TAS-102 followed by Regorafenib identified as optimal treatment sequence in pretreated metastatic colorectal cancer

Dr. Michel P. Ducreux, Ph. D.

Treatment with trifluridine/tipiracil (TAS-102; Lonsurf) before regorafenib (Stivarga) appears to provide greater benefit than treatment with regorafenib followed by TAS-102 in patients with metastatic colorectal cancer (mCRC) after progression under 2 or more chemotherapy protocols, according to the updated results of the phase 2 SOREGATT/PRODIGE 68 study (NCT04450836) presented atESMO 2024 Congress on Gastrointestinal Cancers.¹

Results showed that 47.9% of patients in the study population (n = 234) were treated with 2 or more cycles of each treatment sequence; this represented 40% of patients in arm A (TAS-102 followed by regorafenib; n = 115) and 55.5% of patients in arm B (regorafenib followed by TAS-102; n = 119). Sixty percent of patients in arm A and 44.5% of those in arm B did not complete at least 2 cycles of each regimen.

“Despite the premature termination of this study due to the publication of data from the (phase 3) SUNLIGHT trial (NCT0437187)… which was very good news for our patients… this study continued to provide important information,” said presenting author Michel P. Ducreux, MD, PhD, during an oral presentation. “…There is indeed a sequence effect that is proven, and starting with TAS-102 was better for the patients.”

Ducreux is head of the gastrointestinal oncology unit and the gastrointestinal oncology tumor committee at Gustave Roussy, as well as professor of oncology at Paris-Saclay University in France.

Regorafenib andtrifluridine/tipiracil The anticancer agents are FDA-approved for patients with metastatic colorectal cancer whose disease has progressed after two prior lines of chemotherapy, Ducreux explained. However, randomized data examining the optimal sequencing of these agents are lacking. Therefore, the phase 2 study assessed how many patients could receive both treatment sequences and compared survival outcomes to determine the best regimen in this setting.

This multicenter, international, comparative, open-label trial recruited patients aged 18 years and older with mCRC. Patients must have an ECOG performance status (PS) of 0 or 1 and have previously progressed on chemotherapy based on fluoropyrimidine, oxaliplatin and irinotecan; a VEGF inhibitor; and an EGFR inhibitor, if they have RAS wild-type disease. At enrollment, patients were stratified by ECOG PS, age (65 years vs over 65 years), and country.

Notably, investigators had initially planned to screen 340 patients. However, screening was prematurely halted in light of results from the SUNLIGHT trial of third-line TAS-102 plus bevacizumab (Avastin).

After screening, 234 patients were randomly assigned 1:1 to a parallel study group. In group A, patients received regorafenib followed by TAS-102; this sequence was reversed for patients assigned to group B. During cycle 1, regorafenib was administered at a daily dose of 80 mg at week 1, 120 mg daily at week 2, and 160 mg at week 1. 3, followed by one week without treatment. For all subsequent treatment cycles, regorafenib was administered at a dose of 160 mg. TAS-102 was administered orally at 35 mg/m2 twice daily on days 1–5 and 8–12 during each 4-week treatment cycle. Treatment with either regimen was continued until disease progression or unacceptable toxicity.

The primary endpoint of the study was the feasibility of administering regorafenib followed by TAS-102, and vice versa, defined as the percentage of patients treated with 2 or more cycles of each regimen. Secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS) per RECIST v1.1, disease control rate (DCR), objective response rate (ORR), time to treatment failure (TTF), and time to deterioration (TTD). Safety and quality of life were additional secondary endpoints.

Of the patients randomly assigned to arms A and B, 112 and 119 were treated, respectively. Three patients did not complete treatment due to changes in general condition, disease progression, and physician decision.

The median number of cycles received across all arms was 4 (range: 1-17; interquartile range (IQR): 2-6). A median of 2 cycles were received by patients in phase 1 (range: 1-13; IQR, 2-3) and phase 2 (range: 1-14; IQR, 2-3), respectively. Reasons for treatment discontinuation included disease progression (85.7% in phase 1; 78.7% in phase 2), toxicities (10.8%; 16.8%), death (2 .2%; 2.6%), investigator decision (1.3%; 0.6%) and patient decision (0.0%; 1.3%).

Reasons for not switching included worsening general condition of patients (37.3% overall; 22.7% in arm A; 58.1% in arm B), death (17 .3%; 22.7%; 9.7%), progression (10.7%; 13.6%; 6.5%). %), patient decision (6.7%; 11.4%; 0.0%), toxicity (9.3%; 9.1%; 9.7%), expiration of 4 weeks (5, 3%; 9.1%; 0.0%), investigator decision (6.7%; 6.8%; 6.5%), and other reasons (6.7%; 4.5). %; 9.7%). Notably, this information was missing for 1 patient in arm B.

In the overall population analyzed (n = 234), 58.5% of patients were men and 65.8% of patients had an ECOG PS of 1. The median age of patients was 67 years (range 32, 86; IQR, 59-73). , the median body mass index was 24 (range: 14-39; IQR: 21-28) and the median time to initial tumor diagnosis was 29.9 months (range: 7-137.3; IQR : 18.6-49.8). The majority of patients had tumors in the left colon (40.6%), followed by the right colon (32.5%) and the rectum (26.9%).

Further assessment of secondary endpoints showed that there was no statistically significant difference in median overall survival between the two groups. Median overall survival was 6 months in group A versus 6.9 months in group B (HR, 0.87; 95% CI, 0.67-1.14; P = 0.3). Benefit was demonstrated with treatment sequence in patients aged 65 years or older (HR, 0.87; 95% CI, 0.66-1.14; P = 0.3066) and in group B (HR, 0.87; 95% CI, 0.66-1.14; P = 0.2954). Conversely, the HR was 1.00 for patients younger than 65 years, as well as those in group A. The HRs were 1.00 and 1.69 (95% CI, 1.26- 2.27; P = 0.0005) in patients with ECOG PS of 0 vs 1, respectively.

“In terms of multivariate analysis of OS, the most important clinical factor, and we know this in our clinical practice, was the PS of the patients. The fact that they (had an) ECOG (PS of) 0 was a better prognostic factor,” Ducreux emphasized.

Median PFS was 1.87 months (95% CI, 1.84-1.94) in arm A and 1.97 months (95% CI, 1.84-2.10) in arm B, which translates to an HR of 0.81 (95% CI, 0.62-1.05; P. = .10). The 6- and 12-month PFS rates in group A were 8.70% (95% CI, 4.79%-15.27%) and 1.74% (95% CI, 0.48%-6.12%); these respective rates were 10.08% (95% CI, 5.86%-16.80%) and 2.52% (95% CI, 0.86%-7.15%) in group B.

During the presentation, Ducreux stressed that it is important to consider that these are real patients with a fairly good PS. (However), this is, in terms of prognosis, a group of patients with a poor prognosis… (they have a) median OS of 6 to 7 months, and the median PFS was very limited.

The time from randomization to progression on the 2nd treatment sequence (PFS2) was 3.7 months (95% CI, 2.86-3.84) in arm A and 3.9 months (95% CI, 3.65-4.17) in arm B (HR: 0.75; 95% CI, 0.57-0.97; P. = 0.03). The 6- and 12-month PFS rates in group A were 16.07% (95% CI, 10.41%-23.98%) and 3.57% (95% CI, 1.40-8.82); these respective rates were 26.89% (95% CI, 19.74%-35.49%) and 5.88% (95% CI, 2.88%-11.65%) in group B.

The median TTF in Arms A and B was 3.19 months (95% CI: 3.27 to 3.45) and 3.71 months (95% CI: 3.52 to 4.01 months), respectively. ). The 6- and 12-month FTT rates were 12.17% (95% CI: 7.39%-19.40%) and 3.48% (95% CI: 1.36%-8. 60%) in arm A; in arm B, they were 22.69% (95% CI: 16.09%-31.00%) and 5.04% (95% CI: 2.33%-10.56%) . The median treatment duration was 102 days (range: 1-648; IQR: 52-157) in the overall population, 94 (range: 7-516; IQR: 48.5-125) days in arm A and of 111 days (range: 7-516; IQR: 48.5-125). 1-648; IQR, 74-178) in arm B.

Ducreux added that “in the multivariate analysis, there was a clear difference in the independent arm value (depending on treatment) and also… in terms of the patient's ECOG PS. »

Regarding safety, all patients in both groups experienced an adverse event (AE). In groups A and B, 68% and 64% of patients, respectively, experienced grade 3 or higher AEs. One or more treatment-related AEs (TEAEs) grade 3 or higher occurred in 38% and 37% of patients in groups A and B, respectively. At least 1 serious AE was reported in 5% and 7% of patients in these respective groups. Grade 3 or higher AEs observed included blood and lymphatic system disorders (11.71% in group A; 24.37% in group B), cardiac disorders (0.90%; 0.0% ), gastrointestinal disorders (1.80%; 5.04%), general disorders (9.01; 6.72%), hepatobiliary disorders (0.90%; 0.84%), infections (0.90%; 1.68%), metabolism and nutrition disorders (6.31%; 0.0%), musculoskeletal and connective tissue disorders (0.90%; 0.0 %), renal and urinary disorders (0.0%; 1.68%), respiratory, thoracic and mediastinal disorders (0.90%; 0.0%), skin and subcutaneous tissue disorders (11.71%; 4.20%), and vascular disorders (2.70%; 1.68%).

“A translational analysis is underway to determine which patients responded to regorafenib,” Ducreux concludes.

Disclosures: Dr. Ducreux discloses receiving institutional funding from Roche, Merck Serono, and Keocyt; serving on advisory boards for Roche, Merck Serono, Amgen, Abbvie, Sanofi, Bayer, Zymeworks, Servier, Beigene, MSD, Arcus, Astellas, Scandion, and Abcely; and speaking at conferences for Roche, Merck Serono, Ipsen, Beigene, Amgen, Bayer, MSD, Servier, and Pierre Fabre.

The references

1. Ducreux M, Ben Abdelghani M, Tougeron D, et al. PRODIGE 68 – UCGI 38 – SOREGATT: A randomized phase II study comparing regorafenib (reg) and trifluridine/tipiracil (t/t) sequences after failure of standard therapies in patients (pts) with metastatic colorectal cancer (mCRC). Presented at: ESMO Gastrointestinal Cancers Congress 2024; June 26-29, 2024; Munich, Germany. Abstract 3O.
2. Sequences of REGorafenib and trifluridine/​tipiracil in patients with metastatic colorectal cancer (SOREGATT). ClinicalTrials.gov. Updated March 1, 2024. Accessed June 27, 2024. https://clinicaltrials.gov/study/NCT04450836