 With the advent of genomic profiling of esophagogastric cancers, we do see that certainly for gastroesophageal junction and esophageal adenocarcinomas. About 95% of these cancers are what we call genomically unstable. That category applies to about 50% of gastric adenocarcinomas. With genomically unstable tumors, a significant percentage have amplification of receptor-associated tyrosine kinase pathways, pathways like HER2, which we know is targetable in the first line with trastuzumab. EGFR is also amplified in a small percentage of patients along with FGF [fibroblast growth factor] and MET. These are all potentially targetable pathways. The only one that has really borne fruit to date has been HER2. HER2 amplified patients’ benefit for the inclusion of trastuzumab in first-line chemotherapy. Unfortunately, the EGFR drugs did not improve outcome when added to first-line chemotherapy, but those trials were largely in patients with unselected biomarkers.

FGF is a viable target in esophagogastric cancer. There are a small percentage of patients who have abnormalities in the FGF pathway. Probably the most common would be 

 gene amplification. We see this amplification in genomically unstable tumors in esophagogastric cancers. The concern is, what’s the best biomarker? The FIGHT trial is now looking at bemarituzumab, which is an anti-FGFR receptor blocking antibody, so it blocks the receptor and potentially could show synergistic activity with chemotherapy. The trial is selecting patients with FGF receptor gene abnormalities, and patients are randomized to get a fluorinated pyrimidine-oxaliplatin with or without bemarituzumab. This is an ongoing trial. The concern is, what is the best biomarker? We are learning in other cancers that the patients most susceptible to FGF receptor–targeting drugs may be the patients with gene fusions and gene rearrangements, that amplification and gene mutation may not convey sensitivity to these drugs. We’ll see what the trial shows; our hope is that patients with activating mutations with gene amplification will be targetable with FGF receptor drugs. But what we have learned from other cancers is it’s really the patients with gene fusion and gene rearrangement who are the ones susceptible to these drugs. This certainly is an area of tremendous interest, and we await the results of the randomized trial.

I will comment that some earlier trials looking at FGF receptor tyrosine kinase inhibitors in patients with gene amplification did not show a clear benefit. But some of those trials were terminated early, and it may be because the biomarker was not the correct biomarker. Perhaps gene-amplified patients are not the right group of patients.

Videos

Metastatic Gastric Cancer: Novel Agents Targeting FGF

In the first-line setting using PD-1 or PD-L1 antibodies, CheckMate649 (NCT02872116) is a very attractive regimen because the population is more than 2000 patients. It’s a very huge randomized controlled trial. In addition, nivolumab and ipilimumab as an IO/IO combined regimen is very promising for me. It is a huge randomized controlled trial, but the primary end point is very simple and the α was limited. As you know, the KEYNOTE-062 trial (NCT02494583) has many primary end points and the α was divided. The primary end point was with very limited data. Given noninferiority in overall survival with pembrolizumab monotherapy versus chemotherapy, the frontline standard of care was established. However, CheckMate649 is huge and has very limited α. That’s very promising to show the benefit of overall survival.

Second is ATTRACTION-4 (NCT02746796). It’s mainly Asian countries’ data with doublet chemotherapy plus nivolumab or nivolumab plus doublet placebo. This trial is also very promising, with limited α and more than 600—around 680—patients involved. At the end of this year, it will be open in overall survival data.

Another promising first-line treatment is the KEYNOTE-811 trial (NCT03615326). These are patients who are HER2-positive gastric cancer being treated with a doublet plus trastuzumab plus pembrolizumab therapy compared with standard of care doublet plus trastuzumab therapy. An already opened trial, a single-arm phase 2 trial from Memorial Sloan Kettering Cancer Center, showed very good data and an overall response rate of more than 70%. Good data are shown in that phase 2 trial, and we hope there will be phase 3 positive data in KEYNOTE-811.

Gastric Cancer: Frontline Checkpoint Inhibitor Trials 

The SOLAR study (NCT02322593) was done in Asia and it was evaluating this drug,TAS-118, which is essentially S-1 [tegafur/gimeracil/oteracil]—an oral fluoropyrimidine that is available in Asia and not in North America—in combination with leucovorin. It was used in the first-line setting in combination with oxaliplatin and compared with S-1 plus cisplatin. It was a little bit odd in that they changed the constant, the platinum, where we do know that there is some evidence in randomized studies comparing oxaliplatin and cisplatin that oxaliplatin is certainly better tolerated. Patients may get active therapy for longer. But it may just be more active in the disease. Two variables were changed there, and, ultimately, it was slightly better on the order of less than 1 month improvement in median overall survival. I certainly wouldn’t think it’s a slam dunk, and it doesn’t affect us here in North America that readily because we don’t have access to S-1.

 There was a phase 2/3 trial, which compared modified FOLFOX [folinic acid, fluorouracil, oxaliplatin] versus modified FOLFOX plus varlitinib in the first-line treatment of patients with metastatic gastric or gastroesophageal junction adenocarcinoma. This trial consisted of 2 parts. The first part was the phase 2 part, and the primary end point was response rate. Then there was a phase 3 part. I didn’t see results of this trial, but there has been a [news] release saying that the primary end point of the trial was not met. Response rate, in fact, was improved slightly and was around 20% with completion in the experimental arm versus 12% or 13% in the control arm. However, this was not statistically significant.

SPOTLIGHT (NCT03504397) is a first-line trial in the gastric cancer field. IMAB362 for claudin 18.2–positive gastric cancer already was studied in a randomized phase 2 trial of EOX [epirubicin, capecitabine oxaliplatin] versus EOX plus this agent. It’s clearly beneficial in overall survival and progression-free survival. Now it’s in a randomized phase 3 trial. Claudin 18.2–positive disease occurs in around 50% of gastric cancer [cases]. We hope it is positive in selective patients in the first-line setting for advanced gastric cancer. However, until now, many targeted agents for gastric cancer failed. We would like to expect this trial will have good data results.

 The ARMANI trial (NCT02934464) is an interesting trial evaluating switch maintenance for standard chemotherapy with a doublet. The switch maintenance compares continuing chemotherapy, which is the standard arm, or switching to paclitaxel and ramucirumab. This is a phase 3 trial, which is ongoing and still recruiting patients. The primary end point of this trial is progression-free survival, and I think that approximately 280 patients are going to be enrolled in this trial. I think results are expected in a few years.

Metastatic Gastric Cancer: Promising Frontline Trials

Until now, many multitargeted agents have been developed in the gastric cancer field. However, almost all multitargeted agents failed to produce an overall survival benefit. For example, MET; EGFR; HER2, except for trastuzumab; anti-angiogenesis, except for ramucirumab; STAT3 inhibitors, and so on. With FGFR, similar trials failed in overall survival. However, now we are focusing on patients with FGFR abnormality. In clinical trials, FGFR is very promising. Claudin 18.2 inhibition is also promising in its first trial. It was a randomized phase 2 trial, very good data. A newer agent, DS-8201a, also called Enhertu, is very promising for HER2-positive gastric cancer. It is also active in HER2-low expressing gastric cancer. HER3 is attractive; however, it is now under evaluation.

At this moment, it has very limited impact on the gastric cancer field. But now there are many attractive agents being developed in the gastric cancer field. Later, I hope NGS [next-generation sequencing] or the many-biomarkers direction becomes impactful on the gastric cancer field.

In addition to some of the predictive biomarkers that we’ve discussed with respect to immunotherapy—such as MSI [microsatellite instability]-high status, PD-L1 status, and others—there are a number of emerging biomarkers that may render some predictive utility, both for immunotherapy or other targeted therapies. Speaking with respect to immunotherapy, EBV [Epstein–Barr virus]–positive tumors, which have extremely high expression of PD-L1, may derive some benefit. I think it’s very rare and it’s hard to get a robust data set around that, but there’s potential.

Another potential marker is tumor mutation burden. We know that MSI-high tumors have extremely high tumor mutation burdens, but other tumors that are microsatellite stable have high tumor mutation burden. I think that data are emerging and more studies are needed to really define whether tumor mutation burden independently will help to predict benefit from immunotherapy. For example, in microsatellite-stable patients who are PD-L1 negative, is that something that might be useful and help predict patients who might respond?

Outside of immunotherapy, there are other genomic biomarkers that are promising and have some data around them. 

 gene amplification are all receptor tyrosine kinases akin to 

 gene amplification. We already know that in the first-line setting, anti-HER2 monoclonal antibody therapy with trastuzumab leads to improved outcomes when combined with chemotherapy. There are a number of smaller phase 2 studies that show consistent response rates—not all of them, but in a subgroup of each of those biomarker groups—that are worth mentioning.

In terms of biomarkers of prediction for anti-angiogenesis therapy, this has been elusive not only in this tumor type but across tumor types, where efforts over the last few decades have tried to find a predictive biomarker to help enhance or enrich benefit among those patients getting anti-angiogenesis therapy. But a number of biomarkers have been very elusive, and there’s no routine biomarker implemented to date to help enrich for patients who might benefit and spare others.

In fact, my sense is that there is a modest benefit across all patients. It’s not in 1 subgroup that you see a remarkable benefit and in others, not. It’s different than other targeted therapies where you don’t have the biomarkers. For example, without 

 amplification, anti-HER2 therapy is not going to be effective. If you do have it, then you will substantially enrich for benefit. Anti-angiogenesis drugs work differently. They modify the tumor microenvironment, and so they work generally across all tumor types to a modest degree.

Emerging Biomarkers in Metastatic Gastric Cancer

In the later-line setting in gastric cancer, when patients have received first-line and second-line treatment, we offer patients who still have good performance status cytotoxic drugs known to be efficient and non–cross-resistant to the previously used compounds. Not just docetaxel, paclitaxel, and irinotecan; it depends on the performance of the regimens that have been administered in the first- and second-line settings. Later on in the course of disease, we do use immunotherapy, which means checkpoint inhibitors. It depends on the country. In Germany, we limit the use of these drugs to patients having either MSI [microsatellite instability] or the PD-L1 overexpression. But sometimes, we use them in patients with high mutational burden. These may be the most frequent drugs used in the later-stage setting.

FTD/TPI [trifluridine/tipiracil or TAS-102] is one standard of care as a third-line or later-line option in advanced gastric cancer. The reason why is that trials show a strong benefit in overall survival in such lines of gastric cancer. The data are very similar to ATTRACTION-2 with nivolumab. The TAGS trial shows a hazard ratio in overall survival of 0.69. Median overall survival time of trifluridine/tipiracil is 5.7 months, quite similar to the nivolumab arm in an Asian population in ATTRACTION-2. TAGS and TAS-102, ATTRACTION-2 and nivolumab, and pembrolizumab in the United States: 3 agents are our standard of care as third-line or later-line treatment for advanced gastric cancer. TAS-102’s disease control rate is very similar to nivolumab or pembrolizumab, around 40%. However, response rate was only 4% in the TAGS trial with trifluridine/tipiracil, a little bit lower compared to ICI, or immune checkpoint inhibitors. If we hope the patient needs tumor shrinkage, we often use ICI therapy in the third-line or later-line setting.

We now have defined third and fourth lines of therapy in gastric cancer, based on randomized clinical trials. Typically in the West, a patient would get up-front FOLFOX [folinic acid, fluorouracil, oxaliplatin] and second-line treatment would be paclitaxel plus ramucirumab. Third line, we could consider an irinotecan-based treatment, and now we have randomized trial data to support active treatment options in the refractory disease setting.

In the West, the most recent positive trial in the refractory disease setting was the TAGS trial, which was the randomized trial of TAS-102. This is a combination of tipiracil and a fluorinated pyrimidine in an oral preparation. Testing TAS-102 versus placebo plus best supportive care in chemotherapy-refractory gastric cancer, the TAGS trial did show a modest 2-month progression-free survival benefit for TAS-102 versus supportive care alone, and a modest 2-month survival improvement over best supportive care. Based on this study, TAS-102 is now a treatment option for patients with chemotherapy-refractory gastric cancer. Now we have an approved third- or fourth-line option for patients with advanced gastric cancer.

The other option is in patients who are PD-L1 positive. Based on the KEYNOTE-059 trial, which was a large phase 2 expansion cohort looking at pembrolizumab in esophagogastric adenocarcinoma with nearly 250 patients. A little bit more than 50% of patients did test PD-L1 positive. What this large expansion cohort showed was a meaningful response benefit for pembrolizumab in patients who were PD-L1 positive. Response rate was approaching 15%. If we took out the patients where were MSI-high, it was about a 10% to 12% response rate with a tail on the survival curve. For the patients who were PD-L1 negative, the response rate was 5% or less.

Based on this signal of activity, pembrolizumab was approved in the United States for patients with chemotherapy-refractory esophagogastric adenocarcinoma whose tumor tests PD-L1 positive. That is also an option.

How would I line up these treatments in a patient who’s progressing on first- and second-line treatment, if they’re PD-L1 positive? Third line, I would probably use pembrolizumab as the approved option. If they’re PD-L1 negative, I would probably consider use of TAS-102 as the first salvage option. The MSI-high patients also factor in here as well. We might consider earlier use of immune checkpoint inhibitors in these patients. Certainly, in an MSI-high patient who’s progressing on first- and second-line treatment, checkpoint inhibitor therapy would be the first choice because we see quite high response rates; 40%, 50%, 60% of patients are responding, and many are not even achieving a median survival. The response and survival benefits are ongoing for these patients. So in patients who are MSI-high, checkpoint inhibitors would be high on the list in terms of salvage options as well.

Later Lines of Therapy in Metastatic Gastric Cancer 

In the second-line setting, we mostly use ramucirumab plus paclitaxel, so we prefer the combination over monotherapy. However, ramucirumab monotherapy still plays an important role in patients who do not want to have cytotoxic agents or in patients who have contraindications against paclitaxel or irinotecan. There’s also a group of patients for whom we try monotherapy. This group consist of patients who have very minimal metastatic disease at remission, such as small lymph nodes only, where you could try with monotherapy. In most cases, we prefer a combination of paclitaxel and ramucirumab over the ramucirumab monotherapy.

The other issue that comes up with the use of ramucirumab is that the drug did get regulatory approval by itself as a second-line treatment. The trial of ramucirumab versus best supportive care without chemotherapy was also a positive trial, indicating modest improvements in progression-free and overall survival. But ramucirumab alone really doesn’t induce responses, and it’s at best a stabilizing drug. Really, because patients in the second line are often going to be more symptomatic with an advancing disease burden, the preference would be to combine ramucirumab with an active chemotherapy drug, paclitaxel. We saw a response rate approaching 30%, which is clinically meaningful.

Ramucirumab alone achieved no greater response than placebo, although there was more disease control and disease stabilization. There would be rare, if any, circumstances in which I would give a patient ramucirumab alone. The argument is that we can give this drug to the sicker patient with poor functional status, but that’s the patient who’s not going to benefit because there’s no response. If some patients are on paclitaxel/ramucirumab and they develop cumulative taxane toxicity, neuropathy, and other issues, and they’ve shown response, we might consider ramucirumab maintenance therapy later, but that would be the exception.

Another consideration—and we’ll talk about this in the discussion of adjuvant treatment—is that the standard preoperative chemotherapy for gastric cancer now is the FLOT regimen, which is infusional 5-FU [fluorouracil], leucovorin, oxaliplatin, and docetaxel. Increasingly, patients will have had previous exposure to a taxane, so when there’s recurrence, we could argue that the patient has already seen a taxane and that combining a taxane with ramucirumab as a salvage option may not be optimal. We’re particularly concerned in patients who have disease progression within six months of receiving a perioperative or adjuvant treatment. Based on this, there was a recent clinical trial conducted in Germany. It was a randomized phase 2 trial that has only been published in abstract form, but they compared second-line treatment with paclitaxel/ramucirumab to FOLFIRI [folinic acid, fluorouracil, irinotecan] plus ramucirumab. It’s a phase 2 trial, and many of the patients on this trial had received a previous taxane as an adjuvant or neoadjuvant treatment. The trial did suggest a higher response rate for FOLFIRI/ramucirumab versus paclitaxel/ramucirumab.

Acknowledging that many patients will now be getting a taxane as part of their preoperative or adjuvant treatment, we don’t really expect that the benefit of ramucirumab is a chemotherapy-dependent one. We think it’s a biologic drug that enhances the efficacy of chemotherapy, and we don’t expect that benefit to be limited to a taxane. Based on this, the NCCN [National Comprehensive Cancer Network] guidelines have endorsed—in appropriate patients, particularly if they had recent taxane exposure or progression on a taxane—considering FOLFIRI/ramucirumab as an appropriate partner for a second-line treatment, which makes sense clinically.

In Western countries, FLOT is increasingly being used as a perioperative treatment, as well as first-line treatment. In Japan, S-1 [tegafur/gimeracil/oteracil] plus docetaxel has become the new standard treatment for stage III advanced gastric cancer as adjuvant therapy. In Asia, DOS—docetaxel, oxaliplatin, and the S-1 triplet regimen, including taxanes—is increasingly used as a perioperative chemotherapy. Please refer to the PRODIGY trial. If taxanes are already being used in previous therapy, I believe that irinotecan-based therapy should be used in the second-line setting. Of course, it is reasonable to add ramucirumab to it. It is a strategy that is already widely used in colorectal cancer.

Chemotherapy + Ramucirumab as Second-Line Therapy in mGC

Recent clinical trials have more clearly defined lines of treatment in metastatic esophagogastric cancer. We now have randomized trials clearly indicating a benefit for patients in moving on to second-line treatment after progression on first-line therapy. We had some pivotal early randomized trials indicating that after progression on fluorinated pyrimidine platinum, we see a survival benefit for patients receiving docetaxel versus best supportive care alone from British data. Japanese trials looked at allowing patients to receive either paclitaxel or irinotecan versus best supportive care, and those studies also showed a survival benefit for second-line chemotherapy.

In the second line, we have the advent of ramucirumab. That was really a game changer in the second-line treatment of metastatic esophagogastric cancer. The pivotal RAINBOW trial, in patients progressing on first-line treatment, assigned patients to paclitaxel alone weekly or paclitaxel plus ramucirumab. That trial showed unequivocal benefit with ramucirumab. There was an improvement in response rate that was clinically meaningful and improvement in progression-free and overall survival, with a median overall survival of nine months, which arguably approaches what we achieve with first-line FOLFOX [folinic acid, fluorouracil, oxaliplatin] therapy. Paclitaxel/ramucirumab is now the standard second-line therapy in esophagogastric cancer, and really should be the control arm of any future trials trying to evaluate other treatment options in the second-line setting.

We would really reserve irinotecan for third-line treatment. We’ll talk about this later, but immunotherapy drugs have shown benefit in the PD-L1–positive patients in the chemotherapy refractory setting, beyond second- or third-line treatment.

My second-line therapy of choice in metastatic gastric cancer is ramucirumab plus paclitaxel for patients who are not taxane pretreated. In Germany and in many parts of the world, taxane pretreatment is increasing because taxanes have proven to be efficient in the neoadjuvant setting or in the adjuvant setting. In the cases where patients have received a taxane, it’s important to look at how much time has passed since the last administration of taxane. In patients progressing shortly after a previous taxane, we tend to use irinotecan in the second-line treatment.

In general, the drugs used in the first-line setting are not used in the second-line setting and beyond. Most of the time, it is because patients have built up a tolerance. It is important to wait to link the second- and third-line treatments sequentially through proper timing, using effective agents. Typically, we often use second-line paclitaxel plus ramucirumab or nab-paclitaxel plus ramucirumab. We rarely ever perform ramucirumab monotherapy.

There are a number of cytotoxic agents that have shown some activity in the second-line setting in gastric cancer. These include docetaxel, paclitaxel, and irinotecan. There have been multiple randomized trials with different quality standards showing that these compounds do have activity. However, overall survival rates have been relatively short, being four to five months, with these agents. Overall, I think these agents are valuable and we do use them in different lines of the treatment. But still it’s important to highlight that addition of ramucirumab to paclitaxel is superior to paclitaxel alone, where paclitaxel is not superior to the other drugs like docetaxel and irinotecan.

Global Use of Second-Line Therapy in mGC

How do we determine that a patient is progressing on first-line treatment? Typically, we do CT [computed tomography] scan imaging every 2 to 3 months; we follow blood work, liver function studies, and blood counts; and we see the patients and assess symptoms. Certainly, trigger signs would be the development of increasing fatigue or weight loss or abdominal pain or pain at the sites of known metastatic disease. Clinical deterioration would certainly prompt us to order earlier imaging. It’s always challenging when we have a patient who’s on frontline treatment and they’re doing well symptomatically but their imaging shows progression of disease. Then we have to determine if the progression of disease is significant enough such that we would change treatment. Certainly, if we see substantial disease progression on imaging, even in the absence of symptoms, that would be a trigger to change to second-line treatment.

In addition to clinical symptoms that signal progression on first-line therapy, we have nonclinical signs that we can see. These include increasing tumor markers, for example. We often follow tumor markers CEA [carcinoembryonic antigen] and CA [carbohydrate antigen] 19-9. Even if they’re normal at onset in the newly diagnosed setting, occasionally these will start to rise over time on therapy, whether it be on full doublet chemotherapy or even on maintenance therapy.

In addition to that, we’re looking at scans and we routinely use imaging: preferably CT scans of the chest, abdomen, and pelvis every 8 weeks or so. We will obviously be looking at those. Sometimes patients are progressing on tumor markers and/or scans without having clinical progression. These would be grounds for considering changing therapy. Finally, there is the notion that we can identify progression earlier than with clinical symptoms, tumor markers, and CT scans. One day, we might be looking at ctDNA [circulating tumor DNA] analysis in the blood by next-generation sequencing. We know that we can identify this in the blood at baseline in 85% or more of patients with newly diagnosed disease.

There is a subgroup of patients who aren’t shedding DNA. Those would be patients who have low tumor burden and patients with diffuse peritoneal disease only. They don’t have high levels in the blood. The vast majority, on the other hand, will have ctDNA in the blood at baseline. Over time, we know that with therapy, most patients will have a drop in the ctDNA in the blood. It acts like a tumor marker. Over time, when they’re generating resistance, you will see that to start to rise. We see that happen several months before we would see tumor markers rise, CT scans change, or symptoms worsen.

This would be another nonclinical way of identifying progression. But at this time, we don’t really use that to change therapy because there’s not enough evidence to show that would change much. But that’s an area of investigation, and changing to a more effective therapy in the second line earlier may allow for continued control for longer. That remains to be proven as opposed to waiting for our normal clinical methods of identifying progression, which are the tumor markers, CT scans, and clinical symptoms.

The most important trigger to proceed from first-line to second-line treatment is disease progression. In gastric cancer, time to progression is unfortunately relatively short. The majority of patients experience disease progression within five months in the first-line setting. What we try to do is to be very cautious and perform MRI [magnetic resonance imaging] or CT scans to discover disease progression early and switch the treatment or change the treatment to a second-line treatment. In terms of planning the treatment or in terms of sequencing the treatment, I think that we should make a treatment plan that enable patients to receive as many lines of treatment as appropriate. We know that survival is longer when patients receive multiple lines of treatment. The scheduling is dependent on the previous therapy. Depending on the previous therapy, we plan the second-line therapy and we try to use drugs that are not completely cross-resistant to the compounds the patient has received in first-line therapy, or even in more recent settings.

Metastatic Gastric Cancer: Identifying Disease Progression

We need to consider what do we do with a patient who’s receiving upfront chemotherapy. With a regimen like capecitabine/oxaliplatin or FOLFOX [leucovorin, fluorouracil, oxaliplatin], which includes 5-FU [5-fluorouracil] and oxaliplatin, we’re limited with the continuation of the platinum agent because of the risk of sensory neuropathy. Typically, around the fourth or fifth month, if the patient is still responding to treatment or has stable disease, we would change that patient to maintenance 5-FU alone. Some would argue to switch them to capecitabine to avoid the infusional part of the treatment.

GI [gastrointestinal] oncologists have never favored observation of patients off treatment. We tend to continue treatment until disease progression. That upfront maintenance therapy would be to continue the fluorinated pyrimidine until progression, and then second-line options would come into play later. What about switch maintenance? It goes against oncologic principles. If a patient is stable or responding to a treatment, we’re not going to change that treatment. The standard of care would be to continue the maintenance therapy with infusional 5-FU or capecitabine.

The JAVELIN Gastric 100 trial was a randomized trial in which all patients got upfront fluorinated pyrimidine platinum chemotherapy, and if they were responding or had stable disease four months or so into treatment, they were then randomized to continue maintenance therapy with the fluorinated pyrimidine or switch to maintenance therapy with a biologic, avelumab. This trial was looking at superiority for the avelumab maintenance arm, and this was a negative trial. It did not show that avelumab was superior to chemotherapy. Obviously, patients would respond early on to their chemotherapy regimen, but patients do continue to show response to ongoing treatment. There was a trend toward higher response in the avelumab arm, but no significant differences in progression-free and overall survival.

As with all the immunotherapy trials, there’s a subset of patients who benefit. We often see a late benefit with immunotherapy trials, which makes the argument that we should continue to use these drugs in most patients later line and that these patients don’t benefit from earlier use of these drugs. The tail on the curve, the late benefit, really supports the current usage of these drugs, which is in PD-L1–positive patients who are chemotherapy refractory, where we will see a benefit. The exception would be the MSI [microsatellite instability]-high patients, but that was not the subject of the JAVELIN Gastric 100 study. It was really trying to identify superiority for switch maintenance with immunotherapy, and the trial failed to achieve that outcome. However, it did not show that immunotherapy was inferior: it just wasn’t better than chemotherapy. But the trial does not make the argument that earlier use of immunotherapy as a maintenance strategy should be standard.

Switch Maintenance in Gastric Cancer: Results of JAVELIN Gastric 100 

In gastric cancer, I do not think the concept of maintenance therapy has been accepted yet, unlike in colon and lung cancer. However, due to the toxicity of platinum agents such as cisplatin and oxaliplatin, it cannot be used for long periods. Fluoropyrimidine monotherapy is often used as a single agent during the first-line treatment. This will result in performing maintenance therapy. This is continuation maintenance therapy, so to speak.

In terms of switch maintenance therapy, there have been trials with IO [immunotherapy]. Both ipilimumab as a CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] antibody and avelumab as a PD-L1 [programmed death-ligand 1] antibody, tested in JAVELIN Gastric 100, have had negative results in overall survival. Maintenance strategy for advanced gastric cancer has not been established at this moment. However, theoretically, and considering the mechanism of action of IO, a maintenance strategy with IO treatment is not a wrong direction to go.

Maintenance therapy in gastric cancer is not a standard of care yet. Despite this, many experts and oncologists use a type of maintenance therapy. The decision to go for maintenance therapy is based on the individual characteristics of the patient, like a patient’s perspectives and response, etc. Many oncologists de-escalate the chemotherapy regimen from a triplet to a doublet, or from a doublet to a monotherapy, after 4, 6, or 8 cycles of treatment to reduce toxicity. However, there are no studies to show that maintenance therapy is more active than no maintenance therapy. Personally, in patients who are HER2 [human epidermal growth factor receptor 2]-positive, I like to eliminate the platinum and continue treatment with a HER2 antibody plus fluoropyrimidine after approximately 8 cycles of treatment. But there is no clear standard of care in terms of a maintenance treatment.

With respect to the issue of maintenance therapy for gastroesophageal cancer, we don’t have a lot of evidence to support this. That said, we do extrapolate from other tumor types, such as colorectal cancer, where we have the OPTIMOX studies. OPTIMOX-1 dropped oxaliplatin and continued fluoropyrimidine, intermittently adding oxaliplatin back in. The OPTIMOX-2 study initiated a complete chemotherapy holiday and then intermittently added chemotherapy back on.

We have data to show, especially in OPTIMOX-1, that by dropping oxaliplatin we can limit the buildup of cumulative neurotoxicity, which is one of the main issues, and therefore increase the longevity of using oxaliplatin over time by intermittently adding it back in. In those studies, it was added routinely in a regimented manner: 2 months on, 2 months off. In our practice, both in colorectal cancer and in gastroesophageal cancer, I stop oxaliplatin after 4 months, which is usually the time at which neuropathy is really starting to creep in. Patients then go on a fluoropyrimidine monotherapy, whether it’s IV [intravenous] or oral. I reserve the reintroduction of oxaliplatin for when there is actual RECIST [Response Evaluation Criteria in Solid Tumors] progression, tumor markers start to increase, symptoms increase, or there is a combination thereof.

I tell my patients that it can be years before we have to reintroduce oxaliplatin. On the other hand, it could be after just 2 months of being off oxaliplatin that you start to see signs that you need to start thinking about reintroducing it. The only other thing to say is that in the HER2-positive tumor type, which is about 15% of our patients with gastroesophageal adenocarcinoma, we would include trastuzumab therapy along with fluoropyrimidine as maintenance and then intermittently add the platinum agent back in.

I will say that about 50% of patients are still not able to experience reintroduction of the platinum agent in my practice, and that’s because they still have residual neuropathy that we don’t want to push. At that point, we would switch to second-line therapy, but there are a number of patients who you can reintroduce oxaliplatin in and regain control for a period and not use up later lines of therapy.

Gastric Cancer: Global Perspectives on Maintenance Therapy 

Now, the advent of immunotherapy is complicating the discussion of first-line treatment in gastric cancer. We have approval in the West for pembrolizumab, the anti–PD-1 [programmed cell death protein 1] drug. In Japan, there is approval for nivolumab, an anti–PD-1 drug. Both of these approvals are in the refractory disease setting. We’ll talk about later-line therapy, but in the first-line setting, we have results from the KEYNOTE-062 trial, which was a trial in patients who were PD-L1 [programmed death-ligand 1] positive at 1% or higher. It was a head-to-head comparison of chemotherapy alone, fluorinated pyrimidine platinum chemotherapy plus pembrolizumab, or pembrolizumab alone. What we saw from this study comparing chemotherapy with or without pembrolizumab is that there was no meaningful difference in combining an immunotherapy drug up front with chemotherapy compared to chemotherapy alone. There was a slightly higher response rate, but no meaningful differences in progression-free and overall survival [OS], really arguing against the combination of an immunotherapy drug with first-line chemotherapy.

Interestingly, between chemotherapy alone versus chemotherapy plus immunotherapy, there was no difference in terms of CPS [combined positive score] or PD-L1 score. If you look at the 1%, or the 10% or higher patients, there was still no benefit in adding immunotherapy to chemotherapy up front compared to chemotherapy alone. The exception would be patients who are MSI [microsatellite instability]-high. That was a very small percentage of patients on KEYNOTE-062: it was only about 6% or 7% of patients. But in those patients, the checkpoint inhibitor may have behaved better than chemotherapy as first-line treatment. There were higher response rates, more durable response, and median survival wasn’t even reached.

The exception in first-line treatment would be the possibility of using drugs like pembrolizumab for MSI-high patients. These patients have exceptionally high response rates and a durable response. On that trial, there was also evaluation in MSI-high patients of immunotherapy plus chemotherapy, and it didn’t seem that chemotherapy added benefit to immunotherapy. I think the exception would be MSI-high patients.

Now, we have to remember that sometimes when our patients with advanced metastatic disease walk in the door, we don’t have results back from mismatch-repair studies or MSI status or genomic profiling. My suspicion would be that these patients would start with chemotherapy, and then if we detected that they’re mismatch-repair deficient or MSI-high, we consider transitioning them to immunotherapy. It’s not clear whether combining chemotherapy with immunotherapy is any better than immunotherapy alone. In the first-line setting, immunotherapy can be considered for the MSI-high patients. Knowing that when they walk in the door we won’t have results of that testing, we would often start them on chemotherapy and then consider earlier-line use of immunotherapy drugs.

As you know, the KEYNOTE-062 trial demonstrated noninferiority of overall survival in pembrolizumab monotherapy compared to standard chemotherapy for the CPS 1 or higher cohort. In addition, the forest plots in subgroup analysis for OS show clear benefit in Asia in contrast to the West. The trend is more pronounced in patients with a CPS of 10 or higher. Furthermore, the MSI-high population, which occurs only 5% of the time in advanced recurrent gastric cancer, has a clear benefit from IO [immunotherapy]. When IO is used as a first-line therapy, MSI-high is the most promising biomarker in the case of a single-agent IO. CPS 1 or higher—especially CPS 10 and above—are also promising biomarkers.

In the second-line setting, specifically with respect to MSI-high patients, immunotherapy, of course, is the standard option if they’ve not had exposure to immunotherapy earlier. Another subgroup of patients may benefit based on the KEYNOTE-061 study, which was a randomized study of paclitaxel or pembrolizumab, open label. In a subgroup analysis, it appeared that in addition to MSI-high tumors, patients with higher levels of PD-L1 expression—a CPS score of 10 or higher, specifically—seemed to derive a benefit. In other subgroup analyses of other studies, such as KEYNOTE-062, this was not the same. There was a yin-yang effect, even in the CPS 10 or higher group, in the KEYNOTE-062 study comparing pembrolizumab monotherapy to a chemotherapy arm.

Whether CPS 10 is the optimal cutoff is yet to be determined. These have all been retrospective unplanned analyses in small subgroups that are subject to a lot of random variation. In one study, we see benefit; in another study, we don’t. But I think that the general trend that we consistently see is that, after excluding MSI-high tumors—so among the MSS [microsatellite stable] patients—the higher the level of CPS score, the higher the probability that a patient will benefit. It’s not guaranteed that they will benefit at a very high level of CPS, CPS 9 for example, but they have a really good chance. The lower the level, the lower the chance of benefit, to the point where if you’re less than CPS 1, you have a very low chance, if any, of deriving benefit.

It’s more of a linear parameter. We like to think in a binary fashion of yes/no or positive/negative, where we have to make cutoffs; but ultimately, that’s going to be subject to false negatives and false positives at any cutoff level. Whether CPS 10 is the optimal cutoff, or an even higher CPS score, is yet to be determined. But I think that one day we will, in addition to MSI-high tumors, be offering monotherapy checkpoint blockade to this optimal subgroup that we can define: if not as second-line or first-line therapy, at some point early in their disease course. I think that will be best for those subgroups of patients.

Is Frontline IO Therapy Appropriate in Gastric Cancer?

Metastatic Gastric Cancer: Factors in Selecting Frontline Therapy

What cytotoxic regimen do I use for the first-line treatment of metastatic gastric and G [gastroesophageal]-junction cancer? Generally, the go-to regimen is a doublet chemotherapy with fluoropyrimidine and platinum. The preferred platinum is oxaliplatin, so FOLFOX [folinic acid, fluorouracil, and oxaliplatin] chemotherapy is the general go-to first-line chemotherapy for our patients.

As a first-line regimen in the treatment of gastric cancer, we usually use a doublet consisting of oxaliplatin and fluoropyrimidine, either capecitabine or 5-FU [fluorouracil] or S-1 [tegafur, gimeracil, oteracil]. We sometimes use cisplatin, but in most patients, we would prefer doublets of oxaliplatin and fluoropyrimidine, like XELOX [capecitabine and oxaliplatin] or FOLFOX. In some patients, however, we also use triplets: most often FLOT, which is 5-FU, leucovorin, oxaliplatin, and docetaxel. I would say that we only use triplets in young, fit patients requiring intensive treatment. Approximately 20% of our patients would receive a triplet, but the majority of patients are treated with a doublet.

We in Japan, and many other Asian countries, commonly use fluoropyrimidine plus platinum doublet therapy as the standard of care first-line treatment for advanced gastric cancer. On the other hand, in addition to doublets, triplet regimens such as FLOT [fluorouracil, leucovorin, oxaliplatin, docetaxel] or DCF [docetaxel, cisplatin, fluorouracil] are often considered as the standard of care first-line treatment in Western countries.

Furthermore, Asian GI [gastrointestinal] oncologists, including Japanese oncologists, prefer oral fluoropyrimidine agents, such as S-1 or capecitabine. SOX [tegafur, gimeracil, oteracil plus oxaliplatin], CAPOX [capecitabine and oxaliplatin], S-1, or capecitabine plus cisplatin regimens are widely used. Of course, FOLFOX is frequently administered in poor oral intake cases or peritoneally disseminated patients, which is very prevalent in advanced gastric cancer.  

Why are there such different treatment approaches between Asia and the West? In Asia, especially in Japan, it is common for gastric cancer to be treated sequentially: first, second, third, and fourth line, and so on. However, in Europe and the United States, patients often end up on second-line therapy at most.

In terms of molecular testing, we test all patients in the first-line setting for HER2 [human epidermal growth factor receptor 2] overexpression. HER2 is the most established biomarker in gastric cancer, so every patient will be tested for HER2. In terms of other biomarkers, like MSI [microsatellite instability] or PD-L [programmed cell death-ligand] score, these biomarkers are tested later in the course of treatment in most cases, prior to second-line or third-line therapy. We also use NGS [next-generation sequencing], but not prior to first-line therapy. Currently, NGS is done later in the course of the treatment.

Daniel V. Catenacci, MD, University of Chicago

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