortrup et al, ESMO 2015).
Phase II study evaluating the combination of capecitabine (2000 mg/m2 days 1-14) with TMZ (150 mg/m2 days 10-14) every 4 weeks in patients with refractory mCRC (EUDRACT: 2012-002327-15). The main inclusion criteria were: histologically confirmed KRASwt mCRC; PD during or after therapy with fluoropyrimidine, irinotecan, oxaliplatin, and an anti-EGFR-inhibitor; PS 0-1. The primary endpoint of the study is progression free survival (PFS). Secondary endpoints were RR, OS and predictive markers. Tumor tissue and liquid biopsies has been collected to search for predictive markers (including MGMT in tumor tissue).
Forty patients with refractory KRASwt mCRC from 3 Danish oncological departments were included from June 2013 to October 2015. Median age was 65 years (47-77), 33% were women. No patients achieved PR, mPFS was 1.9 (1.7-3.4) months, and mOS was 7.1 (5.8-7.9) mo. Toxicity was modest, only 1 patient stopped therapy due to toxicity.
The combination of TMZ and capecitabine is safe and has activity comparable to regorafenib and TAS-102 in patients with heavily pre-treated KRASwt mCRC. A search for predictive markers including MGMT expression is ongoing.
Clinical trial identification
Legal entity responsible for the study
Clinical Research Unit at department of Oncology Odense University hospital
Clinical Research Unit at department of Oncology Odense University Hospital
All authors have declared no conflicts of interest.