John Marshall, MD

: This is a big positive event for us with HER2-positive gastric and gastroesophageal [GE] junction cancers. It's not as if we haven't been trying. There have been a bunch of clinical trials in lines of therapy in HER2-positive metastatic disease, GE junction, and gastric cancer. They have been basically suggestive, but not positive. This trastuzumab deruxtecan therapy is a breakthrough for us as it maintains a response rate. It maintains the benefit through lines of therapy, and again in patients, 70% of which didn't have repeat testing. However, there are still many questions to be asked about this. What will be the role of this therapy in earlier lines of therapy? Can we combine it with other treatments? Can we combine it with immunotherapy for example? There are some fascinating studies being done in that space.

I sense that this will be a medicine that's here to stay and will be incorporated in other settings. HER2 treatment in the adjuvant world and in the neoadjuvant world has yet to be firmly established, so still is a clinical trial question and is again being studied to try and demonstrate if we could add HER2 targeting to neoadjuvant approaches, or in the postoperative adjuvant setting to improve outcomes as we see in some other cancers. Overall, that is still a research question, but we all hope that we will get data that supports doing that and improve our overall outcomes. Let's face it, this is still a very difficult disease where we are failing to the level that we need to do. The biggest point about this new evidence is that we must be doing molecular testing. We want to do that at first-line. You want to incorporate HER2 targeting in first line, but you now have HER2 targeting into second- and subsequent lines of therapy to add to the several other recently approved therapies in this space.

You are getting an increased therapeutic portfolio. It is dictated by molecular testing, so molecular testing must be done and must be documented. If you're using trastuzumab deruxtecan in second or third line, watch out for the interstitial lung disease. Know that you've got a new medicine in hand that can deliver significant response rates and improvements in outcome for our patients with HER2-positive gastroesophageal and GE junction cancers. Thanks a lot.

This transcript has been edited for clarity.

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An expert in gastric cancers provides insight on the recent advances and future directions for the management of locally advanced and metastatic gastric cancers. 

Recent Advances and Future Directions in the Management of HER2+ Gastric Cancer 

The DESTINY-Gastric01 trial has been very important advance in our treatment of HER2-positive gastric and GE [gastroenterostomy] junction cancers or adenocarcinomas. [The study was published] in the 

 in 2020. We now have a new FDA approval. This is a cool medicine, right? It is trastuzumab, but tied to the trastuzumab is deruxtecan, basically as a loaded smart bomb, is the way I like to think of it. The trastuzumab still tracks to the receptor, which is up-regulated on the tumors. In doing so, yes, it blocks the pathway itself, but it also brings with a payload of a TopA-1 inhibitor, deruxtecan. Chemotherapy is in fact brought to the table. The clinical trial demonstrated a significant response rate in patients who had seen prior HER2-targeted therapy. Primarily done in Asia, and primarily done in third-line therapy, the response rates were good. in the United States, it was approved both in second- and third-line patients.

Now, one of the questions because in other HER2 diseases, we've gotten the routine of repeat HER2 testing. And yes, in this clinical trial, 30% of patients did undergo repeat testing to confirm their HER2 positivity. However, 70% did not. A large proportion of these patients did not undergo repeat testing and were using their baseline testing for HER2 as entry criteria. It’s not a requirement to repeat HER2 testing for this for this treatment. However, it's certainly appropriate to do that if tissue is available or if you can get that testing on circulating samples. Now, the treatment is an IV [intravenous] treatment. It has [chemotherapy-like adverse] effects.

We do have myelosuppression, and there is some nausea and vomiting that is associated with it, so you do need to manage patients through those toxicities. One that has all our antennae up, even though very rare that needs to be monitored is interstitial lung disease. This is often very subtle, as you know. You're used to it in some of your other therapies to track it. However, if patients were getting short of breath or getting cough and you detected interstitial lung disease, typically on a CT scan, the recommendation is to stop the treatment, institute steroids with a higher grade of grade 2 or higher. Do not retry the medicine with lower grade, grade 1 that you picked up maybe on a screening scan. You can treat with steroids reversed and try again at a modified dose. You can rechallenge if the ILD [interstitial lung disease] was very early grade 1. If it is more significant than that, the recommendation is to stop. This comes off more like a chemotherapy, with that ILD as an important toxicity that you need to watch out for. That can occur anytime during the treatment course.

Dr John Marshall discuss the DESTINY-Gastric01 trial and the implications of the study results to clinical practice for HER2+ metastatic gastric cancer.

The DESTINY-Gastric-01 Trial

 Beyond first line, there are a host of different treatment options that have come forward. We have taxanes. We have irinotecan. We have ramucirumab, a VEGF inhibitor. Until recently, we have not had a HER2 beyond-progression therapy that was showing any benefit. Front-line, yes. When we explored HER2, even combination HER2 therapy beyond first-line, we failed to demonstrate a clear clinical benefit. Therefore, your HER2 treatment was first-line and that was it. As you move from first- to second-line, there are choices. Now in a HER2-positive patient, we have newer data, fam-trastuzumab deruxtecan, which shows strong responses in benefit. That doesn't mean your taxanes aren't in play. It doesn't mean irinotecan is not in play or ramucirumab is not in play. This brings in another treatment option for our HER2-positive patients. Each of these regimens has the potential to cause a regression. You look at the patient in front of you and make decisions about where are they at the moment. What have their side effects been so far? How's their cardiac function? 

If you can do repeat testing, is HER2 still overexpressed, or has some emergence of resistance come forward? Molecular testing will help you with that. It is not required in this setting but can be helpful. You take your known portfolio of treatment options and you look at the patient in front of you and make the best decision for that patient together. With gastric cancer, unlike colorectal cancer, we often don't get the chance to get many lines of therapy in. The disease, while it often is responsive to first-line therapy, it often is quite aggressive in subsequent lines of therapy. Very commonly get peritoneal carcinomatosis, which of course causes a significant decline in performance status, etc. We are developing new therapies, new HER2 therapies, new IO therapies, and we have new oral therapies with tipiracil/trifluridine. We are seeing people getting into second- and third-lines of therapies, depending on how serious the patient's cancer is at this moment, how life-threatening it is at this moment, and it gives you a sense of what card you should play in terms of sequencing. If you need a response, you have some choices. If stable disease is OK, you have some choices. I do think as we are doing in colorectal cancer increasingly in upper-GI [gastrointestinal] gastric cancers, we are thinking more of lines of therapy and sequential therapy and treatment sequencing.

John Marshall, MD, reviews options for second- and later line therapies and considerations for treatment sequencing in patients with HER2+ gastric cancers. 

Second- and Later Line Treatment Options for Metastatic HER2+ Gastric Cancer

: Front-line treatment for patients with metastatic adenocarcinoma of the GE [gastroenterostomy] junction is… doublet chemotherapy is the most commonly offered recommendation. We know in neoadjuvant treatment that we will often use triplet therapy. The FLOT [5FU, folinic acid, oxaliplatin, docetaxel] regimen is commonly used in the neoadjuvant setting. When we look at triplet therapy with 3 chemotherapy agents in the metastatic setting, there hasn't been any demonstration of clear benefits by adding that third medicine, with a few rare circumstances, specifically doublet chemotherapy typically with a fluoropyrimidine and a platinum. I think it's a legitimate choice to use a platinum and a taxane in frontline therapy.

I do think you have choices there. Increasingly we have biologics, which are combined with that doublet therapy obviously in HER22-positive patients. We have trastuzumab in PD-L1 [programmed death-ligand 1]-positive patients. We have different I-O [immuno-oncology] therapies which are being combined with chemotherapy. If you have alternative markers, there may be other front-line options that come into play. They aren't apart from predictive markers, which drugs to use, there aren't many strong prognostic markers. There are genetic inherited cancer genetic markers such as 

 that are important to test in most patients. We are referring most of our patients for genetic counseling to do germline testing as we are increasingly seeing germline abnormalities in these patients.

Dr John Marshall discusses frontline systemic treatment options for metastatic HER2+ gastroesophageal junction cancer and gastric cancer in general.

Frontline Treatment in Metastatic HER2+ Gastric Cancer 

This is a typical case and course for a patient with HER2-positive metastatic gastroesophageal cancer. We know that molecular testing is incredibly important for our patients with upper GI [gastrointestinal] cancers and is now required before anyone starts front-line therapy. You got to know HER2. You need to know PD-L1 [programmed death-ligand 1]. You need to know microsatellite stability or instability [MSI]. This is a very common type of patient that we all would see in front-line. Age is appropriate. The genetic testing symptoms are all appropriate. I think the good positive finding here is that when you do have a target such as HER2, the therapy is effective. It's more effective than traditional chemotherapy on its own. You don't want to miss the opportunity to identify these patients.

As I said, molecular testing for HER2, PD-L1, and MSI needs to be done in frontline therapy. The good thing is that all of those can be done relatively quickly, mostly using immunohistochemistry. HER2 often needs reflective fish testing, but local laboratory studies can do that. PD-L1 is straightforward to do, and MSI is straightforward to do all using immunohistochemistry. The testing can be quick. The turnaround time is quick. If you have adequate tissue sample, I encourage broader molecular testing than those 3 markers, as we often do uncover other molecular abnormalities that may play in either first line or even later lines of therapy.

An expert in gastric cancers describes when and for whom molecular testing should be done in patients with metastatic HER2+ gastric cancer, and which tests are move relevant to treatment decision-making.

Molecular Testing for Metastatic HER2+ Gastric Cancer 

: Hello, everybody. My name is Dr John Marshall. I am the Chief of Hematology and Oncology at Georgetown University at the Lombardi Comprehensive Cancer Center in Washington, DC. I'm also the Director of the Otto J. Ruesch Center for the Cure of GI [gastrointestinal] Cancers. I'm pleased that you've joined us for a case-based discussion drilling down on some new data in upper GI cancers, gastric cancer, GE [gastroenterostomy] junction cancer specifically. Our case today is a 67-year-old man who had locally advanced and metastatic HER2-positive gastric cancer. A 67-year-old man comes in, and he presented with new-onset fatigue.

He's got some right upper-quadrant pain that worsened with eating and some unintentional weight loss. He does have a left hip that got fixed, with some arthritis there. He has some hypertension, and a little bit of pre-diabetes. However, his physical exam's unremarkable, as is common in patients like this, and his ECOG [Eastern Cooperative Oncology Group] performance status is 1. He undergoes a typical workup. His hemoglobin is pretty good, at 12. His white [cell] count is 10 and his platelet's 235. He has kidney function, bilirubin, liver function normal. His CEA [ carcinoembryonic antigen] is normal. His CA99 [cancer antigen 19-9] is just marginally elevated at 41, so the tumor markers haven't really helped. He does end up undergoing an upper endoscopy with the finding of a 4-centimeter mass at the GE junction. He undergoes right after that a CT scan showing unresectable liver metastases. The endoscopic biopsy comes back positive for adenocarcinoma, and he gets sent appropriately for testing for HER2. It comes back immunohistochemistry-positive for HER2 at 3-plus, so no reflex testing is needed. PD-L1 [programmed death-ligand 1] is negative, and genetically was found to be microsatellite-stable, all key molecular markers that are needed in a workup of a patient such as this.

John Marshall, MD, reviews the case of a patient with metastatic HER2+ (human epidermal growth factor receptor 2) gastroesophageal junction cancer. 

John Marshall, MD | Authors

Articles

Recent Advances and Future Directions in the Management of HER2+ Gastric Cancer

The DESTINY-Gastric-01 Trial

Second- and Later Line Treatment Options for Metastatic HER2+ Gastric Cancer

Frontline Treatment in Metastatic HER2+ Gastric Cancer

Molecular Testing for Metastatic HER2+ Gastric Cancer

Case Presentation: Metastatic HER2+ Gastric Cancer