Metastatic Gastric Cancer: Promising Later-Line Trials

Daniel V. Catenacci, MD: The DESTINY studies are a number of studies across different tumor types. The DESTINY-Gastric01 study coming out of Asia is a 220-patient monotherapy study looking at this DS-8201a compound, which is trastuzumab conjugated to deruxtecan, an irinotecan derivative. The study certainly has shown promise in HER2+ patients who have failed prior anti-HER2 therapy with trastuzumab. It has, of course, been showing benefit in other tumor types, such as breast cancer and having recent approvals. This has led to the next set of studies, DESTINY-Gastric02 for gastric cancer, which are ongoing in the Western populations to look at the differences, if there are any, between Western and Eastern populations.

This study is solely in second line after progression on first-line trastuzumab. It’s an important study, since there is no standard option for HER2+ patients who have failed anti-HER2 therapy with trastuzumab in the second-line setting. Except if they were eligible for the RAINBOW study with paclitaxel and ramucirumab, and only a small subset of that study was HER2+ second-line patients. That is the control that one must consider and the benchmark to compare with. We will see, because this is a single-arm study looking at an open label of this new compound in second-line setting for HER2+ patients.

The other important point is that we’ve learned that patients who are HER2+ at newly diagnosed disease are not necessarily HER2+ throughout their treatment course. A subgroup of patients, it’s an unclear percentage because many of the studies have been small analyses, ranging from 15% up to even 70% of patients will evolve to have tumors that are now no longer driven by HER2, that are now HER2 nonamplified.

Prior second-line studies have failed because of the complicating factor of patients who were no longer HER2+ but were assumed to be based on their pre–first-line therapy. This DESTINY-Gastric02 study requires reassessment by biopsy at the time of first progression to ensure they’re still HER2+ to be eligible, and that’s being tested centrally. That’s a critical component of this, and we’re looking forward to seeing these results.

Salah-Eddin Al-Batran, MD: The ANGEL trial was 1 of the most important trials recently published in later-stage gastric cancer. This trial enrolled approximately 400 patients and randomized them to receive either apatinib, which is a VEGFR tyrosine kinase inhibitor, or best supportive care in the third-line or beyond setting. The primary end point of this study was overall survival. Unfortunately, the study did not meet its primary end point, which was published as an abstract at ESMO [European Society for Medical Oncology Congress] 2019, as overall survival was similar in both arms and was approximately 5.8 versus 5.1 months. However, progression-free survival was improved and was 2.3 months versus 1.7 months in the experimental arm versus the control arm. There were also some improvements in subgroups, but overall we do not expect apatinib to be pursued in the Western countries because it still does not meet its primary end point.

Kei Muro, MD: INTEGRATE showed a benefit in overall survival. It is a randomized phase 2 trial, comparing regorafenib monotherapy with best supportive care. This is a late-line study in the gastric cancer field in Australia and Canada. Regorafenib is a kinase inhibitor for VEGFR targeting. However, we already have ramucirumab therapy. As you know, apatinib from the ANGEL trial failed in the gastric cancer field as a late-line trial. Regorafenib is active for HER2 cancer and hepatocellular cancer and, we hope, gastric cancer. Ongoing is the randomized phase 3 trials, regorafenib versus placebo in late-line gastric cancer. The amendment of this trial and newer INTEGRATE trial, regorafenib plus nivolumab regimen versus best supportive care as a late-line trial for gastric cancer, is now preparing. As you know, phase 1b trials for using regorafenib plus nivolumab are very good data in very selective patients in gastric cancer. Only 25 patients, but around a 40% of response rate as shown in this phase 1b trial.

Daniel V. Catenacci, MD: The third-line trial, ALTER0503, is anlotinib, another tyrosine kinase inhibitor that is an antiangiogenesis drug looking at randomizing in the phase 3 setting to placebo in the third-line setting or higher. This is another study we can include in the list of studies using tyrosine kinase inhibitors that are antiangiogenesis agents, including regorafenib, which is in the INTEGRATEII study, the apatinib in the ANGEL study, and in the preceding study that was a Chinese-only study.

We’re seeing this trend in the late line of these oral tyrosine kinase inhibitors. First, we should just say that the ANGEL study, the phase 3 multinational study, unfortunately was negative compared with placebo. This has not confirmed what was seen in the prior phase 3 study that was in the Chinese-only population. We’re seeing other studies, like INTEGRATEII and ALTER0503, with similar agents in the same class looking at the same question.

If there are benefits, they will be marginal benefits. These drugs will come with toxicity. We have to weigh that, and we’ll have to look at what the magnitude of benefit is compared with nothing. These are placebo-controlled studies in the best supportive care arm, and we have to look at whether these truly are going to be moving the needle or providing an option for patients. We have to also consider that in the interim, there have been approvals of other third-line agents like TAS-102 [trifluridine and tipiracil hydrochloride] or trifluridine tipiracil from the TAGS study, which is in the third-line setting and ultimately should be a benchmark if these patients are going to get any therapy. These other studies are now having placebo control. We’re going to have to do cross-trial comparisons to put them into context, unfortunately. But they are options for patients if these studies do read out, and more options are always a positive.

Transcript edited for clarity.