Ramucirumab/TAS-102 Combo Aims to Overcome Toxicities in Gastric/GEJ Cancer

Rutika Mehta, MD, MPH

Researchers hope that the novel combination of ramucirumab (Cyramza) with TAS-102 (trifluridine/tipiracil; Lonsurf), which is under investigation in a phase II trial, will overcome the significant adverse events (AEs) seen with ramucirumab/paclitaxel in patients with advanced gastric and gastroesophageal junction (GEJ) cancer, said Rutika Mehta, MD, MPH.

The recommended frontline treatment for patients with metastatic gastric/GEJ cancer typically consists of a fluoropyrimidine with a platinum-based agent, usually oxaliplatin, which is known to induce neuropathy over time. While ramucirumab is currently FDA approved in combination with paclitaxel in the second-line setting, many patients are unable to tolerate the regimen as paclitaxel is also neurotoxic, said Mehta, a gastrointestinal medical oncologist at Moffitt Cancer Center.

In an effort to address this need, the phase II study (NCT03686488), which is still accruing, will combine ramucirumab with TAS-102, a novel oral formulation of trifluorothymidine and a thymidine phosphorylase inhibitor.¹ Those with gastric or GEJ adenocarcinoma who have received ≥1 prior line of treatment, have an ECOG performance status of 0 or 1, and have preserved organ function, are eligible for enrollment. Ramucirumab will be administered at 8 mg/kg every 2 weeks and TAS-102 at doses of 35 mg/m² twice daily. Each cycle length will be 28 days. The primary endpoint is 6-month overall survival (OS), and secondary endpoints are safety, objective response rate, and progression-free survival.

Prior to this research, TAS-102 demonstrated a median OS of 5.7 months compared with 3.6 months in those who received placebo in the phase III TAGS trial.² These data led to the FDA approval of the agent in February 2019 for the treatment of 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.

Ramucirumab was FDA approved for use as a single agent in April 2014, and subsequently for use in combination with paclitaxel in November 2014. Data showed that OS was increased in patients who received ramucirumab in both the monotherapy (HR, 0.78; 95% CI, 0.60-0.998; P = .047) and combination trials³ (HR, 0.81; 95% CI, 0.68-0.96; P = .017) evaluating its use.

In an interview with OncLive during the 2019 ASCO Annual Meeting, Mehta provided insight on the ongoing study combining TAS-102 with ramucirumab in the treatment of patients with advanced gastric/GEJ cancer.

OncLive: Could you highlight the recent progress made in advanced gastric cancer?

Mehta: Like most other cancers, gastric cancer research is also advancing at a very fast rate. The focus of immuno-oncology in gastric cancer is taking precedence in this field. We have several novel combinations that are being tested now. We have frontline options, second-line options, and now, third-line options. There was a point in time where we only had chemotherapy options available; now, we have targeted treatments and immunotherapy options that have taken over the space.

What data do we currently have with ramucirumab?

Ramucirumab, based on data from the RAINBOW and REGARD trials, has been FDA approved either alone or in combination with paclitaxel in the second-line setting after patients have already progressed on a fluoropyrimidine and platinum-based doublet.

Could you speak to the tolerability challenges with ramucirumab and paclitaxel? How are these challenges being addressed?

Most commonly, prescribers will recommend a fluoropyrimidine with a platinum-based agent, usually oxaliplatin, in the frontline setting for metastatic gastric and GEJ cancer. The challenge that lies in this combination is that oxaliplatin can induce neuropathy over time in these patients. When we then turn to ramucirumab and paclitaxel as a second-line treatment, paclitaxel is also neurotoxic and can worsen this neuropathy. This severely limits the administration of this combination.

What was the goal of combining TAS-102 with ramucirumab?

Given that we see a lot of neurotoxicity and overlapping toxicities between the first- and second-line treatments these days, the novel challenge has been to have unique combinations to avoid this toxicity. Therefore, we have many clinical trials that have been emerging in this space to explore novel combinations with ramucirumab. We have several combinations that have been presented at the 2019 ASCO Annual Meeting, and our trial focuses on combining ramucirumab with TAS-102, an oral agent.

What is the design of the study?

We are currently accruing to the phase II clinical trial of ramucirumab with TAS-102. [We aim to] accrue a total of 25 patients. We have just started this trial not too long ago, and we have about 7 patients accrued so far. We are pretty excited about this combination. Patients who are eligible for this trial are those who have progressed on a prior fluoropyrimidine and platinum-based doublet in the first-line setting. These patients should have received at least 1 prior line of treatment; they should not have received prior ramucirumab or TAS-102 therapy. Patients who have received immunotherapy could also be eligible. Patients with high bleeding risk or who have an arterial clot are not eligible.

What is the expected toxicity profile of this combination?

We are using standard doses that have been approved individually for ramucirumab and TAS-102. The most common [AE] with TAS-102 that has been noted in previous studies has been neutropenia, which we are also expecting with this study. Some other toxicities can be related to bleeding risk with ramucirumab and some additional bone marrow suppression with the combination.

What would you want your colleagues to take home about this ongoing research?

Gastric and GEJ cancer are challenging diseases, and I encourage all of my colleagues to encourage their patients to enroll them on clinical trials that will lead to more data in this field. Since this trial is enrolling only at Moffitt Cancer Center, I highly encourage my colleagues to refer their patients to see if they would eligible for this trial.

References

1. Mehta R, Kim RD, Shah N, et al. A phase II study of TAS-102 in combination with ramucirumab in advanced, refractory gastric or gastroesophageal junction (GEJ) adenocarcinoma. J Clin Oncol. 2019;37(suppl 15; abstr TPS4149). doi: 10.1200/JCO.2019.37.15_suppl.TPS4149.
2. 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.
3. Casak SJ, Fashoyin-Aje I, Lemery SJ, et al. FDA approval summary: ramucirumab for gastric cancer. Clin Cancer Res. 2015;21(15):3372-3376. doi: 10.1158/1078-0432.CCR-15-0600.