Daniel Catenacci, MD

The treatment landscape for gastric cancer is evolving. The use of biomarkers and implementation of testing to improve outcome later on in the course of treatment are being more important. Daniel Catenucci, MD, a

Chicago, IL discussed this topic during a virtual Targeted Oncology Case-Based Roundtable event. 

This has been a very dynamic time [in gastric cancer] with a lot of new changes with data that have come up.

 I think the most important factor—although we consider all the biologic testing—is going to be performance status and goals of the patient when you’re in the palliative setting. With that being said, molecular testing is extremely important for the management of metastatic gastric cancer. We’re going to be checking things like HER2 status, microsatellite instability [MSI], PD-L1 expression with a combined positive score [CPS]. We’re also looking for other things like 

 fusions. I like to send a complete next-generation sequencing [NGS] panel if I can, to get all this information, because there may be other trials like an FGFR inhibitor trial or something similar that may open up opportunities. But at a bare minimum, I would say HER2, MSI, and PD-L1, for sure.

 I think you stated it right. The bare minimum would be, these days, MSI testing, PD-L1 testing, and HER2 testing. Then, if you’re getting in a panel, whether it’s a tumor-based NGS panel or a circulating tumor DNA [ctDNA] panel, you’re inherently going to get a lot of other things including pan-tumor approvals like 

 fusion and other things now emerging like 

 Those molecular testing variables that were talked about is what we order. We are looking at PD-L1 based on CheckMate 649 [NCT02872116]. The dose levels become even more important. We look at DNA mismatch repair, HER2, and 

. These are some of the main molecular markers that we are looking for. The PD-L1 is going to be important because if they have a proficient MMR and are HER2 negative, then based on CheckMate 649, we are going to be looking at chemotherapy and immunotherapy. That’s a paradigm shift that we are looking at. I have a few patients right now—there’s 1 squamous cell carcinoma and 2 adenocarcinoma cases and they’re all starting out with chemotherapy and immunotherapy in combination. With 1 of them, there has been some pushback from the insurances. But those are the molecular markers that are really important to inform how we choose the next regimen for patients.

CATENACCI: What are you getting pushback on right now from insurance?

CHOWDHARY: For the patients with adenocarcinoma, not as much, but I have a patient who had squamous [cell histology] stage IV esophageal cancer. I wanted to use pembrolizumab [Keytruda] plus a platinum therapy drug. I had to do a peer-to-peer [consultation] and the physician on the other line said the patient’s PD-L1 is only 1% or 2%. He was giving me a lot of pushback and I was very surprised by that. I was telling him that we have data with pembrolizumab based on KEYNOTE-590 [NCT03189719]. We have very clear data now that regardless of PD-L1 level...[but] espicially if they have expression of 1% or higher, pembrolizumab with chemotherapy is a very important regimen now.¹ But I’m still in the appeal process. That patient started cycle 1 today with FOLFOX [folinic acid, fluorouracil, oxaliplatin]. I explained to him today that I’m still in the appeal process of trying to get pembrolizumab with cycle 2.

 It’s a bit outside the scope of gastric cancer but still in the realm here in terms of KEYNOTE-590, which was more so in esophageal cancer. What are your thoughts on a new diagnosis of adenocarcinoma, stage IV with CPS of 1? What are you doing for those patients these days?

[I have] run into similar issues. We’d like to give the pembrolizumab with chemotherapy, but sometimes we are limited and they make us wait until second line to give the pembrolizumab, which we’re anxious to give in the first line. So a lot of times I’ll do FOLFOX for about 8 cycles until they have neuropathy and then I’ll consider them intolerant to oxaliplatin and move to the pembrolizumab quickly.

CATENACCI: What are you doing for first-line treatment in patients just given diagnoses who are MSI high?

 I usually try to use pembrolizumab first line. Although, technically, the FDA approval is for at least the second line. I suspect that it’s going to be like colorectal cancer, where we’re going to want to use it first line versus chemotherapy, but until we have those data, sometimes we’re stuck. As long as we’re talking about MSI high, [I will] also mention that tumor mutational burden [TMB] is another factor that we’ll look for on the NGS panel due to the recent pan-approval for TMB-high patients.

 For patients with adenocarcinoma, I have used FLOT [fluorouracil, leucovorin, oxaliplatin, and docetaxel] a couple of times in very healthy patients in the stage IV setting. But I was wondering whether that’s some-thing that you [all] have ever considered using. FOLFOX has been my go-to for most of them, but I wanted to get your thoughts on that as well.

If I have a really young patient and they have good performance status, I’ll offer FLOT to them with the understanding that it really hasn’t been tested in this specific situation—particularly if I need a response. But the majority of our patients have poorer performance status and are older. In that case, when I’m in the palliative setting, I’m thinking more about quality of life. FLOT can be a pretty tough regimen for people. I’m pretty judicious with whom I give it to.

KEYNOTE-590 was a study that enrolled patients with esophageal squamous cell carcinoma, esophageal adenocarcinoma, and gastroesophageal junction [GEJ] adenocarcinoma,

 as opposed to CheckMate 649, which was gastric adenocarcinoma, GEJ adenocarcinoma, and esophageal adenocarcinoma but no squamous cell disease.

 So there was overlap in those studies with GEJ and esophageal cancer; those patients were eligible for either study. Both of those studies, KEYNOTE-590 and CheckMate 649, overlap in their eligibility.

Their primary end point was in all-comers, not by PD-L1 score. But if you look at the subgroup analysis, the benefit appears to be in patients with PD-L1 CPS of 10 or higher. In the National Comprehensive Cancer Network [NCCN] guidelines, [both] are now currently listed for esophageal adenocarcinoma and squamous cell histology [if the PD-L1 CPS] is 10 or higher with chemotherapy for now.

 ...The NCCN guideline recommendations are CPS of 5 or higher for gastroesophageal for nivolumab in adenocarcinoma, and 10 or higher for esophageal cancers that are adenocarcinoma or squamous cell carcinoma.

[Editor's note: The FDA has approved nivolumab combined with chemotherapy for patients with metastatic gastric cancer and esophageal adenocarcinoma as of April 16, 2021.⁴ Keeping pembrolizumab's accelerated approval was voted against by the FDA's Oncologic Drugs Advisory Committee for patients with PD-L1–positive recurrent or advanced gastric or GEJ adenocarcinoma who had received 2 or more lines of therapy, but the FDA decision has not been made yet.⁵]

CATENACCI: Based on that, does anyone have a strong opinion as to whether PD-L1 should be tested at all? Should we be giving it to everybody? Or does anyone have the other opinion that we should be really stringent and make it a CPS of 10 instead of 5?

I think CheckMate 649 is a game changer. I’m interested to see whether the FDA is going to make CPS 1 versus 5. I envision a lot more people being able to get pembrolizumab with chemotherapy first line. Most of us will use FOLFOX first line anyway, so I think it’s a nice pairing. I’m anxious to see whether we’re going to have to go by CPS at all, whether they’ll make us do CPS of 5.

I agree with everything that’s been said already. I test everybody. Ideally, I would like to give [immunotherapy] to everybody up front. But for right now, I’m just using the CPS cutoff of 5 or higher. I’m showing people data when I try to get insurance approval, and the NCCN guidelines. So at least if it’s an NCCN [recommendation], I won’t get insurance pushback right now.

 If CPS is above 5, I think you’ll be fine. It’s the ones less than 5 that I think you’re going to get push-back on like Dr Chowdhary was saying. When and where do you get PD-L1 testing done?

 For all of my metastatic patients, I send NGS on, whether it’s FoundationOne or Tempus. I send it up front. But our pathologist will add it on if we ask to test the tumor itself. If there’s enough specimen, they’ll test it on the tumor. Otherwise, we’ll revert to ctDNA. But I try to get all the information up front.

CATENACCI: Anyone else have their pathologists doing PD-L1 internally for them? Or is everyone relying on an outside vendor, like FoundationOne or Tempus?

I do a lot of in-house NGS panels. I think we have everything important included in our panel. We have a faster turnover, so if I need results fast I would do in-house. If I can start people on first line and wait for other options down the line, I’d probably send for FoundationOne or Tempus.

Let’s clarify all of this first, because PD-L1 testing is not going to be given to you in an NGS panel. It’s the chemistry with various antibodies. Nivolumab is paired with one and pembrolizumab is paired with a different one. They have different properties, and they have different cutoffs for what’s positive. That’s where the question comes from [regarding whether we] are relying on our pathologists to give that to us or we are clicking the box on the Tempus form and asking for NGS and the PD-L1 results.

Basically, when I’m doing testing, I do both together. If I do in-house, I’ll do both in-house. If I send out, I’ll send both out. Sometimes I need it immediately. If I really need to know the results to put orders and get insurance approval, I may turn to our pathologists for help.

KOZLOFF: Do you do it in-house or do you send it to Tempus?

 That’s a good question. Essentially, if there’s a test that’s internal, like HER2, we do it internally because it’s reflexive and it’s standardized. They’re using kits that are FDA approved and companion diagnostics for HER2. These newer PD-L1 antibodies and scoring systems are very specific with specific platforms. There are many studies that show if you tinker with it and you’re doing your internal laboratory-developed tests, you can get different results. For example, we don’t have the [PD-L1 immuno-histochemistry] 22C3 [pharmDx kit using the] Dako platform from Merck to do that assay [at my institution]. So they have antibodies to score “PD-L1” but I don’t know what that means in terms of its validation. This was not what was studied prospectively in these phase 3 trials.

To answer your question, we send it out until we can get that panel properly done internally. Now the other complicating factor is that the CheckMate 649 study with nivolumab has a different antibody and a different platform. We expect a different companion diagnostic approval from the FDA for that one. The incidents of CPS 5 or higher in the study was 60% of the patients. But when we do CPS 5 or higher with the Merck antibody test with pembrolizumab, it’s about 30% of the patients.

We’re not sure which ones to use, so this is becoming a little messy in a way. But for now, we’re using the 22C3 antibody [test], because that’s what we’ve been using all these years. This is the first time now that the Bristol Myers Squibb nivolumab assay is coming on the scene. The next months are going to be interesting [regarding] how that interplays.

The Mayo Clinic in-house testing does this for us. I don’t really have to make the decision too much. They figure it out and do it, so we do an in-house one, usually.

 If I use FOLFOX in the first-line setting, I usually scan after every 4 cycles, just knowing that the progression-free survival isn’t that long. I’m also going by patients’ symptoms. Sometimes changes in the tumors are harder to anticipate, especially if we’re using checkpoint inhibitors. We have to worry about pseudoprogression. So I’m going by their symptoms; if tumors look a little bigger but patients are doing great and feeling great and I have them on immunotherapy, I might continue that in the first line and make sure it’s to progression instead of pseudo-progression. My main triggers are going to be the scans and how they’re feeling. We’ve all treated these patients where it’s obvious when they’re progressing because they’re feeling crummy. That’s typically a sign to get a scan and move onto the next line.

My [triggers are] pretty similar in that sense. Definitely symptoms because most of these patients at least are usually symptomatic up front. Usually with using FOLFOX, we’re seeing them frequently, so we have a chance to check for toxicities. But immediately after the first cycle, we usually have a nurse practitioner who checks in on them. That’s where telehealth has been a bit more helpful, where we’re able to check in on them for toxicities, especially early on.

Similarly, I usually scan after about 3 to 4 cycles and use that to assess disease progression. To change to second-line therapy, definitely [once we see] both symptoms and then radiographical progression because the more we’re going into further lines of therapy, the less effective and the less likely we’re going to have an impact. I try to keep that first-line therapy going and, with small changes, I’ll give it a bit longer—maybe do some short interval imaging to make sure before I would switch to second line, especially if their symptoms are well controlled.

Essentially [we look at] symptoms and do x-ray study or CT scan as needed. I generally don’t do every 3 or 4 weeks. I just go by symptoms.

 I use cancer antigen, but in gastric cancer it’s not as useful as, say, colon cancer. But I still use it.

 I follow the tumor markers, but I don’t make decisions on the tumor markers. The decision I may make is to get a scan earlier on the tumor marker.

Only about half of patients go on to next line [of] therapy with this disease. Despite knowing that there are options that have improved survival advantages, patients aren’t getting there. One of the thoughts is that some patients may be on therapy too long and you’re waiting too long to make the switch. That’s one concept. Many times, patient scans don’t show overt progression, but they’re progressing. Because they may have peritoneal-only disease, as an example. You’re not picking it up on the scan, but they’re progressing.

Many of you said symptoms are important too. I use tumor markers. I use carcinoembryonic antigen and cancer antigen 19-9. I check them, at minimum, once a month, because very often those are going up long before any changes in symptoms or scans. I tend to do a scan every 2 months on my patients generally with FOLFOX. Four doses, then scan and reassess them. But if I’m seeing the tumor markers skyrocketing, I might scan them after 3 [weeks] to pick it up early and switch so that you don’t miss your window before they fall off [with therapy] because then you can’t treat them anymore. That’s how we deal with it to try and get as many patients on to effective later-line therapies. There are more now that we just don’t use enough, I think.

Kato K, Shah MA, Enzinger PC, et al. LBA8_PR - Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: The phase 3 KEYNOTE-590 study. 

. 2020;31(suppl 4):S1142-S1215. doi:10.1016/annonc/annonc325

2. NCCN. Clinical Practice Guidelines in Oncology. Gastric cancer, version 2.2021. Accessed March 17, 2021. https://bit.ly/3qXLusW

3. Tabernero J, Alsina M, Shitara K, et al. Health-related quality of life associated with trifluridine/tipiracil in heavily pretreated metastatic gastric cancer: results from TAGS. 

. 2020;23(4):689-698. doi:10.1007/s10120-020-01053-9

4. Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. 

. 2018;4(5):e180013. doi:10.1001/jamaoncol.2018.0013

5. Moehler M, Shitara K, Garrido M, et al. Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): first results of the CheckMate 649 study. 

. 2020;31(suppl 4):S1191. doi:10.1016/j.annonc.2020.08.2296

6. Satoh T, Xu RH, Chung HC, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN--a randomized, phase III study. 

. 2014;32(19):2039-2049. doi:10.1200/JCO.2013.53.6136

Articles

The treatment landscape for gastric cancer is evolving. The use of biomarkers and implementation of testing to improve outcome later on in the course of treatment are being more important.

Roundtable Discussion: Catenacci Compares Frontline Treatment for Patients With Gastric Cancer

Evaluation of a Patient With Gastric Cancer

Considerations for Therapy in Gastric Cancer

Second-Line Treatment Options in Gastric Cancer

Beyond Second-Line Therapy in Gastric Cancer

HER2-Positive Gastric Cancer

Understanding the DESTINY-Gastric01 Trial

Case: A 71-Year-Old Man With HER2+ Gastric Cancer

A 71-year-old man complained of a 3-month history of abdominal pain and bloating, a sensation of fullness

PMH: HTN, medically controlled; colonoscopy at age 53 was unremarkable; no family history of cancer

PE: patient appeared tired, abdominal distention; otherwise unremarkable



Labs: Hb 9.7 g/dL, plt 111 x 109/L; other lab values WNL

Upper endoscopy with biopsy: showed an ulcerative lesion 5.8 cm mass in the cardia of the stomach; biopsy confirmed gastric adenocarcinoma

CT of chest/abdomen/pelvis confirmed a 5.8 cm lesion with indistinct margins in the cardia of the stomach; 2 suspicious hepatic lesions

EUS: gastric cancer lesion confirmed invasion of the muscularis propria

Stage IV gastric adenocarcinoma; ECOG 2



He was started on XELOX/CAPOX + trastuzumab

Dose reduced due to grade 2 diarrhea; unable to control after 4 cycles; discontinued treatment

After 24-months of treatment without progression of disease pembrolizumab was discontinued

The patient was started on trastuzumab deruxtecan; repeat HER2 expression testing was not indicated

Videos

Daniel Catenacci, MD, reviews the case of a 71-year-old man with gastric cancer.

A 71-Year-Old Man with Gastric Cancer

 There is a novel agent called trastuzumab deruxtecan, which has been approved in breast cancer also in late-line [therapy]. This is an antibody-drug conjugate [ADC] that was studied there as trastuzumab backbone with irinotecan analogue conjugate, and it was also studiedin gastroesophageal cancer in the DESTINY-Gastric01 study.

This study was done solely in Asia, and it was a randomized phase 2 study. And the makeup of the patients were very late lines. About half of the patients were third line, and half were fourth line or higher.

To see third-line patients is only around 30% of our practice; fourth-line is about 10% of our practice, and so on. The question of whether these patients represent what we see more commonly is unknown. That said, this study, the primary end point was response rate, and secondary end points were survival and progression-free survival. This was a randomized study to physician’s choice of chemotherapy versus trastuzumab deruxtecan. And the response rate was clearly better in the trastuzumab deruxtecan arm after central review of responses. The final response rate was in the mid-40% range, which is good in the third-line or higher setting.

Progression-free survival and the overall survival were also clearly better compared to the control arm of chemotherapy alone. This study led to approval in Japan already, and is being done now in Western populations in separate studies. The DESTINY-Gastric02 trial, which has already completed accrual, is a single-arm phase 2 study in Western populations in the second-line setting. And importantly, that study required rebiopsy at the time of starting second-line therapy to confirm persistent 

 amplification. That’s an important selection criteria. It’s going to help to enrich those who are most likely to benefit.

The mechanism of action of trastuzumab deruxtecan, as an antibody-drug conjugate, is to deliver this novel cytotoxic agent to cells harboring trastuzumab expression. Now there have been other ADCs around that we’re familiar with, like T-DM1 [trastuzumab emtansine], but this is a different linker that links the antibody to the drug, and it’s a different drug. Even though T-DM1 did not work well in this disease, that possibly at least contributed to the fact that we weren’t requiring a repeat biopsy to select for persistent HER2 positivity, but also because this is a different agent that’s conjugated to the trastuzumab.

In addition, there is some discussion, and some early data with small sample sets, that suggest that this trastuzumab deruxtecan molecule can even result in an effect in patients who have low levels of 

 with amplification. That’s through a so-called bystander affect, where the drug is delivered to an area where there’s low-level 

 expression, and then it can diffuse to regional areas and have cell kill.

Whether that will bear fruit, we’ll need to see in larger sample sets. But clearly the drug is effective in 

 highly amplified tumors in breast cancer, and there’s this phase 2 study in the randomized setting, in the third-line setting or higher in Japan, that has shown a signal there.

There’s also a DESTINY-Gastric04 study, which is a global randomized phase 2 study in the second-line setting with a control arm of paclitaxel and ramucirumab versus trastuzumab deruxtecan. That will be the pivotal study to confirm its role here in HER2-positive patients.

My personal experience with the drug, I did have the drug here as part of the DESTINY-Gastric02 study. We caught the tail end of that study, and we had a few screen failures of patients who were really sick and just couldn’t get on to the study before disease progression; and 1 patient did enroll.

That’s a good segue to the tolerability of the drug. It is a targeted therapy, so to speak, but it is also a chemotherapy that’s conjugated to it. If you look at the toxicity profile, it had a higher grade toxicity—grade 1, 2, and 3 or higher—than the control arm of chemotherapy alone.

There is a toxicity that is specific to this drug that is pneumonitis or interstitial lung disease [ILD], where about 10% of patients had any grade of ILD. And about a quarter of those were grade 3 or higher.

In the gastric studies, there have not been any grade 5 deaths from the drug, but in other studies in breast and in colon cancer there have been. This is a known, well recognized toxicity of the drug, and we have to pay attention to that.

In the third-line setting or higher, where classically response rates have been 10% or so, and as you get into later lines even lower, this agent would be a welcome addition to the arsenal we have, and counterbalance with the toxicity. But when you weigh the pros and cons in that setting, this drug will be welcome there.

On the other hand, moving it earlier into second-line and first-line therapy, where we have effective agents that don’t have these toxicity profiles, we need to see some head-to-head data to weigh the pros and cons and know what we’re getting into before moving forward with it.

In summary, we’ve talked about both the HER2-positive space and the HER2-negative space, which essentially, as a standard of care after first line, is similar, but we are now starting to see anti-HER2 therapies beyond progression, and assessment there. It’ll be interesting to see what these larger studies show and whether this becomes warranted.

The other thing to note is that immunotherapy is a common topic at this point in all cancers, including this one. What we’ve learned over the last several years with a number of studies, 10 or more phase 3 studies, is that immunotherapy can work very well in MSI [microsatellite instability]-high tumors, and that in patients who have PD-L1 scores that are 10 or higher at least, as monotherapy, it could be considered, especially if patients have low burden of disease, not very symptomatic, good performance status. That’s where you would want to do that.

But also we’ve now learned from ESMO [the European Society for Medical Oncology annual meeting], the first time we’ve seen chemotherapy plus immunotherapy, particularly in PD-L1–negative tumors, where what is being seen, even though the data have not fully been presented, are that patients that have higher PD-L1 scores are the ones who derive the most benefit. That’s where we expect the approval to be, in the CPS [combined positive score] of 5 or higher in the first-line setting.

Dr Catenacci discusses the DESTINY-Gastric01 study, including personal experience using trastuzumab deruxtecan.

 What is the utility of anti-HER2 therapy beyond progression in the first line? This comes on the back of anti-HER2 therapies being evaluated in breast cancer through later lines, which of course a number of studies have shown a benefit with even trastuzumab beyond first progression, lapatinib, T-DM1 [trastuzumab emtansine], etc. Even pertuzumab in the first-line setting, in addition to trastuzumab, and perioperative approaches. Breast cancer has had a lot of success with continued and altering of manners of inhibiting HER2.

On the other hand, unfortunately in gastroesophageal cancer, the first study, ToGA, did show a benefit, but a number of second-line studies and first-line studies have been negative. In the first-line setting, lapatinib plus chemotherapy was not shown to be better than chemotherapy alone for HER2-positive tumors in the LOGiC study.

Pertuzumab, added to chemotherapy plus trastuzumab, was not better than chemotherapy plus trastuzumab, although it trended, it was not statistically significant, and it’s not an improved indication for pertuzumab in the JACOB study. In the second-line setting we’ve had a number of studies beyond progression anti-HER2 therapy. The first was the TyTAN study, which was paclitaxel with or without lapatinib, which was a negative study, as well as the GATSBY study, which was T-DM1 versus taxane in the second-line setting, which was also negative.

We’ve also had a smaller phase 2 study that was randomizing to chemotherapy with or without trastuzumab beyond progression, and that study did not show benefit.

What we’ve learned though since those studies were done, and even during those studies, is that the mechanism of resistance to trastuzumab in the first-line setting for gastroesophageal cancer tends to be different than in breast cancer. In breast cancer, there are mechanisms that lead to resistance while the patient retains 

 amplification in their tumor cells, and signaling for HER2 is still dependent.

On the other hand, in gastroesophageal cancer, or at least a subgroup of them, there is evolution of the disease that is no longer HER2-dependent, it is no longer 

 amplified. If you rebiopsy the disease that’s progressing, it is HER2-negative if you do immunohistochemistry and FISH [fluorescence in situ hybridization] testing. The reason for that is because the biology of the cancer is different, and it’s heterogenous even within the patient. They have the same founder mutations and tumor suppressors, 

, etc, but then they have branched evolution, where only a subset of the disease is 

 amplified, while other components of the patient’s cancer are not.

When you treat with HER2 therapy in the first-line setting you can control those 

amplified clones, but the HER2-negative clones blossom and become the new burden of disease.

In all of the second-line studies that were done, it was assumed that a patient’s tumor was still 

 amplified because it was before first-line therapy, and that is at least partially responsible for why they have likely failed because up to half of the patients enrolled weren’t having HER2-positive disease.

The question of whether selecting patients for continued anti-HER2 therapy beyond first progression, if their cancer is still HER2 dependent, if is there a benefit from any of these anti-HER2 therapies, remains an open question.

Dr Catenacci highlights clinical trials in HER2-positive gastric cancer that may provide insight on differences in mechanism of resistance from one tumor type to another.

 After second-line therapy, we would follow similar principles in terms of when to switch from second to third line, even more so now there’s an even larger drop-off in clinical trials and databases in terms of what percentage of patients get to third-line therapy, where it’s less than 30% of patients. Going to fourth-line therapy, probably 10% or less will get to that point, and maybe 1% of our patients, those extreme outliers, will get to fifth line or higher.

What do we decide, and what are we doing at the time in third line after these patients that we’ve discussed, these 2 hypothetical patients who have received pembrolizumab, if they’re MSI [microsatellite instability]-high, and then started a general tract therapy of FOLFOX [folinic acid, fluorouracil and oxaliplatin] with paclitaxel, ramucirumab? Or in the HER2-positive setting of a patient who had FOLFOX [folinic acid, fluorouracil and oxaliplatin] with trastuzumab, then paclitaxel with ramucirumab. Now they’re progressing on their respective therapies, what would we do in the third line?

There are a number of standard approaches. The first and classic one would be to use whichever chemotherapy was remaining of the taxane or irinotecan, whichever one had not been used yet. Typically platinum in first line; 1 of the 2, irinotecan or taxane in the second line; and then the reverse in third line. That has always been a benchmark option there. The response rate there is not very good. It has a lot of room for improvement, but it’s a benchmark to compare to, and it’s about a response rate of 10%.

We also know that trifluridine, tipiracil, or Lonsurf, is an option based on the TAGS phase 3 study, which randomized patients in the third-line setting or higher, a global study, and showed a survival benefit with that agent. So that’s a known option as well in third line or fourth line if you were sequencing all of the regimens we just mentioned.

And then finally, based on the KEYNOTE-59 study, we know that pembrolizumab is an option for patients who have a combined positivity score [CPS] of PD-L1 of 1 or higher. That has been shown to be an incidence of around 60% of patients will have that score. And there’s certainly a known benefit to enriching with PD-L1–positive tumors. The response rates of PD-L1–positive tumors with that cutoff is around 13% for microsatellite stable tumors in the third-line setting or higher. It’s less than 5% for PD-L1–negative patients, and therefore it was not approved.

We also recognize that the higher the level of PD-L1, the better, and the more likely a patient will respond to immunotherapy checkpoint inhibitors that are monotherapy, especially. We have some choices in the third line that would be considered standard.

I would choose one of those chemotherapy versions for the most part, certainly for PD-L–negative tumors. But for PD-L1–positive tumors, we have the added option of pembrolizumab. And if they haven’t had immunotherapy earlier in their sequence course, then it could be considered here.

The reason why is because although the current standards are as I just mentioned, FOLFOX [folinic acid, fluorouracil and oxaliplatin] with trastuzumab for HER2-positive tumors in first line, or FOLFOX [folinic acid, fluorouracil and oxaliplatin] for HER2-negative tumors, there’s been a lot of activity in the first-line setting of this disease with a number of phase 3 studies evaluating FOLFOX [folinic acid, fluorouracil and oxaliplatin] chemotherapy plus a targeted agent. The CHECKMATE 649 study, which I had mentioned earlier, was FOLFOX [folinic acid, fluorouracil and oxaliplatin] plus nivolumab versus FOLFOX [folinic acid, fluorouracil and oxaliplatin] alone, an open-label study, a phase 3 study that the primary end point was for patients with a PD-L1 score of 5 or higher. That study showed a clear survival benefit and progression-free survival on response rate improvement, with toxicity. Grade 3/4 toxicity increased around 15%.

We expect this will become our new standard option in the first-line setting for a CPS of 5 or higher for all gastroesophageal adenocarcinomas. That’s a matter of time, and at the time of doing this presentation that has not occurred. But within the next several months, we do expect that to happen. Patients who have already received it in first line would not be indicated to continue it into later lines of therapy, say a third line where it had been previously been approved, except for those patients who have a PD-L1 score of 1 to 5, where typically they won’t be eligible in the first line, at least that’s anticipated. So in the third-line setting, after failing FOLFOX [folinic acid, fluorouracil and oxaliplatin] chemotherapy, then chemotherapy plus ramucirumab in the third-line or higher setting with a PD-L1 score of 1 to 5, one could consider doing that at that point, especially if the patient doesn’t have a heavy burden of disease, a maintained performance status, and not heavy symptoms because immunotherapy won’t work there no matter the PD-L1 score, especially if it’s really low level.

Daniel Catenacci, MD, discusses treatment options after second-line therapy, highlighting options for patients who are PD-L1 positive.

 The change to second-line therapy is an important one, and it’s one that’s often discussed because only around 40% to 50% of all patients actually get second-line therapy in the databases in this country, and also globally in large studies. Part of that is due to the aggressiveness of the disease no doubt, where patients are getting treated, and even if they have a response, they can get rapid progression and decline quite rapidly. Even when you’re paying attention, you can miss your window of switching to next-line therapy.

I strategize when the patient is first diagnosed and profile the patient’s tumor, so that you know what you’re going to do in each line of therapy and plan it out. As a standard of care, what are the sequences that you’re going to use? We always tell the patients as well of course that there are a number of factors that go into what’s going to trigger a change to next-line therapy. Those include how you’re feeling and how you’re doing. And if there’s truly a toxicity that we just cannot manage, and/or there’s progression of the cancer in that setting, then clearly you would switch to another line of therapy.

In addition to how one’s feeling from a cancer-related standpoint, and symptom-wise, and also tolerability, we are always closely tracking tumor markers. We followed CEA [carcinoembryonic antigen] and the CA [cancer antigen] 19-9 tumor markers. They often are what’s going up earliest, and heralding a progression even before you see it on scans or with patients’ symptoms. And that’s preparing us to not do another scan 3 months later, because that’s when you’re going to miss your chance and miss your opportunity to switch. There you would be doing no more than a 2-month scan, and sometimes there I’ll do a 6-week scan after 3 cycles of a FOLFOX [folinic acid, fluorouracil, oxaliplatin]-based therapy to not miss your chance.

Of course, we look at CT scans, but many times patients have peritoneal disease that’s difficult to follow on scans. And it’s more of a sense of how a patient is doing, how the tumor markers are doing, and evaluating that in the absence of many changes on the CT scan, so that you don’t miss your chance to change to the next active therapy.

Daniel Catenacci, MD, examines factors that help decide when to switch treatment from first to second line, and when to change mechanism of action in treating gastric carcinoma.