Sequencing After Progression on IO-Based Therapy for mGC

Daniel Catenacci, MD: That may be a good transition point to getting to the next lines of therapy and what we’re looking for in terms of when we feel like the first therapies failed and when it’s time to switch. What are the symptoms? What are the signs? What are we looking for [for] us to make that choice?

Sam Klempner, MD: Yes. It’s an important teaching point that sometimes we see a lot of this disease has just a little bit larger reference to understand some of the early progression that may not be already appreciated radiographically. Certainly, clinical symptoms, early satiety, dysphasia, abdominal bloating that maybe suggestive of the development of ascites, are the classical things. Fatigue, nausea, et cetera, things that would be related to changes in the primary. It’s relatively rare that pulmonary metastasis or small liver metastasis produce any clinical symptoms, but all are always concerning for that peritoneal disease at the porta hepatis. But then we still rely on radiographic tools as the primary assessor. Some patients have good tumor markers and that’s an important aspect. We try to draw CA [carbohydrate antigen] and CA 19-9 and follow if they’re elevated. They can be a relatively early marker. I’ll ask you the same question. In a research setting, rising levels of circulating tumor DNA [ctDNA] may also ultimately fit into this paradigm, but we don’t have high-level evidence for that quite yet. Let’s take that same patient who now has definitively progressed and you’re moving beyond first-line setting, how are you thinking about second-line triggers and both agents in the setting of more patients getting frontline chemotherapy and IO [immunotherapy]?

Daniel Catenacci, MD: I agree with you. I don’t have much to add. I say this to the patient when I’m making a decision whether a therapy is working or not. I’m looking at you and how you’re doing. Are you tolerating therapy or you are having worse symptoms that are cancer-related? I’m looking at tumor markers and ctDNA and I’m looking at scans. Sometimes it’s not clear, and as you point out it does take some investigation—paying attention and seeing patients more frequently. A real problem might be that we’re missing the opportunity to switch to the next line. It’s worth noting that only about half of patients in the country get to second-line therapy. Part of that is unavoidable even when we’re paying attention, the disease just progresses so rapidly that you can’t change, you are not well enough to get to the next line. But that speaks to the fact that you can be doing scans every 3 months and not seeing them for long periods of time and really making that assessment, so that when you start to see that progression—when you smell that—it’s time to switch type of thing. That’s how I practice. In terms of what I switch to classically, until recently especially, it would be paclitaxel/ramucirumab [Cyramza] or FOLFIRI [folinic acid, fluorouracil, and irinotecan]/ramucirumab as you and I contributed to that understanding that you could make that switch. And then you have a choice based on comorbidities and other toxicities, which might work better for the patient. For example, previous neuropathy from oxaliplatin and avoiding paclitaxel, using irinotecan which is not neurotoxic. The only other point to say is if we’re on the HER2 path, that we also know that now with trastuzumab [Herceptin]/irinotecan being approved in second-line or higher, that continuation of anti-HER2 therapy of some sort, whether it’s that, or as many of us have already been doing, continuing trastuzumab and switching the chemotherapy, would probably be how I would approach persistently HER2-positive tumor at the time of progression. How about you?

Sam Klempner, MD: We approach it the same way, that IO [immunotherapy] is not going to dramatically impact this in the short-term, and that an evidence-based approach is still paclitaxel and ramucirumab after progression on FOLFOX [folinic acid, fluorouracil, and oxaliplatin] and nivo [nivolumab (Opdivo)] There may even be some mechanistic rationale as to why that may have a better efficacy. I’ll just comment briefly on some retrospective data from Asia and in the United States. Again, it comes back to what chemotherapy and IO may be doing and we may be decreasing these negative features like T regulatory cells and tumor-associated macrophages that may predispose the post-IO patient to a VEGF [vascular endothelial growth factor] inhibitor. That remains to be seen and there are some studies that will test that prospectively but it’s at least 2 separate pieces of evidence. I know that there’s some analysis of post-frontline therapy in KEYNOTE-062 may even shed a little bit more light on whether pac/ram [paclitaxel/ramucirumab] was more active. Although it’s hard to do those analysis unplanned.

Daniel Catenacci, MD: Right. I can’t see how it would be worse to not give pac/ram after that. Like you suggest, if anything, there’s some suggestion that patients that had preceding immunotherapy do better by getting pac/ram than those who didn’t have the immunotherapy first. That’s the standard benchmark with which to compare to at this point. At least that’s my opinion. Are there any patients that you use monotherapy ramucirumab based on regard?

Sam Klempner, MD: I honestly can’t think of the last patient that I did that.

Daniel Catenacci, MD: Me neither. It’s always preferred to do it with chemotherapy. I guess maybe patients who can get chemotherapy but could get that, but it’s uncommon.

Sam Klempner, MD: It’s very uncommon. Honestly, although the data from the TAGS trial is real. I also have relatively infrequently used Lonsurf [trifluridine/tipiracil] as a later line agent. But that’s also because we have the luxury of availability of other options. It is an option.

Daniel Catenacci, MD: Right. Are there any biomarkers? There aren’t any real biomarkers to predict benefit from anti-angiogenesis, that’s been a holy grail of biomarker work for 20 years. There’s some leads but never really anything definitive, right?

Sam Klempner, MD: Yes. Not that I’m aware of. People have looked at various circulating angiogenesis-associated factors, even finding one and then ultimately translating it to the clinic is another story. But yes, I’m not aware of any reliable robust biomarkers for that setting. Maybe since we’re talking about later line settings we can talk about, what do you do, let’s say someone has progressed after that pac/ram and you’re looking in the third-line space, and particularly, what do we do now that the FDA [Food and Drug Administration] has removed the label for pembrolizumab [Keytruda] in the CPS [combined positive score]-positive patients?

Daniel Catenacci, MD: Yes. I mentioned my preferred second-line is FOLFIRI [folinic acid, fluorouracil, and irinotecan]/ram [ramucirumab]. If it’s my patient and they’ve gone through FOLFOX/nivo or FOLFOX and then FOLFIRI/ram, then I would consider taxane, which would still be an effective option at that point. There are studies evaluating chemotherapy plus ram beyond progression after second-line ram and ram in third-line, but that’s a study that’s ongoing. I wouldn’t do that off-label at this point. The other option you already mentioned was trifluridine and tipiracil, the other oral chemotherapy agent based on the randomized phase 3 TAGS study. And then the other only option had been pembrolizumab for CPS1 or higher tumors but as you point out, it’s been reviewed by and it was recommended to be removed. Not to mention, most, if not all, of these patients that are PD-L1 at least 5 or higher, are going to be getting it in first-line. For me, in my practice, the patients who should be exposed to immunotherapy would already have been and those that hadn’t been exposed, those the less than 1 or 0, there is a reason why they weren’t exposed and clinical trials are always recommended. There might be an argument for rechecking if they’re a 0 or less than 5, they’ve not had a PD-L1 inhibitor, and if it was positive, one could consider trying to get nivo vs for first-line. If they’re a HER2-positive patient and didn’t get trastuzumab in first-line, you might try to get it for later if you found out later they were HER2 positive. Something like that. Overall, that the third-line setting, only about 30% of patients get to third-line, and always clinical trials should be encouraged and emphasized at that point.

Sam Klempner, MD: Yes. I don’t have much to add there. There’s this weird window period where there’s going to be some patients who have been on FOLFOX frontline, never got IO, and maybe that’s someone to be considered in this period while frontline IO is uptaking.

TRANSCRIPT EDITED FOR CLARITY