Pivotal Trials Lead to Significant Implications in Gastric/GEJ Cancer

Timothy L. Cannon, MD

Several pivotal studies have recently read out in the gastric/ gastroesophageal junction (GEJ) cancers space—all of them bearing clinical implications for oncologists, said Timothy L. Cannon, MD, and future research will likely focus on bringing novel combinations forward in the paradigm.

In February 2019, the FDA approved TAS-102 (trifluridine/tipiracil; Lonsurf) for the treatment of adult patients with metastatic gastric or GEJ adenocarcinoma who were treated with ≥2 prior lines of chemotherapy. The approval was based on positive data from the phase III TAGS trial, results of which demonstrated a median overall survival (OS) of 5.7 months for patients treated with TAS-102 versus 3.6 months for those who were given placebo.¹ Further, the 1-year OS rate with TAS-102 was 21% versus 13% with placebo. The 6-month progression-free survival rates were 15% and 6%, respectively.

However, there has been recent interest in investigating the potential of pembrolizumab (Keytruda) in this setting, as the agent has shown antitumor activity in patients with pretreated gastric/GEJ cancer. As such, in the KEYNOTE-061 trial, patients were randomized to receive either pembrolizumab monotherapy or paclitaxel.

Although the median OS was 9.1 months versus 8.3 months in favor of the checkpoint inhibitor, this difference was not determined to be statistically significant.² However, for patients with good performance status and whose tumors have high PD-L1 expression, it may be reasonable to administer this agent prior to chemotherapy, according to Cannon.

Meanwhile, the antiangiogenic agent ramucirumab (Cyramza) has maintained its role in the second-line setting. However, in the frontline setting, results from the phase III RAINFALL study, did not demonstrate any benefit to adding ramucirumab to standard frontline chemotherapy in patients with gastric cancer. In the intent-to-treat population, median PFS was 5.85 months in the ramucirumab arm compared with 5.55 months in the control arm. Although the addition of ramucirumab resulted in a 25% reduction in the risk of disease progression or death, it did not result in improved OS.³

OncLive^®: What are some recent clinical trials in this space worth highlighting?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Cannon, a medical oncologist at Inova Medical Group, discussed how these pivotal clinical trials have impacted the gastric cancer treatment landscape.Cannon: I focused on a few larger trials that I thought had the most significant clinical implications for oncologists in 2019. The first one is the TAGS trial, which is a phase III study comparing the use of TAS-102 with placebo in the third-line treatment of [patients with] gastric cancer. That trial showed an OS benefit of approximately 2 months. The therapy was generally well tolerated other than some bone marrow suppression. As such, [TAS-102] may be a reasonable treatment option in the third-line setting for these patients.

The second study I spoke about was KEYNOTE-061, a comparison of second-line pembrolizumab versus second-line paclitaxel in gastric or GEJ adenocarcinoma. In that study, pembrolizumab did not show a survival benefit compared with chemotherapy, although it was a little bit better tolerated. The OS was 9.1 months in the pembrolizumab arm and 8.3 months in the paclitaxel arm. Therefore, what I have concluded from that is, while pembrolizumab is a reasonable second-line option, so is chemotherapy. Of course, the trial failed to show a superiority for immunotherapy in that setting. That trial, by the way, only included patients who expressed PD-L1 in their tumors.

Where does this leave the standard of care? How do you approach patient selection for these treatments?

The third trial I spoke about was using ramucirumab in the frontline setting added to capecitabine plus cisplatin. The addition of ramucirumab did not improve PFS very much—it was technically statistically significant, but it was only 0.3 months, which is not clinically significant. I would not consider ramucirumab the standard for frontline therapy.First of all, the TAGS trial definitely established that TAS-102 is a reasonable drug to use in the third-line setting. As far as the KEYNOTE-061 trial goes, one of the problems with that study is that it was conceived before the combination of ramucirumab and paclitaxel became the standard second-line therapy in gastric cancer. However, KEYNOTE-061 suggests you can give either [treatment]. If you have good performance status, you tend to do better with pembrolizumab. If you are selecting a patient for second-line therapy with a great performance status and high PD-L1, it might be reasonable to give pembrolizumab before chemotherapy. If the patient is fading quickly and declining, you probably do not have the luxury of waiting 2 months for a response. Pembrolizumab would not be the best option for this patient; you would probably want to give paclitaxel or another chemotherapy agent.

What is the role of targeted therapies in this space?

Where would you like to see future research headed?

As far as the third study I talked about, adding ramucirumab to the frontline setting is just not useful. It still has a place in the second-line setting, but it is not something that clinicians will be using for the frontline standard.There is not a lot going on with targeted therapies in gastric cancer. For the refractory patients, we are considering doing genomic sequencing to see if the patients have one of the very rare, but impactful, mutations like NTRK or BRAF. For the most part, gastric cancer is probably a disease that has less in the realm of targeted therapies than some other cancers. I do not think there was anything from 2018 that was groundbreaking in this area.The momentum is probably building towards different immunotherapy combinations or targeted therapies plus checkpoint inhibitors. That is of a lot of interest in gastric cancer, and that is probably where a lot of the money is being devoted. I would like to see more treatments based on RNA sequencing and proteomics—that would help us a little bit as well. Chimeric antigen T-cell therapy is another area of interest, so I would like to see if we can develop a target for that in gastric cancer.

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. Fuchs CS, Ozguroglu M, Bang Y-J, et al. Pembrolizumab (pembro) vs paclitaxel (PTX) for previously treated advanced gastric or gastroesophageal junction (G/ GEJ) cancer: phase 3 KEYNOTE-061 trial. J Clin Oncol. 2018;36 (suppl 15; abstr 4062). doi: 10.1200/JCO.2018.36.15_suppl.4062.
3. Fuchs CS, Shitara K, Di Bartolomeo M, et al. RAINFALL: a randomized, double-blind, placebo-controlled phase III study of cisplatin (Cis) plus capecitabine (Cape) or 5FU with or without ramucirumab (RAM) as first-line therapy in patients with metastatic gastric or gastroesophageal junction (G-GEJ) adenocarcinoma. J Clin Oncol. 2018;36 (suppl 4; abstr 5). doi: 10.1200/JCO.2018.36.4_suppl.5.