Based on the current diagnostic and treatment guidelines, regorafenib and TAS-102 monotherapy are both standard third-line treatment options for patients with metastatic colorectal cancer (mCRC), yet the overall treatment sequence or preference is not clear. A retrospective study directly compared the efficacy of regorafenib and TAS-102 monotherapy for third-line treatment of mCRC, and found similar efficacy between the two treatments. However, the benefits of current third-line monotherapy for mCRC are still limited. Patients who receive oral regorafenib monotherapy have an ORR of less than 5%, disease control rate of 50-60%, and TAS-102 has an ORR of 1.1%-1.6% and a disease control rate of less than 50% in third-line treatment of mCRC. These drugs have limited prolongation of progression-free survival (PFS), and disease progression and drug resistance often occur shortly after medication use. Most mCRC patients have a high tumor burden during third-line treatment, and how to improve the remission rate of treatment, improve patients' quality of life due to high tumor burden, increase disease control, and further bring better survival benefits is still a big challenge for third-line treatment. Regorafenib and TAS-102 have different mechanisms of action and different adverse reaction spectra. When the two drugs are used in combination, they may complement each other in terms of efficacy and are also less likely to have toxic effects.

In the RECOURSE study, 17% of patients in the TAS-102 treatment group had received prior treatment with regorafenib. Subgroup analysis showed that the efficacy of TAS-102 was not dependent on whether or not the patient had previously received regorafenib treatment. Therefore, the combination of regorafenib and TAS-102 may be a valuable treatment option for refractory mCRC. However, there is little clinical research data on whether the combination therapy could further improve efficacy and prolong patient survival compared to monotherapy. In 2021, a phase Ib small-sample study from Germany explored the combined use of regorafenib and TAS-102 in third-line treatment of mCRC. The study included 12 patients who received combined treatment with regorafenib and TAS-102 in third-line treatment. After a 3+3 dose-exploration trial, three cases of DLT were all grade 3 hypertension related to regorafenib. The combination of TAS-102 25 mg/m2 twice daily and regorafenib 120 mg was well tolerated, with a median PFS of 3.81 months (95% CI: 1.51-5.2), and a median OS of 11.1 months (95% CI: 2.3-18.2). The results of this early-phase clinical trial suggest that compared to regorafenib monotherapy in the CORRECT study with a median PFS of less than two months and a median OS of less than seven months, the third-line combination treatment of regorafenib and TAS-102 may potentially provide patients with greater clinical benefits. In conclusion, the combination therapy of regorafenib and TAS-102 may be further explored and studied for late-stage colorectal cancer in third-line or after third-line treatment.

The aim of this study is to evaluate the clinical benefits and safety of the combination of regorafenib and TAS-102 compared to regorafenib monotherapy in patients with advanced colorectal cancer who have failed second-line or later treatments. The efficacy and safety of the combination therapy will be fully evaluated, and explorations of efficacy, PFS, OS, safety, and related biomarkers associated with the combined treatment of regorafenib and TAS-102 will be conducted.