No difference in OS and PFS between regorafenib followed by trifluridine/tipiracil or trifluridine/tipiracil followed by regorafenib after failed standard therapies for metastatic colorectal cancer

After the failure of first-line treatments for metastatic colorectal cancer, patients are eligible for either regorafenib or trifluridine/tipiracil, both of which are approved for treatment after two lines of chemotherapy have failed. However, no randomized trials have yet investigated the optimal sequence of these drugs. To address this, the SOREGATT trial was designed to compare the feasibility of different treatment sequences and to evaluate the impact on patient outcomes. The results of this study were presented by dr. Michel P. Ducreux (Villejuif, France).¹

Study design
The SOREGATT trial is a multicenter, international, open-label phase II study. It included patients with metastatic colorectal cancer (mCRC) who were 18 years or older, had an ECOG score of 0-1, and had failed fluoropyrimidine-based chemotherapy combined with oxaliplatin and/or irinotecan, plus EGFR (if RAS wild-type) and/or VEGF inhibitors. Participants were randomly assigned in a 1:1 ratio to either arm A (regorafenib followed by trifluridine/tipiracil) or arm B (trifluridine/tipiracil followed by regorafenib). Regorafenib was dosed at 160 mg per day for three weeks according to the ReDOS schedule for the first cycle. Trifluridine/tipiracil was dosed at 35 mg/m² orally twice daily on days 1-5 and 8-12 of each four-week cycle. Treatment continued until progression or unacceptable toxicity, after which patients switched to the subsequent treatment. The primary endpoint was the feasibility of trifluridine/tipiracil, assessed by the percentage of patients able to receive at least two cycles of both treatments. Important secondary endpoints were the median treatment duration, the overall survival (OS), the progression-free survival (PFS) in the first and second phase, time to failure of strategy (TFS), and safety.

Results
A total of 340 patients from 30 centers were screened, with 234 meeting eligibility criteria and being randomly assigned to arm A (N=114) or arm B (N=119). All patients in arm B followed the study protocol, while three patients in arm A did not due to general state alteration, disease progression, or physician decision. The study was prematurely stopped due to the publication of the SUNLIGHT trial, which showed significantly improved clinical outcomes for trifluridine/tipiracil combined with bevacizumab.² At data cut-off, the median follow-up was 19 months. The median age was 67 years, with 51% male in arm A and 66% in arm B. Tumor locations were right colon (30.4% vs. 46.1%), left colon (23.5% vs. 34.5%), and rectum (35.3% vs. 30.3%).

The percentage of patients receiving at least two cycles of each treatment was 40.0% in arm A and 55.5% in arm B, which was statistically significant (p=0.018). The median treatment duration was 94 days in arm A versus 111 days in arm B. Main reasons for ending treatment were progression (82 in first phase, 80 in second phase) and toxicity (14 in first phase, 12 in second phase). In total, 39% of patients in arm A did not switch to subsequent treatment compared to 27% in arm B. The OS was not significantly different between the arms (6.0 vs. 6.9 months; HR: 0.87 [0.67-1.14]). The PFS also showed no significant differences between the groups (1.87 vs. 1.97 months; HR: 0.81 [0.62-1.05]). However, the PFS after the second phase was significantly longer in arm B (3.7 vs. 3.9 months; HR: 0.75 [0.57-0.97]). Median TFS was 3.2 months [2.4-3.5] in arm A and 3.7 months [3.5-4.0] in arm B. Grade 3 or higher adverse events were similar in both groups (68% in arm A vs. 64% in arm B), with the most frequent adverse events being blood and lymphatic system disorders, general disorders, and skin and subcutaneous tissue disorders.

Conclusions
The SOREGATT trial shows that the sequence of trifluridine/tipiracil followed by regorafenib is more feasible in terms of the percentage of patients able to receive at least two cycles of both treatments. Although survival outcomes showed a small trend favoring arm B, these differences were not statistically significant. Future translational analysis aims to identify patients who respond well to regorafenib.

References

1. Ducreax M, et al. PRODIGE 68 - UCGI 38 - SOREGATT: a randomized phase II study comparing the sequences of regorafenib (reg) and trifluridine/tipiracil (t/t) after failure of standard therapies in patients (pts) with metastatic colorectal cancer (mCRC). Presented at ESMO GI, abstract 30.
2. Prager GW, et al. Trifluridine–tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med 2023;388:1657-67.