The SUNLIGHT study is the first phase 3 study in the setting of refractory metastatic colorectal cancer to demonstrate an improvement in overall survival vs an active control, according to Josep Tabernero, MD, PhD.
The addition of bevacizumab (Avastin) to trifluridine (FTD)/tipiracil (TPI; Lonsurf) resulted in favorable survival and disease control rates (DCRs) in patients with metastatic colorectal cancer (mCRC) compared with patients who received trifluridine/tipiracil alone, according to results from the phase 3 SUNLIGHT study (NCT0437187). The survival benefit was also observed in all clinically relevant subgroups.
“The SUNLIGHT study is the first phase 3 study in the setting of refractory metastatic colorectal cancer to demonstrate an improvement in overall survival vs an active control,” Josep Tabernero, MD, PhD, head, Department of Medical Oncology, Vall d’Hebron University Hospital, and director, Vall d’Hebron Institute of Oncology in Barcelona, Spain, said during the presentation of study data at the 2023 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.1
The study evaluated 492 patients with histologically confirmed mCRC who had been previously treated with fluoropyrimidine, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody (not necessarily bevacizumab), and/or an anti-EGFR monoclonal antibody in those patients whose tumor harbored a RAS mutation. Patients were stratified by geographic region (North America, the European Union, or the rest of the world), time since diagnosis of first metastasis (<18 or ≥18 months), and RAS status (wild-type or mutant). Participants were randomly assigned 1:1 to receive either 35 mg/m2 of FTD/TPI twice daily on days 1 through 5 and 8 through 12 of a 28-day cycle, and 5 mg/kg of bevacizumab on days 1 and 15 (n = 246) vs FTD/TPI alone (n = 246).
The primary end point was overall survival (OS) and secondary end points included progression-free survival (PFS), DCR, and safety. The study was designed to confirm the efficacy and safety of FTD/TPI and bevacizumab vs FTD/TPI alone in patients with refractory mCRC.
Median age in the treatment arm was 62 years (range, 20-84) and 64 years (range, 24-90) in the control arm. “Seventy percent of patients in the treatment arm had RAS mutant status compared with 69% in the control arm, demonstrating an unmet need,” Tabernero said. Across both arms, prior treatment with bevacizumab was equal (72%).
Median OS was 10.8 months in the treatment arm and 7.5 months in the control arm (HR, 0.61; 95% CI, 0.49-0.77; P < .001). At 6 months, the OS rate was 77% vs 61%, respectively, and at 12 months, the OS rate was 43% vs 30%, respectively.
When determining OS benefit by prespecified subgroup, the investigators noted that their analysis revealed that all subgroups benefited from the addition of bevacizumab, and in particular, patients who had not been previously treated with bevacizumab demonstrated greater benefit with the addition of the agent to FTD/TPI.
Median PFS was 5.6 months in the treatment arm and 2.4 months in the control arm (HR, 0.44; 95% CI, 0.36-0.54; P < .001). The 6-month PFS rate was 43% vs 16%, respectively, and the 12-month PFS rate was 16% vs 1%, respectively. Tabernero said a PFS analysis by prespecified subgroup showed similar findings as the OS subgroup analysis, with all subgroups showing benefit.
“Both overall response rate and disease control rate was superior for the experimental arm in patients who were evaluable for tumor response,” Tabernero said. “The absolute gain for overall response rate was 5.4% [P = .004] and the absolute gain for disease control rate was 29.6% [P < .001].”
Turning to quality-of-life characteristics, the median time to deterioration in global health status in the treatment arm was 8.5 months vs 4.7 months in the control arm (HR, 0.50; 95% CI, 0.38-0.65; P < .001). Similarly, the time to worsening to an ECOG performance status of 2 or greater was statistically superior for patients receiving FTD/TPI with bevacizumab (9.3 months) vs FTD/TPI alone (6.3 months; HR, 0.54; 95% CI, 0.43-0.67; P < .001).
“In looking at parameters related to quality of life, both worsening of the baseline global health status and ECOG performance status from zero or 1 to 2 or more was significantly delayed in patients who received FTD/TPI plus bevacizumab compared with FTD/TPI alone,” Tabernero said.
Regarding safety, overall adverse events (AEs) were equally reported for both arms. Investigators reported zero treatment-related deaths, rates of severe AEs were 72% in the treatment arm and 70% in the control arm, and 13% of patients in both arms experienced AEs leading to withdrawal from the study.
Sixteen percent of patients in the treatment arm experienced dose reductions vs 12% in the control arm. The percentage of dose delays was higher in the treatment arm (70%) vs the control arm (53%).
Treatment-emergent AEs were comparable in the 2 arms, although Tabernero noted that hypertension was higher in the treatment arm (10% vs 2%), and that nausea (37% vs 27%) and neutropenia (62% vs 51%) were more common in the treatment arm. “Only 1 patient in the experimental arm experienced febrile neutropenia vs 6 patients in the control arm,” Tabernero said.
“To conclude, the combination of FTD/TPI plus bevacizumab represents a new standard of care for the treatment of patients with refractory metastatic CRC who had previously progressed after 2 lines of therapy,” Tabernero said.
Tabernero J, Prager GW, Fakih M, et al. Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer: The phase 3 randomized SUNLIGHT study. J Clin Oncol. 2023;41(suppl 4):4. doi: 10.1200/JCO.2023.41.3_suppl.4