Approximately 27,000 patients are diagnosed annually with gastric cancer in the United States, more than half of these patients present with unresectable or metastatic disease (CA Cancer J Clin 2020;70(1):7-30). Patients who receive curative intent treatment for localized gastric cancer undergo either a total or partial gastrectomy based on the location of the primary tumor, and a substantial minority of these patients develop recurrent disease in a metachronous fashion (Ann Surg 1999;230(2):170-178). Thus, patients diagnosed with metastatic gastric cancer (mGC) are comprised of two distinct groups—those with synchronous metastatic disease (and retain an intact stomach) and those with metachronous metastatic disease (after a curative intent gastrectomy—total or subtotal). In fact, patients who have undergone gastrectomy comprise approximately 40 percent of patients with mGC (Lancet Oncol 2014;15(11):1224-1235; Lancet 2017;390(10111):2461-2471; Lancet Oncol 2018;19(11):1437-1448; 2018; Lancet 2018;392(10142):123-133).
Patients with mGC have a dismal prognosis, with a median survival of less than 6 months without treatment (CA Cancer J Clin 2015;65(2):87-108; Lancet 2016;388(10060):2654-2664). Trifluridine/tipiracil (FTD/TPI)—an oral therapy comprising the thymidine analogue trifluridine and the thymidine phosphorylase inhibitor tipiracil, which inhibits trifluridine degradation—is approved in the United States for the treatment of patients with mGC who have been treated with ≥ 2 prior chemotherapy regimens (Int J Mol Med 2004;13(2):249-255; Int J Oncol 2004;25(3):571-578).
The TAGS study—a double-blind, placebo-controlled, phase III trial—randomly assigned 507 patients with histologically confirmed mGC, who had progressed on at least 2 prior lines of systemic therapy, to FTD/TPI or placebo in a 2:1 fashion and demonstrated a significantly improved overall survival (OS), progression-free survival (PFS), and disease control rate (DCR), as well as maintenance of Eastern Cooperative Group Oncology Group (ECOG) performance status (PS) in the treatment arm compared with the placebo group leading to its FDA approval (Lancet Oncol 2018;19(11):1437-1448).
Treatment was well-tolerated in this heavily pretreated patient population (63% of patients had exposure to 3 or more lines of systemic therapies); myelosuppression (neutropenia) was the most frequently reported grade 3 or worse adverse event (AE), noted in 25 percent of FTD/TPI treated patients, while grade 3 or worse non-hematological adverse events were reported in less than 10 percent of treated patients.
Since prior gastrectomy was performed in 44 percent of patients enrolled in the TAGS study and FTD/TPI is administered orally, a pre-planned analysis was performed to analyze the efficacy of the drug in this subgroup (JAMA Oncol 2019; doi: 10.1001/jamaoncol.2019.3531). Patients with mGC who have undergone prior gastrectomy tend to be more compromised nutritionally, more heavily pretreated, and more prone to AEs (World J Surg Oncol 2013;11:287; Lancet Oncol 2016;17(3):309-318; BMC Cancer 2016;16(1):900). It is unclear whether these increased incidences of AEs were associated with gastrectomy-induced changes in pharmacokinetic exposure. While several studies have demonstrated that gastrectomy does not negatively impact the absorption and pharmacokinetics of oral adjuvant chemotherapy (Anticancer Drugs 2006;17(4):393-399; Cancer Chemother Pharmacol 2007;60(5):693-701; J Clin Pharmacol 2015;55(8):926-935), there are data that point to the contrary as well (Cancer Sci 2007;98(10):1604-1608).
The Japanese phase II study (EPOC 1201) that explored the efficacy of FTD/TPI in patients with previously treated mGC analyzed the pharmacokinetics of the drug in a limited number of patients who had undergone gastrectomy, demonstrating that the Cmax (mean maximum plasma concentration), Tmax (time to reach Cmax), and AUC (area under the curve) were comparable to that of patients who had an intact stomach (Eur J Cancer 2016;62:46-53). However, systematic data comparing the efficacy of oral chemotherapeutic agents for mGC in the gastrectomy subpopulation versus those with an intact stomach are lacking, making this analysis highly relevant to the practicing oncologist.
Among the 507 randomized patients enrolled in the TAGS study, 221 (43.6%) had undergone prior gastrectomy (147 randomized to FTD/TPI and 74 to placebo) and 286 (56.4%) had an intact stomach (190 randomized to FTD/TPI and 96 to placebo). Of the 221 patients with previous gastrectomy, 153 (69.2%) had undergone total resection, 56 (25.3%) had undergone partial resection, and extent of resection was unknown for 12 patients (5.4%). Baseline patient demographics and disease characteristics were similar between the patients who had undergone a gastrectomy versus retained an intact stomach, with the following exceptions: presence of 3 or more metastatic sites (42.5% vs. 65%), prior radiotherapy (25.8% vs. 14%), and exposure to at least 3 previous chemotherapy regimens (75.1% vs. 52.8%).
In the gastrectomy subgroup, the OS and PFS in the FTD/TPI versus placebo group was 6.0 versus 3.4 months (HR-0.57; 95% CI, 0.41-0.79), and 2.2 versus 1.8 months (HR-0.48; 95% CI, 0.35-0.65), respectively. In the no gastrectomy subgroup, the OS and PFS in the FTD/TPI versus placebo group was 5.6 versus 3.8 months (HR-0.80; 95% CI, 0.60-1.06) and 1.9 versus 1.8 months (HR - 0.65; 95% CI, 0.49-0.85), respectively.
Analysis of the median time to deterioration of ECOG performance status to 2 or higher in the FTD/TPI versus placebo group demonstrated that the HR was 0.63 (95% CI, 0.46-0.87) in the gastrectomy subgroup and 0.74 (95% CI, 0.56-0.98) in the no gastrectomy subgroup. Among FTD/TPI-treated patients, incidence of grade 3 or higher adverse events (AEs) of any cause were similar between the two groups—122 of 145 patients (84.1%) in the gastrectomy subgroup and 145 of 190 (76.3%) in the no gastrectomy subgroup—but there was a higher incidence of hematologic adverse events in the gastrectomy subgroup (Table 1). In the gastrectomy subgroup, 94 (64.8%) had dosing modifications because of adverse events versus 101 (53.2%) in the no gastrectomy subgroup; 15 (10.3%) in the gastrectomy group and 28 (14.7%) in the no gastrectomy group discontinued treatment because of adverse events. Treatment exposure was similar between the two groups.
The reason for the numerically more pronounced OS benefit in the gastrectomy subgroup—albeit, nominal—is not clear. While the overall safety profile of FTD/TPI was similar among patients who had or had not undergone a gastrectomy, the higher incidence of hematologic AEs among patients who underwent gastrectomy could at least, in part, be attributed to their greater exposure to systemic therapies in the adjuvant and/or neoadjuvant setting. Importantly, the higher incidence of hematologic AEs in the gastrectomy group was managed with supportive care and did not lead to higher treatment discontinuation rate (10.3% in the gastrectomy subgroup vs. 14.7% in the no gastrectomy subgroup).
This subgroup analysis, while pre-planned, was not powered for statistical analyses, therefore, results need to be interpreted with caution. Further, no pharmacokinetic studies—over and beyond the results from the EPOC 1201 study—were performed as part of the TAGS study. However, the safety, efficacy, and outcome data obtained from subgroup analysis of a prospectively randomized, phase III trial can provide valuable clinical information to the practicing oncologist about the use of FTD/TPI in patients who have or not undergone gastrectomy.
In summary, the results of the TAGS subgroup analysis indicate that FTD/TPI is safe and efficacious, and leads to a survival benefit in patients with previously treated mGC, regardless of whether they underwent a gastrectomy or retain an intact stomach.
BEN GEORGE, MD, is Associate Professor of Medicine in the Division of Hematology and Oncology at the Medical College of Wisconsin.