Trifluridine/tipiracil (TAS-102) with or without bevacizumab in patients with pretreated metastatic esophago-gastric adenocarcinoma (mEGA): A Danish randomized trial (LonGas)

Trifluridine/tipiracil (FTD/TPI, also known as TAS-102) prolongs survival in patients with heavily pretreated metastatic gastric cancer (Shitara, Lancet Oncol 2018). The randomized Danish Lonsurf trial showed that a combination of FTD/TPI and bevacizumab prolonged PFS and OS in patients with chemo-refractory metastatic colorectal cancer (Pfeiffer, Lancet Oncol 2020). Inspired by these results, we designed the present investigator-initiated randomized trial testing FTD/TPI and bevacizumab in patients with pretreated mEGA. The main inclusion criteria were histologically confirmed mEGA, previous therapy with a fluoropyrimidine and platinum, PS 0-1. In arm A, FTD/TPI was administered orally at the dose of 35 mg/m2/dose bid from days 1-5 and 8-12 and in arm B the same dose of FTD/TPI was combined with bevacizumab at a dose of 5 mg/kg on day 1 and on day 15 of a 28-day treatment cycle. A total of 96 patients were needed to show an increase in progression-free survival (PFS – primary endpoint) from 2.0 months to 4.0 months. To ensure at least 96 evaluable patients we included 103 patients. Here we report efficacy and safety data of all randomized patients (intention-to-treat population). 103 pretreated patients with mEGA were randomized from October 2019 to September 2021 at 4 Danish University Hospitals. Baseline characteristics were (arm A/arm B): median age 66/64 years, females 19%/22%; PS 0 47%/44%, median number of metastatic sites 2/2, at least 2 prior lines of therapy 42%/42%. Baseline characteristics including blood tests were well balanced. There was no significant difference in PFS (6 months PFS 28% vs 40%, 12 months PFS 6% vs18%, median PFS 3.7 vs 3.9 months; HR 0.71, p=0.11), median OS (9.0 vs 9.9 months; HR 0.86, p=0.53), response rate (2% vs 6%; p=0.35) or disease control rate (47% vs 56%; p=0.43)b. Therapies were well tolerated with adverse events as expected and with no significant difference in severe toxicity. Neutropenia ≥ grade 3 was observed in 49%/46% of patients, but only febrile neutropenia in 8%/10%. Other severe adverse events were fatigue 4%/10% and nausea 6%/6%. In patients with pretreated mEGA, FTD/TPI + bevacizumab did not improve efficacy compared with FTD/TPI monotherapy in patients previously treated with fluoropyrimidine and platinum. Both regimens produced encouraging PFS and OS and both regimens were well tolerated with adverse events as expected. Compared to the heavily pretreated patients in TAGS, only 42% of patients in LonGas had received at least 2 lines of therapy. This may account for the unexpected long PFS in patients receiving FTD/TPI monotherapy.