TAS-102 Continues to Demonstrate Efficacy, Safety in CRC and Gastric Cancers

Howard S. Hochster, MD

Results from a pooled safety analysis of phase III trials of TAS-102 (trifluridine/tipiracil; Lonsurf) show that the agent can be used in patients with colorectal cancer (CRC) and gastric/gastroesophageal junction (GEJ) cancer alike with similar rates of efficacy and toxicity.

“[This means] that [providers] who have used it for CRC can use it in treating gastric cancer with very similar results and toxicity management strategies,” said Howard S. Hochster, MD. “We don't need to be concerned about other problems in treating patients with gastric cancer compared with patients with CRC.”

In 2015, the FDA approved TAS-102 for the treatment of patients with metastatic CRC who have received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biologic product, and an anti-EGFR monoclonal agent, if RAS wild-type, based on data from the phase III RECOURSE trial.

The drug was later evaluated in pretreated patients with gastric/GEJ cancer in the phase III TAGS trial, which showed that treatment with the agent led to a significant improvement in overall survival (OS) compared with placebo. Data from the trial resulted in the February 2019 approval of the agent for use in adult patients with metastatic gastric/GEJ adenocarcinoma previously treated with ≥2 prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.

In the pooled safety analysis, investigators evaluated the safety data of TAS-102 collected from both the RECOURSE and TAGS trials. In RECOURSE, 533 patients received TAS-102, while 265 patients received placebo. In TAGS, TAS-102 and placebo were given to 335 and 168 patients, respectively. Baseline characteristics were well balanced across treatment groups. In the pooled population, the majority (66%) of patients were men and 75% had been treated with ≥3 prior systemic therapies.

Results presented at the 2019 ASCO Annual Meeting showed that the safety profile of TAS-102 proved comparable between trials, with the most common any-cause grade ≥3 adverse events (AE) associated with the drug being neutropenia (34% in TAGs vs 35% in RECOURSE), anemia (19% vs 17%), and leukopenia (9% vs 13%).

Notably, grade ≥3 febrile neutropenia was observed in 2% and 4% of patients enrolled in TAGS and RECOURSE, respectively, and grade ≥3 gastrointestinal AEs occurred in 21% and 12% of patients, respectively. Furthermore, grade ≥3 cardiac-associated AEs were observed in 1% of patients treated with TAS-102 in both trials, which differs from results obtained with other third-line drugs. All AEs were manageable with either dosing delays or dose reductions.

In an interview with OncLive, Hochster, associate director for clinical research, Rutgers Cancer Institute of New Jersey, provided further insight into TAS-102 and highlighted other important research being conducted in the CRC space.

OncLive: Could you discuss the pooled safety analysis from phase III trials of TAS-102 in those with metastatic CRC and metastatic gastric/GEJ cancer?

Hochster: These data, which [were] presented in a poster [at the 2019 ASCO Annual Meeting], relate to the use of the drug TAS-102, or trifluridine/tipiracil, which is now [FDA] approved for both CRC and gastric cancer based on phase III trials where the drug was given in a late-line setting compared with placebo.

In both cases, TAS-102 led to a survival advantage for patients who had been previously treated with 1 or 2 regimens for gastric and all standard chemotherapy drugs for CRC. In this analysis, we pooled the safety data from both studies and showed that it was pretty consistent. Patients mainly have neutropenia, but it's not very deep neutropenia; it's more like the delays in treatment at week 4 with grade 2/3 neutropenia, which is rarely complicated. Therefore, there were low levels of febrile neutropenia and very little other toxicity.

Are there other unanswered questions that remain with this therapy in either patient population?

Trifluridine is a very interesting drug; it's trifluoropyridine, which is a nucleoside analog, and it was synthesized by Charles Heidelberger, who also made fluorouracil (5-FU). It was originally synthesized in 1962, but the drug has a very short half-life, so it wasn't really clinically useful until chemists at Taiho Oncology put it together with an inhibitor of metabolism of that nucleoside [to make it] last longer.

[Then, it] became an oral pill that you could give twice a day. It's kind of an old chemotherapy-type drug but it's active when 5-FU is no longer working, and when cells are resistant to 5-FU. Also, in CRC, we see that it has activity in patients who are heavily pretreated with 5-FU. Therefore, I believe there is a [rationale to] bring it into earlier treatment lines for both gastric and CRC and see how we can use it instead of 5-FU in some earlier regimens to hopefully prolong the survival.

Van Cutsem E, Hochster HS, Shitara K, et al. Pooled safety analysis from phase 3 studies of trifluridine/tipiracil (FTD/TPI) in patients (pts) with metastatic gastric/gastroesophageal junction cancer (mGC/mGEJC) and metastatic colorectal cancer (mCRC). J Clin Oncol. 2019;37(suppl 15, abstr 4039). doi: 10.1200/JCO.2019.37.15_suppl.4039.