In the open-label phase III SUNLIGHT trial, the addition of bevacizumab to trifluridine/tipiracil, also known as TAS-102, significantly improved overall survival in patients with metastatic treatment-refractory colorectal cancer,1 according to Josep Tabernero, MD, Head of the Department of Medical Oncology, Vall d’Hebron University Hospital and Director of the Vall d’Hebron Institute of Oncology in Barcelona.
The addition of bevacizumab to trifluridine/tipiracil resulted in a median overall survival of 10.8 months vs 7.5 months for trifluridine/tipiracil alone (hazard ratio [HR] = 0.61; P < .001). The regimen also achieved improvements in progression-free survival and disease control and delayed worsening of global health status, without increasing serious adverse events or toxicities leading to treatment discontinuation, Dr. Tabernero reported at the 2023 ASCO GI Cancers Symposium.
The safety profile of [trifluridine/tipiracil] plus bevacizumab was manageable and consistent with the individual safety profiles of each.— Josep Tabernero, MD
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SUNLIGHT is the first phase III study in the setting of refractory metastatic colorectal cancer to demonstrate an improvement in overall survival vs an active control,” Dr. Tabernero said. “[Trifluridine/tipiracil] plus bevacizumab represents a new standard of care for the treatment of patients with refractory metastatic colorectal cancer that had previously progressed after two lines of therapy.”
Trifluridine/tipiracil is already approved as a monotherapy for third-line use in refractory metastatic colorectal cancer, based on a significant improvement in overall survival in the phase III RECOURSE study2; the combination of bevacizumab and trifluridine/tipiracil has shown encouraging results in several smaller randomized and single-arm studies.3,4 The phase III SUNLIGHT study was designed to confirm the efficacy and safety of the combination in patients with refractory metastatic colorectal cancer following two chemotherapy regimens.
The study randomly assigned 492 patients, previously treated with two regimens, to receive 28-day cycles of trifluridine/tipiracil plus bevacizumab (trifluridine/tipiracil at 35 mg/m2 twice daily on days 1 to 5 and 8 to 12 plus bevacizumab at 5 mg/kg on days 1 and 15) or trifluridine/tipiracil alone. More than three-quarters of patients (76%) had received prior treatment with a drug targeting vascular endothelial growth factor (VEGF), and 28% had received bevacizumab. About 70% had RAS mutations. The primary endpoint was overall survival in the full-analysis population.
Improvement in All Endpoints
In the full-analysis population, at 6 months, the overall survival rate was 77% with combination therapy vs 61% with trifluridine/tipiracil alone; at 12 months, the rate was 43% vs 30%, respectively. All prespecified subgroups derived benefit from the addition of bevacizumab, including patients previously treated with bevacizumab (hazard ratio [HR] = 0.73; 95% confidence interval [CI] = 0.56–0.92).
Median progression-free survival was 5.6 months in the treatment arm vs 2.4 months in the control arm (HR = 0.44; P < .001), yielding a 6-month progression-free survival rate of 43% vs 16%, respectively, and a 12-month rate of 16% vs 1%. Again, all prespecified subgroups benefited from bevacizumab.
In the discussion period, Dr. Tabernero was asked to elaborate on the outcomes in patients who had previously received bevacizumab, specifically, whether the number of prior bevacizumab-containing regimens and the timing of those regimens affected benefit. “These questions are excellent,” he said, noting that most patients received prior anti-VEGF therapy and for many, this was bevacizumab. “This is something we are literally analyzing right now because this information could be informative about which patients benefit most from treatment.”
Both overall response rate and disease control rate were also superior in the investigational arm. The overall response rate was 6.3% vs 0.9% in the control arm, yielding an absolute gain of 5.4% with bevacizumab (P = .004). The disease control rate was 76.6% vs 47.0%, yielding an absolute gain of 29.6% (P < .001), he reported.
Measures of quality of life also showed the advantage of adding bevacizumab. Median time to deterioration in global health status was 8.5 months vs 4.7 months (HR = 0.50; P < .001) and worsening to an Eastern Cooperative Oncology Group performance status ≥ 2 was delayed, with a median time of 9.3 months vs 6.3 months, respectively (HR = 0.54; P < .001).
These improvements were achieved without notable increases in toxicity, Dr. Tabernero said. There were no treatment-related deaths, and the rates of severe adverse events were similar between the arms—approximately 70% in each. Dose modifications and delays were slightly more frequent in the bevacizumab arm, and the combination group had more hypertension (not unexpected with the use of bevacizumab) and neutropenia but less febrile neutropenia. “The safety profile of [trifluridine/tipiracil] plus bevacizumab was manageable and consistent with the individual safety profiles of each,” he said.
DISCLOSURE: Dr. Tabernero has stock or other ownership interests in Oniria Therapeutics; has been a consultant or advisor to Array BioPharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, F. Hoffmann–Laroche, Genentech, HalioDx, Hutchison, MediPharma, Ikena Oncology, Inspira, IQvia, Lilly, Menarini, Merck Serono, Merus, Mirati Therapeutics, MSD, NeoPhore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio, Taiho Pharmaceutical, Tessa Therapeutics, and TheraMyc; and has had other financial relationships with Imedex/HMP, Medscape, MJH Life Sciences, PeerView, and Physicians’ Education Resource.
1. 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. 2023 ASCO GI Cancers Symposium. Abstract 4. Presented January 21, 2021.
2. Mayer RJ, Van Cutsem E, Falcone A, et al: Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372:1909-1919, 2015.
3. Pfeiffer P, Yilmaz M, Möller S, et al: TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: An investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol 21:412-420, 2020.
4. Yoshida Y, Yamada T, Kamiyama H, et al: Combination of TAS-102 and bevacizumab as third-line treatment for metastatic colorectal cancer: TAS-CC3 study. Int J Clin Oncol 26:111-117, 2021.
The invited discussant of the SUNLIGHT trial, Dustin Deming, MD, the ACI/Schwenn Family Association Professor in the Division of Hematology, Medical Oncology, and Palliative Care and Director of JD Fluno Colorectal Cancer Precision Medicine at the University of Wisconsin, Madison, said the findings ...