89P - Biomarker analysis of regorafenib dose escalation study (RECC study): A phase II multicenter clinical trial in Japan

Background

RAS status can impact on efficacy of chemotherapy for patients with metastatic tumor. However, we reported that RAS mutated clone can emerge in patients with RAS wild tumor, which suggest that the genotype of the tissue obtained at the time of diagnosis might not accurately represent, who are treated with EGFR blockade. In this study, we evaluated whether RAS mutation in tissue and/or in circulating tumor DNA (ctDNA) impact on efficacy of regorafenib. This is the biomarker analysis of RECC study, a phase II multicenter clinical trial in Japan, that confirmed the safety and effectiveness of dose escalation therapy of regorafenib in metastatic colorectal cancer (mCRC).

Methods

We conducted dose-escalation study as a single-arm, prospective, non-randomized, multi-centered open label phase II trial in Japan (RECC study). We set a starting dose of 80 mg/day during the first seven days, then will be increased up to 120 or 160 mg/day weekly. Before first administration of regorafenib, we extracted ctDNA and examined RAS mutation in ctDNA using droplet digital PCR (ddPCR).

Results

Fifty-eight patients with mCRC were registered in this study, and blood samples were available in 45 patients. In all obtained samples, ctDNA were successfully extracted from plasma and the quality and quantity of ctDNA were sufficient for genetic analysis. RAS mutation was detected in tumor tissue of 29 patients (64%) and in ctDNA of 21 patients (47%). In ctDNA, RAS mutation was detected in 21 of the 29 patients (72%) with RAS mutated tumor, and 6 of 16 patients with RAS wild tumor. Five of the 6 patients with RAS wild tumor were treated with EGFR blockade in previous treatment. RAS status both in tumor tissue and ctDNA had no impact on progression free survival and overall survival.

Conclusions

It was reported that RAS mutation has negative impact on efficacy of FTD/TPI. However, RAS mutation showed no impact on the efficacy of regorafenib. EGFR blockade have a potential to emerge RAS mutated clone. Thus, RAS status should be reconfirmed at the last minute before starting late line chemotherapy using liquid biopsy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.