Emerging Approaches in HER2+ Gastric Cancers



Johanna Bendell, MD: Yelena, you have done so much work with the HER2-positive population, and particularly now there are such exciting data in combination with I/O [immunotherapy]. Can you tell us a little bit about where that is and where you’re going with it?

Yelena Janjigian, MD: Sure. We recently published our phase 2 experience, single-center, 37 patients, looking at combination of trastuzumab/pembrolizumab and chemotherapy in the first-line setting. These results were quite promising. The overall response rate was 91%, with promising overall survival and progression-free survival. What’s interesting about the study is that all the correlative work points to the fact that HER2 is the important driver in this subpopulation. It’s not about checkpoint inhibitor effect as much as HER2-positive augmenting the anti-HER2 response. In other words, even PD-L1–negative tumors had a deep response as long as the driver HER2 was there at a high level. It’s very important to characterize these tumors, and we understand that similar as we see in colon cancer, RAS activation really dampens the response to HER2 inhibitors in gastric cancer. Only if you have a very high level of HER2 amplification will then, luckily in gastric, RAS amplifications will take the back seat and the patients may still benefit.

We’re now looking at these data in the phase 3 setting. Hopefully the results of KEYNOTE-811 [NCT03615326] will be available in a year or so, and having CheckMate-649 [NCT02872116] data now showing benefit for I/O therapy in HER2-negative disease, really is reassuring in that setting. We know it’s safe, we know it’s tolerable; combination therapies may be the answer, but the degree of benefit is to be determined.

Johanna Bendell, MD: Very good. Dan, tell us a little bit about MAHOGANY [NCT04082364].

Daniel Catenacci, MD: Building on what Yelena just said, I think there’s evidence in our disease type and also other disease types of this synergistic activity of harnessing both the innate immune system and the acquired immune system. Meaning the acquired immune system with anti–PD-1 inhibitors and the innate system with these RTK [receptor tyrosine kinase] antibodies like trastuzumab or margetuximab, which is sort of an enhanced trastuzumab molecule to enhance that ADCC [antibody-dependent cellular cytotoxicity] effect, which recruits natural killer cells and other macrophage based on the binding to the Fc [fragment crystallizable] domain of the antibody to really get a synergistic response. We also experienced the study that preceded MAHOGANY, which was a second-line study, and showed basically, as we talked about this earlier in second line, I think Ian was mentioning a lot and Yelena—how these tumors evolve to become negative over time in second line. The study with margetuximab did not require ensuring HER2 positivity prior to enrollment. What we saw would be expected, and those patients who were still HER2-positive and certainly PD-L1–positive, those were the ones who were deriving substantial benefit with this chemotherapy-free regimen of margetuximab, and at the time, pembrolizumab, with response rates of 50% to 60% in second line, and survival showing that as well, as a secondary end point.

That led to moving that regimen into the first-line setting, very akin to KEYNOTE-811, but there are 2 major cohorts of that MAHOGANY study. Cohort A is a chemotherapy-free regimen, the same as what was being used in second line. Since the response rates were 50% to 60%, the thought was if we really super-select our patients with IHC [immunohistochemistry score of] 3+ and PD-L1 CPS [combined positive score] of 1 or higher with 22C3 assay, that maybe we can afford not having chemotherapy. That is a single arm, open label, response rate primary end point in the first 40 patients to explore that possibility. Then in the cohort B, it’s more your traditional randomized study. It’s a little bit more complex because there’s a 4-arm phase 2 part of a control arm of chemotherapy plus trastuzumab, then there are 3 experimental arms. One is chemotherapy plus margetuximab; chemotherapy plus margetuximab plus the company MacroGenics, Inc’s PD-1 inhibitor, retifanlimab; and the third experimental arm is chemotherapy plus margetuximab plus a bivalent PD-1 LAG-3 inhibitor. Based on that, pick your winner for the phase 3.

The first-line setting has at least those 2 studies and probably a few others going to start relatively soon, and I think we’ll talk about the other landscape, but we will have the 4. We have the trastuzumab deruxtecan in second-line studies that are ongoing. We have tucatinib and trastuzumab. We have ZW25, and we have ZW49, which is the ADC [antibody-drug conjugate] built on ZW25. There’s a lot of excitement in the HER2 space, and how we implement them and what’s the optimal sequence of those, I think we’ll see over the next few years.

Johanna Bendell, MD: Very good. Ken, can you tell us a little bit about DESTINY-Gastric01 [NCT03329690]? This is the trastuzumab deruxtecan study for patients with HER2-positive gastric cancer, which caused such excitement and finally hope for even improved treatments for these patients with HER2-positive gastric cancer.

Ken Kato, MD, PhD: The DESTINY-Gastric01 trial was presented at the ASCO [American Society of Clinical Oncology] meeting, and they already published it in The New England Journal of Medicine by Kohei Shitara, MD. This is a study of the comparison of paclitaxel versus the T-DXd [trastuzumab deruxtecan], the ADC drug, after failure of a first-line trastuzumab-containing regimen. The survival benefit shows a hazard ratio of 0.59, and the progression-free survival shows 0.47, the superiority of T-DXd [trastuzumab deruxtecan] was shown. In Japan, it was approved this month for the second-line treatment after failure of the trastuzumab-containing regimen.

But there’s some concern about adverse events with this drug. A relatively higher proportion of ILD [interstitial lung disease] was seen during the clinical trial, including the breast cancer and gastric cancer trial. We should manage the ILD carefully, so frequently check the CT scan to monitor the symptoms of the patient. Finally, the proportion of ILD in this DESTINY-Gastric01 trial was around 10%, and most of them were grade 1 and 2. We should be careful about ILD during the course of the T-DXd [trastuzumab deruxtecan], but if we are taking care of the patient, the ILD severity will be decreased.

Transcript Edited for Clarity

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