At the 2023 ASCO Gastrointestinal Cancers Symposium, Josep Tabernero, MD, Vall d’Hebron Institute of Oncology, Barcelona, Spain, presented results from the phase 3 SUNLIGHT study, evaluating trifluridine/tipiracil plus bevacizumab for patients with refractory metastatic colorectal cancer. Trifluridine/tipiracil plus bevacizumab provided a statistically significant and clinically meaningful improvement in overall survival for this patient profile compared with trifluridine/tipiracil monotherapy.

Dr Tabernero stated, “The combination of trifluridine/tipiracil plus bevacizumab represents a new standard of care for the treatment of patients with refractory metastatic colorectal cancer who have progressed after 2 lines of therapy.”

Transcript:

Hello, my name is Josep Tabernero. I'm a medical oncologist based in Barcelona, Spain, in the Vall d'Hebron Institute of Oncology. And on behalf of the co-authors and investigators of the SUNLIGHT study, I'm very happy to present the data that has been presented at the 2023 ASCO Gastrointestinal Cancers Symposium. This study evaluates the combination of trifluridine/tipiracil plus bevacizumab for the third-line treatment of patients with refractory metastatic colorectal cancer.

The rationale for this study is very simple. Actually, it comes through 2 premises: the first one is that the combination of trifluridine/tipiracil significantly improves overall survival and had a favorable safety profile in patients with refractory metastatic colorectal cancer in the phase 3 RECOURSE study. And the second is that results from several phase 2 studies, single-arm and a randomized phase 2 study, show that the combination of trifluridine/tipiracil plus versus bevacizumab did improve overall survival, progression for survival with a manageable safety profile. Consequently, the SUNLIGHT study was designed to confirm the efficacy and safety of the trifluridine/tipiracil plus versus bevacizumab in patients with refractory metastatic colorectal cancer.

The SUNLIGHT study was an international, multicenter phase 3 study that including a total of 490 patients. Patients had to have histologically confirmed metastatic colorectal cancer, had to have failed 2 prior treatment regimens that include fluoropyrimidines, irinotecan, oxaliplatin, and an anti-VEGF therapy and/or an anti-EGFR therapy if patients had RAS wild-type tumors. Patients were randomized 1-to-1 to receive either trifluridine/tipiracil plus bevacizumab in the experimental arm, or trifluridine/tipiracil in the control arm until progression of the disease or an acceptable toxicity. The primary end point of the study was to demonstrate an advantage in overall survival in the full analysis dataset. As secondary endpoints, we evaluated progression-free survival, overall respond rate, disease control rate, safety, and quality of life aspects. Patients were well randomized between the 2 arms. The median age of the patients included in the study was 63 years old, with a 50% balance between male and the female population. And 76% of the patients had previously received an anti-VEGF therapy, and 72% had bevacizumab.

The study met the primary endpoint. Patients included in the SUNLIGHT study who received the combination of trifluridine/tipiracil plus bevacizumab significantly increased overall survival. Not only significantly increased, but also clinically meaningful, with a hazard ratio of 0.61 and a P-value of less than 0.001. The median survival in patients that received trifluridine/tipiracil was 7.5 months, and the median overall survival in those that received trifluridine/tipiracil plus bevacizumab was 10.8 months. And the absolute gain in overall survival was 3.3 months. And actually, interestingly, the curves reversed from the early beginning.

We explored potential predictive biomarkers that could show us particular populations that did not benefit from the addition of bevacizumab. This analysis actually did not show any subgroup of patients that did not benefit from the addition of bevacizumab.

The study was also positive for progression-free survival with a hazard ratio of 0.44, P-value of less than 0.001. The median progression-free survival in the control arm was 2.4 months. The median progression-free survival in the experimental arm was 5.6 months. And again, the forest plot analysis did not show any particular subgroup that did not benefit from the addition of bevacizumab for progression-free survival. Both overall response rate and disease control rate in patients available for tumor response favored the experimental arm, with this difference being statistically significant.

We also looked at quality of life related parameters, for example, the time to deterioration in global health status and the time to worsening in ECOG performance status of 2 or more. And for the 2 parameters, those patients who had received trifluridine/tipiracil plus bevacizumab had a superior effect in all these 2 parameters.

Overall, the safety profile was acceptable with no new safety signals. There were no treatment-related deaths in the study, and the proportion of grade 3 or more adverse events or serious adverse events was comparable in the 2 arms. A slightly superior percentage of patients in the experimental arm with trifluridine/tipiracil plus bevacizumab needed dose modifications, including dose reductions and dose delays. But the number of patients with adverse events leading to withdrawal from the study was the same in the 2 arms. And in considering the treatment-emergent adverse events in 20% or more of the patients, the toxicity profile was very similar in the 2 arms, except for a slightly superior percentage of patients in the experimental arm having hypertension, nausea, and neutropenia. Nevertheless, the increased number of patients that had neutropenia did not translate into febrile neutropenia. Actually, only 1 patient in the combination of trifluridine/tipiracil plus bevacizumab developed febrile neutropenia versus 6 patients in the control arm with trifluridine/tipiracil.

To conclude, the SUNLIGHT study met the primary endpoint. The combination of trifluridine/tipiracil plus bevacizumab resulted in significantly longer overall survival and progression-free survival and improved disease control compared to trifluridine/tipiracil alone. And actually, these improvements in survival occur 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 versus an active control. In terms of quality of life, worsening of baseline global health status and ECOG performance status from 0, 1 to 2, or more was significantly delayed in patients receiving trifluridine/tipiracil plus bevacizumab. Regarding the safety, the combination of trifluridine/tipiracil plus bevacizumab had a manageable safety profile, and consistent with individual safety profiles of trifluridine/tipiracil and bevacizumab.

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 have progressed after 2 lines of therapy.

Thank you very much for your attention.

Source:

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. Presented at 2023 ASCO Cancers Symposium; January 19 – 21, 2023; San Francisco, California. Abstract 4