At present, the third-line therapy in China includes 3 anti-angiogenic small molecule tyrosine kinase (TKI) inhibitors, namely regorafenib, fruquintinib and oral chemotherapeutic agent TAS-102.There are high-level evidences for the above 3 drugs, but their therapeutic effects are still unsatisfactory with the progression-free survival (PFS) of only 2-4 months. As a result, more effective regimens need to be explored. The BOND study found that in mCRC patients with RAS wild-type and irinotecan resistance, cetuximab combined with irinotecan as the third-line therapy could effectively reverse irinotecan resistance with an ORR of 22.9%. The CRIKET study assessed the effect of cetuximab combined with irinotecan in later-line setting for advanced CRC; the result showed that the cetuximab combined with irinotecan therapy achieved an objective response rate (ORR) of 21% (95% CI, 10-40%). In the subgroup analysis, compared with patients with mutations, patients with RAS wild-type confirmed by circulating tumor DNA (ctDNA) had longer PFS benefit (4.0 months vs 1.9 months), which suggested that patients with RAS wild-type mCRC might still benefit from cetuximab plus irinotecan re-challenge in third-line setting after cetuximab treatment. However, third-line therapy options are still limited for another 35% to 40% patients with RAS wide-type mCRC and the prognosis for these patients is relatively poor. More studies are needed to explore other effective regimens.

ctDNA, or liquid biopsy technology, can detect DNA released from tumor cells into the blood. Moreover, it has some detecting advantages, such as real-time, dynamic, comprehensive and noninvasive. More and more studies have shown that this technology is promising and can be widely applied in the whole disease management course of CRC patients, such as early diagnosis, therapeutic target detection, minimal residual disease (MRD) detection and efficacy monitoring. One of previous studies of our team found that the status of RAS and BRAF genes detected by ctDNA in advanced CRC patients would change along with treatment. The study dynamically monitored ctDNA in 171 patients with unresectable mCRC. The results showed that 42.6% of patients with initial RAS mutation were converted to RAS wild-type mCRC after the standard first-line treatment, and such patients were called NeoRAS wild-type mCRC patients. Other studies have also found similar phenomena, but the frequency of NeoRAS wild-type conversion varies among studies (2%-45%), which might be related to several factors such as patients' treatment stage, early treatment regimen, and ctDNA detection method. Therefore, in order to optimize treatment strategies, RAS status should be retested during overall management of patients with RAS mutant mCRC.

The target population for this study is patients with RAS/BRAF wild-type primary left-sided mCRC by blood-based ctDNA testing before third-line therapy, who are initial RAS mutant and BRAF wild-type CRC patients, who have disease progression after first- and second-line therapy (previously treated with fluorouracil compounds, oxaliplatin and irinotecan) and who have tumor progression, during or within 3 months after irinotecan-containing regimen. This population will receive third-line therapy with cetuximab plus irinotecan bi-weekly until disease progression. The primary study endpoint is ORR, and the secondary study endpoints are PFS, OS and drug safety.