1. Fuerst, Mark L.

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A combination of bevacizumab plus trifluridine/tipiracil improves survival in third-line treatment of refractory metastatic colorectal cancer. In the international, multicenter, Phase III SUNLIGHT study, median overall survival (OS) improved by 3.3 months with trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil alone. The survival benefit was observed across all subgroups, irrespective of age, sex, location of primary disease, number of metastatic sites, and RAS mutation status.

Colorectal Cancer. C... - Click to enlarge in new windowColorectal Cancer. Colorectal Cancer

"This is one of the first studies to show improved efficacy over an existing active treatment in patients with refractory metastatic colorectal cancer. In addition, the magnitude of the benefit observed was greater than that seen in other trials and in a population that included patients with poor prognostic factors, such as RAS mutations," said lead author Josep Tabernero, MD, PhD, Head of the Medical Oncology Department at the Vall d'Hebron Hospital Campus and Institute of Oncology in Barcelona, Spain.


The combination of bevacizumab plus trifluridine (a thymidine-based antineoplastic nucleoside analog) and tipiracil (a thymidine phosphorylase inhibitor that increases the viability of trifluridine) has shown in several single-arm Phase II studies and a randomized Phase II study to improve OS and progression-free survival (PFS) with a manageable safety profile.

Josep Tabernero, MD,... - Click to enlarge in new windowJosep Tabernero, MD, PhD. Josep Tabernero, MD, PhD

Study Details

At the 2023 ASCO Gastrointestinal Cancers Symposium, Tabernero presented the results of the Phase III SUNLIGHT study (Abstract 4). The study included 490 patients with histologically confirmed metastatic colorectal cancer who had failed two prior regimens, including fluoropyrimidines, irinotecan, oxaliplatin, an anti-VEGF therapy, and/or an anti-EGFR therapy for those patients who had tumors with RAS wild-type status. Patients were randomly assigned to receive either trifluridine/tipiracil (246 patients) or bevacizumab plus trifluridine/tipiracil (246 patients).


The baseline characteristics were well-balanced between the two arms, he noted. Median age was 63 years and about half the patients were men. About 70 percent in each arm had RAS mutations, 76 percent had previously received an anti-VEGF therapy, and 72 percent received bevacizumab. Results show the study met the primary endpoint. The median survival in the control arm with trifluridine/tipiracil was 7.5 months and 10.8 months in the experimental arm combining bevacizumab, trifluridine, and tipiracil (HR: 0.61).


"The analysis did not show any particular subgroup that did not benefit from the addition of bevacizumab to trifluridine/tipiracil. Of note, those patients that had previously received bevacizumab also gained benefit from the addition of bevacizumab to the combination of trifluridine/tipiracil," Tabernero noted.


The median PFS in the control arm was 2.4 months and 5.6 months in the experimental arm. "Likewise, we didn't observe any particular subgroup that did not benefit from the addition of bevacizumab to trifluridine and tipiracil," he said.


Both overall response rate and disease control rate were superior for the experimental arm in patients evaluable for tumor response. The absolute gain for overall response rate was 5.4 percent, and for disease control rate it was 29.6 percent. Overall, the safety profile of the patients was manageable, and there were no new signals of safety. Adverse events of Grade 3 or higher were reported in 70 percent of patients in the control arm and 72 percent in the bevacizumab arm. Adverse events led to study withdrawal in 13 percent of patients in each arm. No treatment-related deaths were reported.


The percentage of treatment-emergent adverse events was very comparable in the two arms, except for a slightly superior number of patients presenting with hypertension, nausea, and neutropenia in the experimental arm. This did not translate into more patients having febrile neutropenia, Tabernero noted. Only one patient in the experimental arm presented febrile neutropenia versus six patients in the control arm.


"The SUNLIGHT study actually is the first Phase III study in the setting of refractory metastatic colorectal cancer to demonstrate an improvement in OS versus an active control. In looking at parameters related to the quality of life, both worsening of the baseline global health status and ECOG performance status from 0 or 1 to 2 or more were significantly delayed in patients that received trifluridine and tipiracil plus bevacizumab compared to those that received trifluridine and tipiracil alone," Tabernero stated. "To sum up, the combination of trifluridine, tipiracil, plus bevacizumab represents a new standard of care for the treatment of patients with refractory metastatic colorectal cancer who had previously progressed after two lines of therapy."


ASCO Expert in gastrointestinal cancers Cathy Eng, MD, Professor of Medicine at Vanderbilt University Medical Center, commented: "This randomized Phase III trial in European patients after receiving 1-2 lines of prior chemotherapy validates earlier Phase II Danish data demonstrating improved OS of trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil alone."


Mark L. Fuerst is a contributing writer.