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The European Medicines Agency's Committee for Medicinal Products for Human Use has backed approval of TAS-102 for the treatment of adult patients with metastatic gastric cancer, including adenocarcinoma of the gastroesophageal junction, following treatment with at least 2 prior systemic regimens for advanced disease.
Josep Tabernero, MD, PhD
The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has backed approval of TAS-102 (trifluridine/tipiracil; Lonsurf) for the treatment of adult patients with metastatic gastric cancer, including adenocarcinoma of the gastroesophageal junction (GEJ), following treatment with at least 2 prior systemic regimens for advanced disease.
The CHMP based its positive opinion on the phase III TAGS trial, in which TAS-102 reduced the risk of death by 31% compared with placebo in patients with heavily pretreated gastric or GEJ cancer. The TAGS trial also showed improvements in progression-free survival (PFS) and disease control, and demonstrated a predictable and manageable safety profile.
The European Commission will now make a final decision on the application.
“The positive opinion from the CHMP for Lonsurf is very welcomed; patients with metastatic gastric cancer have few therapeutic options remaining, so it is of the upmost importance new therapies are made available. The Phase III trial TAGS demonstrated that Lonsurf was effective and tolerable for these patients and gave patients valuable months of life,” TAGS investigator Josep Tabernero, MD, PhD, Head of the Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona and Director of the Vall d’Hebron Institute of Oncology, said in a press release.
The global phase III TAGS double-blind study enrolled 507 adults with histologically confirmed, nonresectable metastatic gastric/GEJ cancer and an ECOG performance status of 0 or 1 who received ≥2 prior chemotherapy regimens. Patients were randomized 2:1 to receive TAS-102 (35 mg/m2 twice daily on days 1 to 5 and 8 to 12 of each 28-day cycle) or placebo plus best supportive care, and were treated until progression, intolerability, or patient withdrawal.
The primary cancer site was gastric in 71% and GEJ in 29%. Fifty-five percent had ≥3 metastatic sites. Sixty-three percent in each arm had ≥3 prior treatments and 44% in each arm had prior gastrectomy. More than 90% received prior platinum, fluoropyridine, and taxane treatment. About one-third in each arm had prior ramucirumab.
Median OS, the primary endpoint, was 5.7 months for patients assigned to TAS-102 compared with 3.6 months for patients randomized to placebo. The 2.1-month improvement in median OS with TAS-102 over placebo translated into a hazard ratio for death of 0.69 (P = .0003). The 12-month OS rate for the TAS-102 group was 21% versus 13% for the placebo group.
Multivariate analysis the following factors to be prognostic for OS (P <.05): ECOG performance status of 1 (vs 0), 2 prior regimens (vs 33), age <65 years (vs ≥65 years), 1 or 2 metastatic sites (vs 3), and negative HER2 status (vs positive or undetermined). After adjusting for these factors, the treatment effect for TAS-102 was maintained (HR, 0.69; 95% CI, 0.56-0.85).
Median PFS, a secondary endpoint, was also significantly improved with TAS-102 compared with placebo (2.0 vs 1.8 months; HR, 0.57; P <.0001). The 6-month PFS rates were 15% and 6%, respectively. The PFS advantage for TAS-102 was maintained when assessed by subgroups based on age, region, ethnicity, ECOG performance status, primary site, number of metastatic sites, and prior treatment with ramucirumab, among others.
The objective response rate with TAS-102 was 4% compared with 2% for placebo. In the active treatment group, there was 1 complete response (CR), 12 partial responses (PRs), and 115 patients with stable disease (SD), for a disease control rate of 44%. The disease control rate in the placebo group was 14% (0 CR, 3 PRs, 18 patients with SD). The absolute difference between groups in the disease control rate was 30% (P <.0001).
Time to deterioration of ECOG performance status to 2, a secondary endpoint, was longer in the TAS-102 group compared with the placebo group (median, 4.3 vs 2.3 months; HR, 0.69; P= .0005).
Grade ≥3 adverse events (AEs) of any cause occurred in 80% of patients on TAS-102 versus 58% of those assigned to placebo. TAS-102 was associated with more treatment-related AEs of any grade (81% vs 57%). There was 1 treatment-related death in each group. Grade ≥3 febrile neutropenia of any cause was reported in 6 (2%) patients treated with TAS-102.
Dosing modification (dose delay or reduction) to manage adverse events was required in 58% of the TAS-102 group. Treatment had to be discontinued due to adverse events in 13%. G-CSF treatment to manage neutropenia was necessary in 16%. The most common AEs leading to dosing modification were neutropenia and/or decreased neutrophil count (37%), anemia and/or decreased hemoglobin level (9%), and leukopenia and/or decreased white blood cell count (6%).
TAS-102 was previously approved in the EU for the treatment of patients with colorectal cancer (CRC). In the United States, TAS-102 has approved indications for CRC and gastric/GEJ cancer.
Arkenau H-T, Tabernero J, Shitara K, et al. TAGS: a phase 3, randomised, double-blind study of trifluridine/tipiracil (TAS-102) versus placebo in patients with refractory metastatic gastric cancer. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. LBA25.