In the JournalsPerspective

Trifluridine and tipiracil safe, effective for pretreated metastatic gastric cancer regardless of prior gastrectomy

David H. Ilson, MD PhD
David H. Ilson

Trifluridine and tipiracil significantly extended PFS and OS compared with placebo among patients with previously treated metastatic gastric or gastroesophageal junction cancer, according to results of a subgroup analysis of the randomized phase 3 TAS-102 Gastric Study.

The oral nucleoside antitumor agent trifluridine and tipiracil (Lonsurf, Taiho Oncology) — also called TAS-102 — demonstrated safety and efficacy regardless of whether patients had undergone gastrectomy.

“This is an important observation, as TAS-102 is an oral agent potentially influenced by drug absorption and is potentially effective in patients with prior gastrectomy,” David H. Ilson, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center and a HemOnc Today Editorial Board Member, told HemOnc Today. “This follow-up analysis from the pivotal [TAS-102 Gastric Study] indicated that PFS and OS benefits were maintained in patients who had undergone prior gastrectomy — no differences were observed in toxicity or drug delivery.”

Third- and later-line therapy for metastatic gastric cancer, which eventually becomes refractory to chemotherapy, remains an unmet need. Results of previous studies showed trifluridine and tipiracil — which combines the thymidine analogue trifluridine with the thymidine phosphorylase inhibitor tipiracil — extended PFS and OS as late-line therapy compared with supportive care only. However, the agent’s activity among the subpopulation of patients who have undergone gastrectomy had not been determined.

The placebo-controlled TAS-102 Gastric Study enrolled 507 patients (mean age, 62.5 years; 72.8% men) with pretreated metastatic gastric cancer or gastroesophageal junction cancer between Feb. 24, 2016, and Jan. 5, 2018. Patients had an ECOG performance status of 0 or 1, received at least two prior chemotherapy regimens and were refractory to or unable to tolerate the most recent therapy.

The researchers randomly assigned patients 2:1 to oral trifluridine and tipiracil dosed at 35 mg/m² twice daily (n = 337) or placebo twice daily and best supportive care (n = 170) on days 1 through 5 and 8 through 12 of 28-day treatment cycles.

Ilson and colleagues conducted a preplanned subgroup analysis of patients who underwent gastrectomy (n = 221) or had not undergone gastrectomy (n = 286).

OS served as the primary endpoint. Secondary endpoints included efficacy and safety.

Among patients who underwent gastrectomy, those who received trifluridine and tipiracil (n = 147) had longer PFS (median, 2.2 months vs. 1.8 months; HR = 0.48; 95% CI, 0.35-0.65) and OS (median, 6 months vs. 3.4 months; HR = 0.57; 95% CI, 0.41-0.79) than those who received placebo (n = 74).

Among those who had not undergone gastrectomy, researchers also observed slightly longer PFS (median, 1.9 months vs. 1.8 months; HR = 0.65; 95% CI, 0.49-0.85) and longer OS (median, 5.6 months vs. 3.8 months; HR = 0.8; 95% CI, 0.6-1.06) with trifluridine and tipiracil (n = 190) vs. placebo (n = 96).

An analysis of median time to deterioration of ECOG performance status to 2 or higher in the study treatment vs. placebo groups showed HRs of 0.63 (95% CI, 0.46-0.87) for those who underwent gastrectomy and 0.74 (95% CI, 0.56-0.98) for those who did not.

Grade 3 or higher any-cause adverse events occurred more frequently among patients treated with trifluridine and tipiracil who underwent gastrectomy vs. no gastrectomy (84.1% vs. 76.3%). Patients in the gastrectomy subgroup appeared more likely to experience grade 3 or higher events such as neutropenia (44.1% vs. 26.3%), anemia (21.4% vs. 17.4%) and leukopenia (14.5% vs. 5.3%). However, patients who did not undergo gastrectomy were more likely to experience grade 3 or higher fatigue (10.5% vs. 2.1%).

Adverse events led to dosing modifications for 94 patients (64.8%) in the gastrectomy subgroup and 101 patients (53.2%) in the no-gastrectomy subgroup. A larger percentage of patients in the no-gastrectomy subgroup discontinued treatment due to adverse events (14.7% vs. 10.3%).

The subgroup analysis lacked power for statistical significance, which served as the study’s primary limitation.

“Given the activity of [trifluridine and tipiracil] in late-line treatment, the potential to move this drug up to earlier lines of therapy in combination with other agents or other early-line agents is now considered,” Ilson told HemOnc Today. – by Jennifer Southall

For more information:

David Ilson, MD, PhD, can be reached at Memorial Sloan Kettering Cancer Center, 300 E. 66th St., BAIC 1031, New York, NY 10065; email: ilsond@mskcc.org.

Disclosures: Ilson reports grants and advisory role support from Amgen, Astellas, AstraZeneca, Bayer AG, Bristol-Myers Squibb, Eli Lilly & Co., Merck, F. Hoffman-LaRoche, Pieris Pharmaceuticals and Taiho Oncology outside of the submitted work. Please see the study for all other authors’ relevant financial disclosures.

David H. Ilson, MD PhD
David H. Ilson

Trifluridine and tipiracil significantly extended PFS and OS compared with placebo among patients with previously treated metastatic gastric or gastroesophageal junction cancer, according to results of a subgroup analysis of the randomized phase 3 TAS-102 Gastric Study.

The oral nucleoside antitumor agent trifluridine and tipiracil (Lonsurf, Taiho Oncology) — also called TAS-102 — demonstrated safety and efficacy regardless of whether patients had undergone gastrectomy.

“This is an important observation, as TAS-102 is an oral agent potentially influenced by drug absorption and is potentially effective in patients with prior gastrectomy,” David H. Ilson, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center and a HemOnc Today Editorial Board Member, told HemOnc Today. “This follow-up analysis from the pivotal [TAS-102 Gastric Study] indicated that PFS and OS benefits were maintained in patients who had undergone prior gastrectomy — no differences were observed in toxicity or drug delivery.”

Third- and later-line therapy for metastatic gastric cancer, which eventually becomes refractory to chemotherapy, remains an unmet need. Results of previous studies showed trifluridine and tipiracil — which combines the thymidine analogue trifluridine with the thymidine phosphorylase inhibitor tipiracil — extended PFS and OS as late-line therapy compared with supportive care only. However, the agent’s activity among the subpopulation of patients who have undergone gastrectomy had not been determined.

The placebo-controlled TAS-102 Gastric Study enrolled 507 patients (mean age, 62.5 years; 72.8% men) with pretreated metastatic gastric cancer or gastroesophageal junction cancer between Feb. 24, 2016, and Jan. 5, 2018. Patients had an ECOG performance status of 0 or 1, received at least two prior chemotherapy regimens and were refractory to or unable to tolerate the most recent therapy.

The researchers randomly assigned patients 2:1 to oral trifluridine and tipiracil dosed at 35 mg/m² twice daily (n = 337) or placebo twice daily and best supportive care (n = 170) on days 1 through 5 and 8 through 12 of 28-day treatment cycles.

Ilson and colleagues conducted a preplanned subgroup analysis of patients who underwent gastrectomy (n = 221) or had not undergone gastrectomy (n = 286).

OS served as the primary endpoint. Secondary endpoints included efficacy and safety.

Among patients who underwent gastrectomy, those who received trifluridine and tipiracil (n = 147) had longer PFS (median, 2.2 months vs. 1.8 months; HR = 0.48; 95% CI, 0.35-0.65) and OS (median, 6 months vs. 3.4 months; HR = 0.57; 95% CI, 0.41-0.79) than those who received placebo (n = 74).

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Among those who had not undergone gastrectomy, researchers also observed slightly longer PFS (median, 1.9 months vs. 1.8 months; HR = 0.65; 95% CI, 0.49-0.85) and longer OS (median, 5.6 months vs. 3.8 months; HR = 0.8; 95% CI, 0.6-1.06) with trifluridine and tipiracil (n = 190) vs. placebo (n = 96).

An analysis of median time to deterioration of ECOG performance status to 2 or higher in the study treatment vs. placebo groups showed HRs of 0.63 (95% CI, 0.46-0.87) for those who underwent gastrectomy and 0.74 (95% CI, 0.56-0.98) for those who did not.

Grade 3 or higher any-cause adverse events occurred more frequently among patients treated with trifluridine and tipiracil who underwent gastrectomy vs. no gastrectomy (84.1% vs. 76.3%). Patients in the gastrectomy subgroup appeared more likely to experience grade 3 or higher events such as neutropenia (44.1% vs. 26.3%), anemia (21.4% vs. 17.4%) and leukopenia (14.5% vs. 5.3%). However, patients who did not undergo gastrectomy were more likely to experience grade 3 or higher fatigue (10.5% vs. 2.1%).

Adverse events led to dosing modifications for 94 patients (64.8%) in the gastrectomy subgroup and 101 patients (53.2%) in the no-gastrectomy subgroup. A larger percentage of patients in the no-gastrectomy subgroup discontinued treatment due to adverse events (14.7% vs. 10.3%).

The subgroup analysis lacked power for statistical significance, which served as the study’s primary limitation.

“Given the activity of [trifluridine and tipiracil] in late-line treatment, the potential to move this drug up to earlier lines of therapy in combination with other agents or other early-line agents is now considered,” Ilson told HemOnc Today. – by Jennifer Southall

For more information:

David Ilson, MD, PhD, can be reached at Memorial Sloan Kettering Cancer Center, 300 E. 66th St., BAIC 1031, New York, NY 10065; email: ilsond@mskcc.org.

Disclosures: Ilson reports grants and advisory role support from Amgen, Astellas, AstraZeneca, Bayer AG, Bristol-Myers Squibb, Eli Lilly & Co., Merck, F. Hoffman-LaRoche, Pieris Pharmaceuticals and Taiho Oncology outside of the submitted work. Please see the study for all other authors’ relevant financial disclosures.

    Perspective
    Efrat Dotan

    Efrat Dotan

    Ilson and colleagues report an important preplanned subgroup analysis of the phase 3 TAGS study, which evaluated the use of trifluridine and tipiracil for the treatment of patients with metastatic gastric cancer who had received at least two prior lines of therapy. This analysis compared the efficacy and tolerance of trifluridine and tipiracil between patients with prior gastrectomy and those with intact stomach.

    Management of patients with metastatic gastric cancer who have undergone gastrectomy is challenging due to poor nutritional status and decreased chemotherapy tolerance secondary to neoadjuvant or adjuvant treatment. The use of oral medications raises further concerns due to potential decreased absorption and altered pharmacokinetics after gastrectomy. Hence, the data presented in this manuscript are significantly important in guiding therapy for this patient population.

    The results showed similar efficacy of trifluridine and tipiracil among patients who have undergone gastrectomy and those with intact stomach. Median time to deterioration of ECOG performance status of 2 or higher also appeared similar between the groups. Overall rates of grade 3 or higher adverse events did not differ between patients with or without gastrectomy. However, rates of hematologic toxicities, mainly grade 3 neutropenia and leukopenia, were higher in the gastrectomy group. There was a slightly higher rate of dose modification in the gastrectomy group, however, the groups had similar rates of therapy discontinuation due to adverse events, dose intensity and mean treatment duration.

    Based on this analysis, patients with metastatic gastric cancer should be considered for treatment with trifluridine and tipiracil in the third-line setting, regardless of prior gastrectomy. Patients who have undergone gastrectomy while on this regimen should be monitored closely for hematologic toxicities.

    • Efrat Dotan, MD
    • HemOnc Today Next Gen Innovator
      Fox Chase Cancer Center

    Disclosures: Dotan reports no relevant financial disclosures.