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 showed “very exciting advantages in progression-free and overall survival” with the addition of bevacizumab to trifluridine/tipiracil, with only a modest increase in toxicity.
“The SUNLIGHT study was an open-label randomized phase III trial evaluating the combination of TAS-102 (trifluridine/tipiracil) plus bevacizumab vs TAS-102 alone. Of note, 92% of patients were treated in the third-line setting, and 76% had received prior anti-VEGF therapy though they were not required to have had both anti-VEGF and anti-EGFR therapy,” he said. “There is significant clinical benefit, with an improvement in overall survival of more than 3 months, and all the subgroups favored the combination.”
“This trial does change standard clinical practice…. Trifluridine/tipiracil and bevacizumab should be considered the preferred nontargeted regimen in the refractory setting,” he maintained.
Dustin Deming, MD
Multiple Options
As Dr. Deming noted, there are multiple options for patients in the refractory setting, with treatment often determined by subtype. Patients with RAS/RAF wild-type tumors, KRAS G12C mutations, BRAF V600 mutations, mismatch repair deficiency/microsatellite instability, and HER2 amplification can be biomarker-selected for targeted agents that have proven efficacy in these subtypes. For patients lacking these targets, the standard nontargeted treatment options are trifluridine/tipiracil and regorafenib, for which median progression-free survival is about 2 months. Regarding emerging approaches, the findings from phase II studies show that disease progression can be further delayed (to around 4 months) with trifluridine/tipiracil plus bevacizumab1,2 and with fruquintinib.3
Based on earlier findings of significant activity and good tolerability, the SUNLIGHT regimen had already been incorporated into the National Comprehensive Cancer Network Clinical Practice Guideines in Oncology, and this study is further confirmation of its value, Dr. Deming said.
Strengths and Limitations
The study’s strengths include its international population, large size, and randomized design; similar baseline characteristics across the cohorts; and expected adverse-event profile. Its limitations include its open-label design, scant enrollment (3%) from North America, and relatively lower proportion of patients (76%) with prior anti-VEGF therapy as compared with previous studies (approximately 85%).
Commenting on the “modest” response rate of 6.3%, he said: “Further data are needed about the duration and timing of the prior anti-VEGF therapy and how that might impact some of the clinical outcomes.”
Dr. Deming further suggested the findings will have implications for future clinical trials, as the results suggest a new standard for a control arm. “Now, if treatments are going to be studied in the third- and fourth-line settings, TAS-102 and bevacizumab needs to be, at a minimum, an option for patients on those trials.
DISCLOSURE: Dr. Deming has been a consultant or advisor to Bayer, Eli Lilly, Pfizer, and Seagen; and has received research funding from Merck, Genentech, Bristol Myers Squibb, Aadi Biosciences, Pfizer, Curegenix, Promega, Natera, Strata Oncology, Cornerstone Pharmaceuticals, Arcus, Guardant Health, Ipsen, Takeda, Eli Lilly, and Revolution Medicine.
REFERENCES
1. 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.
2. 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.
3. Dasari NA, Sobrero A, Yao J, et al: FRESCO-2: A global phase III multiregional clinical trial evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. ESMO Congress 2022. Abstract LBA25. Presented September 12, 2022.
