Trifluridine-tipiracil combo improves OS in metastatic gastric cancer
Patients with previously treated metastatic gastric adenocarcinoma had improved overall survival (OS) when a trifluridine-tipiracil combination was added to a supportive care regimen compared with best supportive care alone, according to findings of the phase III TAGS* trial.
A total of 507 adults with nonresectable, metastatic gastric adenocarcinoma and radiological disease progression who had previously been treated with ≥2 chemotherapy regimens were randomized to receive best supportive care in addition to placebo (n=170, median age 63 years, 69 percent male) or oral trifluridine/tipiracil (35 mg/m2 twice/day on days 1–5 and 8–12 every 28 days; n=337, median age 64 years, 75 percent male). Patients who received trifluridine/tipiracil and placebo were treated for a mean 12.1 and 7.1 weeks, respectively.
Patients who received trifluridine/tipiracil had better OS compared with those who received placebo (median, 5.7 vs 3.6 months, hazard ratio [HR], 0.69, 95 percent confidence interval [CI], 0.56–0.85; one-sided p=0.00029, two-sided p=0.00058). [ESMO 2018, abstract LBA25; Lancet Oncol 2018;doi:10.1016/S1470-2045(18)30739-3]
Progression-free survival was also longer in patients who received trifluridine/tipiracil compared with placebo (median, 2.0 vs 1.8 months, HR, 0.57, 95 percent CI, 0.47–0.70; two-sided p<0.0001), as was time to ECOG status deterioration (to ≥2; median, 4.3 vs 2.3 months; two-sided p=0.00053). More patients on trifluridine/tipiracil than placebo achieved disease control (44 percent vs 14 percent; p<0.0001), though objective response rate was comparable between groups (4 percent vs 2 percent; p=0.28).
Grade ≥3 adverse events (AEs) occurred in 80 and 58 percent of trifluridine/tipiracil and placebo recipients, respectively. Among patients who received trifluridine/tipiracil, neutropenia and anaemia were the most common grade ≥3 AEs (34 and 19 percent, respectively), while abdominal pain, general physical deterioration, and anaemia were the most common grade ≥3 AEs among placebo recipients (9, 9, and 8 percent respectively). Serious AEs occurred at a comparable rate between trifluridine/tipiracil and placebo recipients (43 percent vs 42 percent).
Eleven and 13 percent of trifluridine/tipiracil and placebo recipients, respectively, discontinued treatment due to grade ≥3 AEs. The two treatment-related deaths were due to cardiopulmonary arrest (trifluridine/tipiracil recipient) and toxic hepatitis (placebo recipient).
“Treatment options are few for patients with heavily pretreated metastatic gastric cancer,” said the researchers. “Trifluridine/tipiracil could be a new treatment option for patients with heavily pretreated advanced gastric cancer after progression on, or intolerance to, two or more previous lines of chemotherapy, including a fluoropyrimidine, a platinum agent, a taxane or irinotecan (or both), and an anti-HER2 therapy (in patients with HER2-positive disease).”
“[F]uture research exploring the treatment in novel combination regimens could be warranted,” they added.
In contrast to other drugs approved for gastric cancer treatment in the third-line setting, the AEs associated with trifluridine/tipiracil use appear to be short-term, said the researchers. “[As such], the safety profiles of these drugs might determine suitability for individual patients, although ideally further biomarker analysis would clarify predictive factors for each drug,” they said.
“Our aim as clinicians now needs to be to identify the patients who benefit most from each treatment to achieve a sustained 12-month survival rather than a somewhat short improvement of survival by 9 weeks,” said Drs Henrik Nienhüser and Thomas Schmidt from the University of Heidelberg in Heidelberg, Germany, in a commentary. [Lancet Oncol 2018;doi:10.1016/S1470-2045(18)30752-6]
They cautioned that the PFS benefit observed in the trifluridine/tipiracil group (approximately 6-day improvement), while statistically significant, had “little clinical relevance”, and called for head-to-head trials to identify the best treatment regimen for patients with heavily pretreated gastric cancer.