For the treatment of metastatic colorectal cancer in patients unfit for intensive chemotherapy, trifluridine/tipiracil plus bevacizumab as first-line therapy was no more effective than capecitabine plus bevacizumab, investigators from the phase III SOLSTICE trial reported in a European Society for Medical Oncology (ESMO) Virtual Plenary session.1 Median progression-free survival was just over 9 months in both arms, but toxicity profiles differed, according to Thierry André, MD, of the Sorbonne University and Saint-Antoine Hospital in Paris.
SOLSTICE is the first phase III study exploring the population of patients [with metastatic colorectal cancer] who are not candidates for intensive therapy.— Thierry André, MD
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As Dr. André pointed out, many patients with metastatic colorectal cancer are unfit for intensive chemotherapy. The combination of trifluridine, a thymidine-based nucleoside analog, and tipiracil, a thymidine phosphorylase inhibitor, is an oral drug approved in the United States, Europe, and Japan as monotherapy for metastatic colorectal cancer in the third or later lines and is believed to have a different safety profile from capecitabine/bevacizumab.
“SOLSTICE is the first phase III study exploring trifluridine/tipiracil plus bevacizumab in first-line metastatic colorectal cancer and the first phase III study exploring the population of patients who are not candidates for intensive therapy,” Dr. André noted. “Median progression-free survival in both arms in this selected population was clinically meaningful, but trifluridine/tipiracil plus bevacizumab did not show statistically significant superiority in terms of progression-free survival assessed by investigators, though there was a trend in favor of it.”
About SOLSTICE
The SOLSTICE trial was conducted in patients with previously untreated unresectable metastatic colorectal cancer not eligible to receive standard doublet regimens with oxaliplatin or irinotecan due to clinical conditions including age (42% of patients), ECOG performance status, comorbidities, low tumor buden, or nonclinical reasons (eg, patient preference).
In the study, 856 previously untreated patients with metastatic colorectal cancer were randomly assigned to receive either oral trifluridine/tipiracil plus bevacizumab every 4 weeks or oral capecitabine plus bevacizumab every 3 weeks. The study’s aim was to demonstrate the superiority of trifluridine/tipiracil plus bevacizumab over capecitabine plus bevacizumab in terms of investigator-assessed progression-free survival. The target for efficacy was a hazard ratio of 0.77 and a one-sided P value of 0.021.
The previous randomized phase II TASCO1 study evaluated these same regimens in 153 patients, finding a nonsignificant improvement in progression-free survival. Overall survival was better with trifluridine/tipiracil plus bevacizumab, but it was a secondary endpoint of the study,2 Dr. André said.
Clinical Outcomes
By investigator assessment, median progression-free survival in SOLSTICE was 9.4 months with trifluridine/tipiracil plus bevacizumab and 9.3 months with capecitabine plus bevacizumab (hazard ratio [HR] = 0.87; P = .0464). “The P value was greater than the prespecified alpha (P = .021) that was required for statistical significance,” he said. By blinded independent central review, median progression-free survival was 10.6 months vs 9.3 months, respectively (HR = 0.85; P = .0265), “which was very near the significance required,” Dr. André further noted.
In the prespecified subgroup analysis, three populations were identified as having a better outcome with trifluridine/tipiracil plus bevacizumab: patients with wild-type RAS, men, and those with a neutrophil-to-lymphocyte ratio < 5. Across all subgroups but not in those with a neutrophil-to-lymphocyte ratio ≥ 5, progression-free survival was “modestly improved” in the experimental arm, he said.
KEY POINTS
- In the phase III SOLSTICE trial, elderly or unfit patients with metastatic colorectal cancer were treated in the first line with trifluridine/tipiracil plus bevacizumab vs capecitabine/bevacizumab, which are thought to have different safety profiles: more neutropenia with trifluridine/tipiracil and more hand-foot syndrome with capecitabine.
- The experimental regimen was not superior to the standard of care, but there was a trend in favor of the experimental arm; median progression-free survival in both arms in this selected population was clinically meaningful: 9.4 months vs 9.3 months.
- Despite no statistically significant improvement in progression-fee survival with the experimental regimen, some elderly or unfit patients may be served by trifluridine/tipiracil plus bevacizumab.
Response rates were higher with capecitabine plus bevacizumab (41.6% vs 35.9%), but stable disease was more common with trifluridine/tipiracil plus bevacizumab (50.5% vs 43.5%), yielding almost identical disease control rates: 86.4% with trifluridine/tipiracil plus bevacizumab and 85.1% with capecitabine plus bevacizumab.
The trifluridine/tipiracil plus bevacizumab arm experienced more grade ≥ 3 neutropenia (66.4% vs 2.3%), whereas patients receiving capecitabine plus bevacizumab had more grade ≥ 3 hand-foot syndrome (14.5% vs 0%), consistent with the known safety profiles of these regimens.
Rationale for the Regimen
The rationale for the combination is based on some key differences between trifluridine/tipiracil and fluorouracil. Up to 85% of fluorouracil and capecitabine is catabolized into inactive metabolites by dihydropyrimidine dehydrogenase (DPD). DPD catabolizes fluorouracil to alpha-fluoro-beta-alanine, which is responsible for cardiotoxicity, hand-foot syndrome, and neurotoxicity; DPD is not a part of trifluridine/tipiracil’s intracellular metabolic pathway.
Other research has suggested that trifluridine may better inhibit mitotic entry into the G2/M phase of the cell cycle. Preclinical data indicated a greater degree of incorporation of trifluridine into DNA compared with fluorouracil, added Dr. André.
DISCLOSURE: Dr. André disclosed financial relationships with AstraZeneca, Astellas, Bristol Myers Squibb, Gritstone Oncology, GlaxoSmithKline, HalioDx, Merck & Co, Pierre Fabre, Seagen, Servier, Transgene, AstraZeneca, Roche/Ventana, Sanofi, Clovis, and Kaleido Biosciences.
REFERENCES
1. André T, Falcone A, Shparyk Y, et al: Trifluridine/tipiracil plus bevacizumab vs capecitabine plus bevacizumab as first line treatment for patients with metastatic colorectal cancer ineligible for intensive therapy: The phase III randomized SOLSTICE study. 2021 ESMO Virtual Plenary. Abstract VP11-2021. Presented December 16, 2021.
2. Van Cutsem E, Danielewicz I, Saunders MP, et al: Phase II study evaluating trifluridine/tipiracil + bevacizumab and capecitabine + bevacizumab in first-line unresectable metastatic colorectal cancer patients who are noneligible for intensive therapy (TASCO1): Results of the final analysis on the overall survival. 2021 Gastrointestinal Cancers Symposium. Abstract 14.
