TAS-102 Becomes Promising Option in Chemorefractory Gastric/GEJ Cancers

David H. Ilson, MD, PhD

TAS-102 (trifluridine/tipiracil; Lonsurf) has become a leading treatment option for patients with chemotherapy-refractory, heavily pretreated gastric and gastroesophageal junction (GEJ) cancers, explained David H. Ilson, MD, PhD.

The FDA approved TAS-102 in February 2019 for adult patients with metastatic gastric or 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. The decision is based on results from the phase III TAGS trial, in which TAS-102 reduced the risk of death by about one-third compared with placebo in patients with heavily pretreated gastric or GEJ cancer (HR, 0.69; P = .0003).

“This trial [shows that TAS-102] modestly improves progression-free survival (PFS) and overall survival (OS) in refractory disease, indicating they are stabilizing drugs,” said Ilson, an attending physician and professor of medicine at Memorial Sloan Kettering Cancer Center. “Additionally, if we look at the quality-of-life data that were presented in the original TAGS trial, there was a slowing of decline and performance status compared with placebo. This drug is an option for patients with refractory disease who don't have other treatment options.”

In an interview with OncLive, Ilson discussed the utility of TAS-102 in gastric and GEJ adenocarcinoma as well as other encouraging research in these spaces.

OncLive: Could you provide an overview of the TAGS trial and its impact on gastric and GEJ cancer treatment?

Ilson: The TAGS trial was a phase III trial in chemotherapy-refractory gastric and GEJ cancers looking at the activity of TAS-102 in advanced disease. This is a novel fluorinated pyrimidine combined with a thymidine phosphorylase inhibitor, which allows oral bioavailability of this oral agent. The drug [was previously] approved for the treatment of patients with chemotherapy-refractory metastatic colorectal cancer based on a randomized trial that showed improved OS and PFS compared with placebo.

The basis of [the TAGS] trial was a phase II trial conducted in Japan called EPOC1201, which showed an encouraging OS of 8.7 months with TAS-102 in chemotherapy-refractory metastatic gastric cancer. Based on that and the positive data for colon cancer, the TAGS trial was initiated.

The TAGS trial was an industry-sponsored, randomized, placebo-controlled, double-blind trial in patients who had received ≥2 prior regimens for metastatic gastric and GEJ adenocarcinoma.

The control arm was supportive care plus placebo, which was compared with active treatment of TAS-102. There was a 2.2-month improvement in OS [with TAS-102] compared with placebo, with a hazard ratio of about 0.7 and a 30% reduction in the risk of death. Additionally, there was improvement in PFS for TAS-102 compared with placebo.

In the updated data of the TAGS trial, about 44% of patients had undergone prior gastrectomy. We wanted to see the toxicity profiles and outcomes of the two arms: TAS-102 and placebo. There is always some concern whether there are issues with absorption in patients with prior gastrectomy.

However, the pharmacokinetic (PK) data from the Japanese phase II EPOC1201 trial that led to this study showed that there was no difference in PK outcomes for TAS-102 in patients who had undergone prior gastrectomy, indicating it probably is not an issue in terms of the availability of the drug.

This updated presentation of the gastrectomy patients looked at the outcomes compared with the overall population, showing a similar [improved] survival benefit for the gastrectomy patient versus placebo with no difference in drug delivery. The dose intensity was the same for the duration of treatment. There was about a 10% higher rate of leukopenia hematologic toxicity on the gastrectomy arm, but it did not translate into any lesser degree of efficacy or dose intensity.

In conclusion, patients who underwent prior gastrectomy had very similar benefit for TAS-102 in terms of improvements in OS and PFS versus placebo.

What other challenges exist within this space and how are they being addressed?

We also have the approval of pembrolizumab (Keytruda) in patients who have PD-L1—positive, chemotherapy-refractory GEJ/gastric cancer who have progressed on FOLFOX, paclitaxel/ramucirumab (Cyramza), and potentially irinotecan. We do not have the option [of pembrolizumab] for PD-L1–negative patients. TAS-102 represents a treatment option in both of these groups of patients in the refractory setting.

Are there any other studies that you would like to shed light on?

The KEYNOTE-180 study looked at chemotherapy versus pembrolizumab in patients with squamous cell adenocarcinoma of the esophagus whose tumors have PD-L1 expression (combined positive score [CPS] ≥10). Pembrolizumab was superior to chemotherapy treatment with paclitaxel in terms of response rate, PFS, and OS. The strongly positive nature of the results indicates that pembrolizumab may become a treatment option even in the second-line setting of metastatic squamous cancers who have CPS ≥10%.

We already had a trial in GEJ and gastric adenocarcinomas that compared pembrolizumab with paclitaxel in second-line therapy that didn't achieve a survival benefit. In gastric and GEJ cancers, pembrolizumab may play a role later, especially in PD-L1—positive GEJ/gastric cancers, where we already have approval.

Another intriguing trial is the phase II combination of pembrolizumab, trastuzumab (Herceptin), and chemotherapy as first-line treatment in HER2-positive GEJ and gastric cancers. There was a very striking response rate of about 87% and the benefit in patients seemed to be PD-L1 agnostic. Based on the strong signal from this phase I trial, it showed the feasibility and tolerability. This will move into a phase III trial fairly quickly.

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. Abstract LBA25.