This is a case of an advanced gastric cancer. The patient presented with about a 10-lb weight loss. He underwent an endoscopy. He was found to have a cardia tumor. Imaging showed metastatic disease to the liver. They were biopsied and confirmed to be metastatic adenocarcinoma, and he started on first-line therapy. He did have a molecular profile that showed that he was HER2-negative, PD-L1negative, and mismatch repair&ndash;deficient, which is unfortunately too frequent, all these being negative. He had initial response to therapy but then progressed, and he&rsquo;s now ready for second-line therapy.

My initial impressions of this case are that, unfortunately, this is really quite typical. The patients typically present with metastatic disease. It really is a silent killer. Patients don&rsquo;t have symptoms of the disease, or their symptoms are vague, and they don&rsquo;t present immediately with these symptoms. Often the weight loss is felt to be intentional, and so the initial weight loss may be even felt to be a good thing. People have abdominal pain, reflux for a long time, and so it often takes time for patients to actually get to medical attention. The prodrome for gastric cancer, unfortunately, is 9 to 12 months. So, that means from the initial symptom that progressed or persisted leading to evaluation and diagnosis often is delayed 9 to 12 months. So, that&rsquo;s one aspect of it.

The other aspect is that his molecular profile was in fact negative for many targeted therapies. So, he was HER2-negative, and that&rsquo;s true in about 80% of patients. He was PD-L1-negative; that&rsquo;s true in about 60% of patients. And he was mismatch repair deficient. That&rsquo;s true in about 80% of patients.

So, as you see, most patients were actually negative for that molecular profile. Although ramucirumab is a targeted agent that we&rsquo;ll discuss, the other targeted agents available in this diseasetrastuzumab and pembrolizumab&mdash;won&rsquo;t be available to him at this time. And then I guess the other aspect of the case is that it&rsquo;s common to start with a platinum 5-FU in the beginning. And then neuropathy does happen. So, his course is actually, unfortunately, quite typical.

Impressions of a Case of Stage 4 GEJ Cancer

The appropriate staging for gastric and GEJ cancers begins with a physical examination and basic blood work. You need an endoscopy to establish the mass and the upper GI tract and to get tissue to make a diagnosis. You need a CAT scan to evaluate the extent of the disease. And that&rsquo;s actually my typical starting pattern: an endoscopy and CAT scan. If the CAT scan is negative and it&rsquo;s not obvious on the CAT scan, if there&rsquo;s no disease or gastric wall thickening, then I would proceed with an endoscopic ultrasound because that can help differentiate early-stage versus locally advanced disease. If patients have early-stage disease, then often you might be able to go straight to surgery. If it&rsquo;s locally advanced, you would consider perioperative therapy. But if the CAT scan shows metastatic disease, then I often do perform a biopsy to confirm this disease, primarily because this diagnosis of metastatic gastric cancer is life changing. It&rsquo;s a terminal illness, unfortunately.

For patients who don&rsquo;t have metastatic disease, we often perform a laparoscopy because occult metastatic disease and peritoneum happens in about 30% of patients. So, patients with locally advanced disease, based on imaging and endoscopic ultrasound, should have a laparoscopy prior to embarking on treatment for locally advanced disease.

Molecular testing is evolving in gastric and GE junction cancers. Just 5 years ago was the first time that we actually got a targeted agent approved, and that was trastuzumab for HER2-positive disease. Since then, we have 2 additional targeted agents that are approved but require 2 additional testings. So, the additional testing that should be done includes PD-L1 testing, for whichif you&rsquo;re positive&mdash;in the third-line setting you can receive pembrolizumab. And mismatch repair deficient testing, which is for pembrolizumab in the second-line setting for tumors that are mismatch repair deficient.

So, our standard panel does include those 3. We do test for HER2 overexpression by IHC or FISH. We test for mismatch repair deficiency, and we also test for PD-L1 expression based on the combined positive score. Most places have a panel, and so do we at Weill Cornell. And so, this is a pretty comprehensive panel. It looks at other features like

, things like that. But right now, they don&rsquo;t have clinical significance, at least in gastric and GE junction cancers.

Diagnostic Workup for Stage 4 GEJ Adenocarcinoma

The care of cancer patients has evolved tremendously in the past 2 or 3 decades. I think that for most solid tumors, including gastric and GE junction cancer, we really do benefit from the multidisciplinary setting. So, at our institution, all patients are in fact presented in a multidisciplinary fashion. That includes the surgeonsthoracic and the general or gastric surgeons&mdash;pathology, radiology, and other medical oncologists, Fellows, and Residents. So, it&rsquo;s a big group of people, and it&rsquo;s educational, but it also helps uniform our care. The care coordination is complex, even for patients with metastatic disease. One issue in this case, for example, is he had 12 lbs of weight loss and dysphasia. The question that could come up is, how do we manage that if he doesn&rsquo;t respond initially to chemotherapy? Should we play the stent? Should we do palliative radiation to the mass and the GE junction? These questions really can be addressed in a multidisciplinary fashion and, I think, for the benefit of patients. So, I think it&rsquo;s actually really challenging if you&rsquo;re practicing in an area where you don&rsquo;t have access to multidisciplinary care. It&rsquo;s tough for patients as well because they often have seen multiple physicians at the same time to get the same level of coordination.

There are many factors that play a role in deciding what treatment is appropriate. Obviously, there are tumor-related factors, such as the extent of the disease and the molecular profile. So, this patient had a locally advanced tumor with metastatic disease to the liver, and his molecular profile was negative for

There are patient-specific factors as well. So, if they have comorbid illnesses like cardiac disease or obesity, or peripheral neuropathy from diabetes, that may affect how we initially treat patients. Most patients really will receive a platinum and 5-FU in the first-line setting. However, if they have significant peripheral neuropathy at the beginning, it may be appropriate to start with FOLFIRI, for example.

Patients who have significant cardiac disease or a stroke may not be a big candidate for ramucirumab in the second-line setting. If they have a reduced ejection fraction, they may not be a good candidate for trastuzumab even if they&rsquo;re

-positive. So, there are patient-specific factors, as well as tissue- or cancer-specific factors, that we address when we&rsquo;re deciding on our treatment options.

GEJ Cancer: Multidisciplinary Assessment & Treatment Factors

In terms of frontline chemotherapy, most patients would really receive a doublet combination of a platinum and fluoropyrimidine. However, there are patients who may be good candidates for a 3-drug combination. There was actually a Cochrane Review that looked at 3 drugs versus 2 drugs. This was in the era when there were more data for epirubicin, platinum 5-FU, and more patients in that review actually had that treated regimen than another.

And the upshot of that review was that if you were physically able to receive the 3-drug regimen, then you would have a better outcome by starting with a 3-drug regimen instead of a 2-drug regimen. But that was also done in an era when most patients received only one line of therapy, not multiple lines of therapy. And that was an argument that actually our Asian colleagues, particularly from Korea and Japan, would make. They said that they use a doublet in the first-line setting because 80% or more of their patients get a second-line or third-line drug, and that wasn&rsquo;t the case in the West.

And so, as you know, patients in Korea and Japan, they have survivals for gastric and GE junction cancer that are far superior to what we see in the West. Part of that might be biology, in terms of the disease subtype that they see, but part of it might be the way they are able to manage the patients with toxicity to trigger a regimen that is less toxic. And if you&rsquo;re able to get to a second-line agent, then you&rsquo;re able to distribute the toxicity across a longer period of time.

The current 3-drug regimen that is having more credence now incorporates a taxane in the first-line setting. So, it&rsquo;s based on a study of DCFdocetaxel, cisplatin, 5-FU&mdash;versus CF. And that study actually wasn&rsquo;t that positive and proved docetaxel in the first-line setting was really quite a toxic regimen. So, since that publication, there have been efforts to figure out ways to administer the 3 drugs by mitigating toxicity.

We created a regimen called the modified DCF regimen, which is a 2-day 5-FU infusion plus reduced doses of docetaxel and cisplatin. And our data were actually evaluated in a randomized phase II setting multicenter. Patients who received the DCF regimen had a substantial survival of 16 months, which was really quite improved, quite notable.

The other regimen that&rsquo;s very similar is the FLOT regimen developed in Germany. That is 5-FU as a 24-hour infusion of oxaliplatin and Taxotere (docetaxel). And I think what we know is that these 3-drug regimens are less toxic than the parent DCF regimen, but they are still toxic. So, they&rsquo;re not for everybody. In select patients, you might consider a 3-drug regimen. I think in the setting of metastatic disease, if you&rsquo;re able to get a 3-drug regimen in the first-line setting, you&rsquo;re also more likely to not be able to get a 2-drug regimen and then a second-line agent. So, I&rsquo;m not certain that there&rsquo;s that much of an advantage to starting with a 2-drug regimen.

The last point I&rsquo;d make is that as we get more drugs approved in gastric cancerso pembrolizumab is approved in the third-line setting&mdash;LONSURF (trifluridine/tipiracil) will likely get approved as well based on the TAGS study. We have irinotecan, we have Taxol (paclitaxel)/Cyramza (ramucirumab), platinum 5-FU. We&rsquo;re getting to a point where we&rsquo;re saturating our options. And so, if we do what we&rsquo;ve historically done, a 2-drug regimen followed by another, let&rsquo;s say Taxol/Cyramza in the second-line setting and then pembrolizumab in the third-line setting, then patients may not actually be able to get the irinotecan or LONSURF. So, then in that setting, adding a third drug in the first line to actually give patients the opportunity to have more drugs might be a consideration.

Frontline Therapy Approach for Stage 4 GEJ Cancer

Unfortunately, this patient did start with the standard 2-drug regimen of FOLFOX, or oxaliplatin and the 5-FU. He had neuropathy, so the oxaliplatin was dosage reduced and then stopped after only a few months of therapy. And I think the response was modest. He progressed a few months after that.

So, you know FOLFOX is an active regimen. I&rsquo;ve had patients who have had a near-clinical CR with FOLFOX. This patient isn&rsquo;t that. I think it&rsquo;s a typical response, modest, but one thing that I always wonder about is whether or not we should push the oxaliplatin a little further. Instead of 4 months, try to do 6 months of therapy. These are questions we really don&rsquo;t have answers to yet from our clinical trials.

Patients with gastric cancer have multiple lines of therapy options. The first-line option tends to be a doublet with oxaliplatin or cisplatin and 5-FU. Unfortunately, most patients with metastatic disease will ultimately die of their disease. The goal of treatment is to control the disease and maintain their quality of life for as long as possible. We are improving our outcomes. Not too long ago, 10 years or so, the median survival for metastatic disease was 8 to 9 months. We&rsquo;re approaching a year now, and I think if a patient is able to get first-line therapy, second-line therapy, third-line therapy, it could be even longer than that. And in my practice, I have many patients who are out 2 years with metastatic disease.

So, in this patient it would be an important discussion to sort of talk about what our goals really should be. He has progressed on first-line therapy. We would talk about second-line options. Our typical option, our preference would be Taxol (paclitaxel) and Cyramza (ramucirumab), which is a VEGFR2 inhibitor. But other options exist. Irinotecan is an active option, and ramucirumab alone is an option as well.

Although those 3 options haven&rsquo;t been compared head-to-head, the Taxol/Cyramza combination is indeed superior to Taxol alone. And Taxol and irinotecan and ramucirumab monotherapy all seem to have similar activity. So, these are the options, and each one has their own toxicity profile that may play a role in the decision.

The time course for a patient, I guess, can play a role in our decision for how we treat the patient. So, most patients can have disease control or response and will be on first-line therapy for longer than 6 months, maybe 8 or 9 months, and then we can switch to second-line therapy. But there is a small cohort of patients who have primary refractory disease. They have early progression, within 3 months or so. There aren&rsquo;t great data for that population. We need to understand this population better. But in my experience, patients who are primary refractory, they rarely have a great response to standard second-line and third-line options. So, we really are looking for clinical trials there. We&rsquo;re looking for targeted agents as well. If the patient is

-positive, they often would have gotten trastuzumab in the first-line setting. But if for some reason they didn&rsquo;t, then that would be an obvious go-to choice. But we don&rsquo;t really have great evidence-based data on what to do beyond our standard options, which are honestly not that great for patients with primary refractory disease.

GEJ Cancer: Chemotherapy & Second-Line Options

So, let&rsquo;s talk about paclitaxel and ramucirumab in some detail. There was a phase III study that compared the combination of paclitaxel/ramucirumab with paclitaxel alone. And the combination did improve survival. The hazard ratio was around 0.8. So, it&rsquo;s 20% improvement in survival with the combination therapy.

Ramucirumab is a VEGFR2 antibody inhibitor. That toxicity profile of ramucirumab is similar to what we see with bevacizumab. So, hypertension and some bleeding riskthat&rsquo;s what we saw on the study as well. We really didn&rsquo;t see a significant increase in perforation, which you did see with bevacizumab in the earlier studies. And we do see a little bit more lymphopenia with Taxol/ramucirumab versus Taxol alone. But generally, the combination is pretty well tolerated with minimal added toxicity over what you see with Taxol alone.

The one thing you might consider is that for patients who have significant neuropathy, you might need to question whether Taxol is the right choice. So, single-agent ramucirumab might be considered. Irinotecan might be considered. There are limited data combining those 2, although theoretically there really shouldn&rsquo;t be any problem with that. The FOLFIRI/bevacizumab option, for example, was really quite active. And in terms of the efficacy, I mentioned the 20% improvement in survival. The response rates are about 20% with the combination. Ramucirumab has really no response by itself, but there is synergy when you combine them.

Supportive care is the key aspect of managing anybody with gastric and GE junction cancer. So, are often issues of nutrition, neuropathy, and also social issues related to depression or anxiety, coping, things like that. And that often requires counseling regularly during our visits. Often patients could seek help from a social worker or group therapy sessions for that. From a nutrition standpoint, seeing a dietitian is important, but sometimes we do need to place a stent for proximal obstructions. Sometimes radiation is helpful. Sometimes a feeding tube is necessary.

In terms of the neuropathy, there are medications that can help mitigate the symptoms of neuropathy. We commonly use gabapentin, Cymbalta (duloxetine), and Lyrica (pregabalin). Alpha lipoic acid can help. But there isn&rsquo;t a great magic bullet for that. Those are, I think, the most prevalent supportive care issues, but many others exist.

GEJ Cancer: Paclitaxel/Ramucirumab and Supportive Care

So, if a patient did receive second-line therapy, let&rsquo;s say Taxol/Cyramza, and then after some time had progression, the question becomes, is third-line therapy an option? And I think that, again, there&rsquo;s a discussion. It depends on the performance status. If a patient is having a lot of ascites, having visceral metastases, spending more time in bed than not in bed, then it&rsquo;s not clear that a third-line treatment would be very beneficial, and it may be better to think about supportive care hospice. If, however, the patient is quite functional, active, and motivated to get third-line therapy, then obviously I would look for a clinical trial. But short of a trial, I would consider a third-line agent, typically irinotecan.

Closing thoughts for this case. We talked about how it&rsquo;s unfortunately a typical presentation, and we talked a lot about the standard options for treatment. I might just mention that I think the options that we talked about in this interview are likely to change in the next 6 to 12 months. Drug development in gastric and GE junction cancer is quite active. Thousands of patients are in clinical trials. We&rsquo;re awaiting the phase III data of the first-line regimen of FOLFOX plus or minus the MMP9 inhibitor andecaliximab. And if that study is positive, that may change options. We&rsquo;re awaiting data from the first-line pembrolizumab study. The first-line nivolumab and ipilimumab phase III study is still accruing, but that may change options. And that&rsquo;s just what we know about now. Just a month ago we received approval of our positive data of LONSURF in the third-line setting, so that will change options as well.

So, I think the shelf life for this interview is, fortunately, not going to be great, or actually you can invite me back, because there will be other options in the not-too-distant future.