TAS-102 Expands Arsenal in Gastric Cancer, But Long Road Ahead for Research

Mark M. Zalupski, MD

Although the recently FDA-approved agent TAS-102 (trifluridine/tipiracil; Lonsurf) has shown modest activity in patients with advanced gastric cancer, this patient population as a whole still represents a significant unmet need, said Mark M. Zalupski, MD.

In the phase III TAGS trial, TAS-102 induced a median overall survival (OS) of 5.7 months compared with 3.6 months in those who received placebo.¹ Although progression-free survival (PFS) was a secondary endpoint of the trial, no statistically significant benefit was reported. For the trial, patients with advanced gastric cancer who had ≥2 prior lines of therapy were randomized 2:1 to receive either 35 mg/m2 of TAS-102 twice daily on days 1 to 5 and 8 to 12 of every 28-day cycle or placebo plus supportive care.

Based on these data, the FDA approved the agent in February 2019 for the treatment of adult patients with metastatic gastric or gastroesophageal junction (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.

Immunotherapy is another area of interest in gastric cancer, although the field has yet to see as much success with this approach as compared with other tumor types. For example, the phase III KEYNOTE-061 trial failed to demonstrate a statistically significant improvement in OS with pembrolizumab (Keytruda) versus chemotherapy in patients with advanced gastric or GEJ adenocarcinoma who progressed after first-line treatment with platinum and fluoropyrimidine doublet therapy. Results showed that single-agent pembrolizumab led to a median OS of 9.1 months versus 8.3 months with paclitaxel (HR, 0.82; 95% CI, 0.66-1.03; one-sided P = .0421).²

“We have to identify ways to better understand who it will work in and how to make this therapy better,” said Zalupski, a professor of medicine at the University of Michigan School of Medicine. “There are a lot of studies in gastric cancer and gastrointestinal oncology, which suggest that we are not very good at enriching the population of patients who we treat for benefit.”

In an interview at the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Zalupski shed light on the current treatment landscape of advanced gastric cancer and the numerous challenges that remain.

OncLive: How has the TAGS trial impacted the advanced gastric cancer landscape?

Zalupski: TAGS was a phase III placebo-controlled trial evaluating the use of TAS-102 in metastatic gastric cancer. These were patients who had to have failed at least 2 regimens, so they were considered chemotherapy-refractory. The trial was a 2:1 randomization of either TAS-102 or placebo. The trial met its primary endpoint in improving OS. In a practical way, this provides another line of therapy that's been shown to increase survival in patients with advanced gastric cancer. TAS-102 is also a tolerable treatment in general.

However, it is insufficient from a patient's or provider's perspective because the time on treatment remained less than 6 months. Nonetheless, it still represents another active agent for consideration in the therapy of our patients.

What are the next steps for this drug?

The next steps will probably involve pairing the drug with other chemotherapies, most obviously oxaliplatin. Use of the treatment in earlier settings—first- and second-line therapy—will also be studied.

What did the KEYNOTE-061 trial inform about the use of immunotherapy in gastric cancer?

The intent of the trial was to demonstrate the value of PD-1 antibody therapy in patients with metastatic gastric cancer. This therapy was compared with chemotherapy. However, the study did not demonstrate that immunotherapy was useful in the second-line setting. This was particularly the case for unselected patients and in patients who had PD-L1 positivity on staining. There was a small fraction of patients who appears to have some benefit from PD-1 antibody therapy, but a large majority of patients had no benefit.

If we focus in on patients who have high combined positive score or microsatellite instability—high tumors, anti–PD-1 therapy might be useful. Combining immunotherapy with chemotherapy in the second-line setting might be useful, but ongoing trials will further define its use and value.

What is the role of ramucirumab in this space?

It is FDA approved for use in the second-line setting, either alone in or combination with chemotherapy. Ramucirumab does increase OS, PFS, and response rates compared with placebo or chemotherapy alone; it does have value. Ramucirumab was also tested in the frontline setting, but it failed to show an improvement in survival. As such, antiangiogenic therapy remains of undefined value for the frontline treatment of advanced gastric cancer.

Are there any promising therapies under investigation?

Based on a randomized phase II study, a monoclonal antibody called zolbetuximab (IMAB362) looks promising. It is currently under investigation in the frontline setting with either FOLFOX or CAPOX.

One of the themes of this State of the Science Summit™ was genetic testing. How prominent is its use in gastric cancer?

It's not so much genetic testing as it is the assessment of molecular characteristics that help define who might benefit from agent “X” or “Y.” In gastric cancer, genomic testing is still fairly limited compared with some other diseases, such as colorectal cancer or lung cancer.

How has the outlook for these patients improved over the last decade?

We have identified new therapies, including targeted therapies or monoclonal antibodies that have definite value for a subset of patients. We have defined second-line therapies that are useful and third-line therapies that have value. However, as with many advanced or metastatic epithelial malignancies, our treatments stop short of curing or helping a majority of patients. From a physician's perspective, we are totally insufficient in what we can offer patients with advanced disease.

References

1. Arkenau H-T, Tabernero J, Shitara K, et al. TAGS: a phase III, randomised, double-blind study of trifluridine/tipiracil (TAS-102) versus placebo in patients with refractory metastatic gastric cancer. Ann Oncol. 2018;29(suppl 8; abstr LBA25). doi: 10.1093/annonc/mdy424.027.
2. Shitara K, Özgüğrolu M, Bang YJ, et al. KEYNOTE-061: phase 3 study of pembrolizumab vs paclitaxel for previously treated advanced gastric or gastroesophageal junction (G/GEJ) cancer. Ann Oncol. 2018;29(suppl 5, abstr LBA-005). doi: 10.1093/annonc/mdy2018.004.