PRINCETON, N.J.—Touting the findings as “extremely significant,” Taiho Oncology Inc. has announced promising results from a subgroup analysis of the Phase 3 TAS-102 Gastric Study (TAGS), evaluating Lonsurf in previously treated adult patients with metastatic gastric cancer (mGC) or gastroesophageal junction cancer (GEJC). The results, published online in the Oct. 10, 2019 issue of JAMA Oncology, indicated treatment with Lonsurf was tolerable and showed prolonged survival versus placebo, regardless of prior gastrectomy.
Lonsurf (trifluridine and tipiracil) is an oral nucleoside antitumor agent discovered and developed by Taiho Pharmaceutical Co. Ltd. The U.S. Food and Drug Administration (FDA) approved Lonsurf in previously treated mGC and GEJ adenocarcinoma in February 2019, based on data from the global, randomized, double-blind, placebo-controlled TAGS trial which demonstrated clinically meaningful and statistically significant improvement in overall survival (OS) and progression-free survival (PFS) when compared with placebo in these patients. The safety profile of Lonsurf was consistent with studies of the drug in metastatic colorectal cancer, and no new safety concerns were reported.
“The outcome of the Phase 3 TAGS trial in this patient population is extremely significant, as nearly half of all patients with metastatic gastric cancer and gastroesophageal junction adenocarcinoma have undergone a previous gastrectomy and are prone to more complications than those without gastrectomy,” says lead author Dr. David H. Ilson, medical oncologist at Memorial Sloan Kettering Cancer Center. “These data provide further evidence of the safety and efficacy of Lonsurf and its utility in patients who may have limited treatment options.”
The overall safety profile of the drug, including the incidence of severe adverse events (AEs) in this heavily pretreated patient population, was similar in patients with or without gastrectomy.
Dr. Martin J. Birkhofer, Taiho senior vice president and chief medical officer, comments, “Metastatic gastric cancer and gastroesophageal junction adenocarcinoma are debilitating diseases that generally have a very poor prognosis. Given the unmet treatment need and sense of urgency once earlier rounds of therapy have failed, we are pleased with the results of the subgroup analysis of the TAGS trial, which provide further evidence for the clinical benefit of Lonsurf in these vulnerable patients with gastrectomy.”
Trifluridine/tipiracil (FTD/TPI) treatment has shown clinical benefit in patients with pretreated mGC/GEJC, the authors state in the paper. Patients who have undergone gastrectomy constitute a significant proportion of patients with mGC/GEJC.
This preplanned subgroup analysis of TAGS—a Phase 3, randomized, placebo-controlled clinical trial—included patients with mGC/GEJC who had received at least two previous chemotherapy regimens, was conducted at 110 academic hospitals in 17 countries in Europe, Asia and North America.
In this subgroup analysis, 221 of 507 patients with mGC or GEJ adenocarcinoma with prior gastrectomy were enrolled and randomized to receive Lonsurf 35 mg/m2 . Patients were randomized 2:1 to receive oral FTD/TPI twice daily or placebo twice daily with best supportive care on days one through five and days eight through 12 of each 28-day treatment cycle.
While the primary end point was overall survival, this subgroup analysis was conducted to examine potential trends and was not powered for statistical significance, the article states. Efficacy and safety end points were evaluated in the subgroups.
Results showed that of 507 randomized patients, 369 (72.8 percent) were male, and the mean age was 62.5 years. Of the enrolled patients, 221 (43.6 percent) had undergone gastrectomy (147 randomized to FTD/TPI and 74 to placebo), and 286 (56.4 percent) had not undergone gastrectomy (190 randomized to FTD/TPI and 96 to placebo). Compared with placebo, FTD/TPI significantly improved OS, the primary end point.
The study also found survival outcomes are poor for patients with mGC/GEJC, with a median survival time of three to five months without chemotherapy. Chemotherapy extends median overall survival (OS) by nearly seven months, but ultimately the disease becomes refractory to chemotherapy, and all patients experience disease progression after first-line treatment, researchers stated. Duration of response to second-line treatment is short, and there are few options for third- and later-line therapy.
Nearly half of all patients with mGC/GEJC have undergone gastrectomy, the research shows. Patients who have undergone gastrectomy tend to be a more compromised patient subpopulation than those who have not undergone gastrectomy, because the malnutrition associated with gastrectomy can delay recovery and potentially render these patients more susceptible to AEs.
In addition, many patients who have undergone gastrectomy have received adjuvant chemotherapy or radiotherapy, according to researchers. Being heavily pretreated, these patients have poorer chemotherapy tolerance. However, studies that have evaluated the safety and efficacy of oral chemotherapy in this subpopulation have primarily involved adjuvant therapy, and few studies have examined patients with metastatic disease.
In a Phase 2 Japanese study (EPOC1201), FTD/TPI showed activity and tolerability among patients with previously treated mGC/GEJC. Although the sample sizes were small, no differences were observed in the pharmacokinetics of either FTD or TPI at the approved dose between patients who had or had not undergone gastrectomy.