Frontline Therapy for Metastatic PD-L1–, HER2+ Gastric Cancer

Daniel Catenacci, MD: We’ve talked a lot about HER2 positive, CPS [combined positive score] PD-L1 positive, and now we’re alluding to other markers. What is the standard of care for HER2 negative for those who believe in PD-L1 low negative tumor? What are we currently recommending? What do you do in that situation for these patients?

Sam Klempner, MD: Sometimes we have patients who come in and may drive. I’ve come to patients several times and I don’t regret it, but in that situation, a HER2-positive patient [who is] PD-L1 negative, the standard remains 5FU [5-fluorouracil] and oxaliplatin with no checkpoint inhibitor. You can make an argument for that based on the [CheckMate] 649 data we discussed for gastric and GE [gastroesophageal] junction adenocarcinomas.

Daniel Catenacci, MD: I agree. I’ve tried to fight that battle too, but it’s, as you mentioned, going against the grain and the media, but all we can do is relay the information and have patients and families make a decision with us so at least it’s an informed decision. If they know the data, what I find is that in that case then no, I won’t do that. I don’t want to take a toxicity risk if I don’t have any chance of benefit. As I alluded to earlier is that we would prefer to try and find another way to help them and whether it’s on a study or whatever preferably, or through the genetic profiling to find other options for them that have even more suggestion that they could drive benefit like you mentioned with EGFR amplification. I’ve lost that discussion a few times, but at least it’s off my chest and then they’re making a decision as opposed to not knowing that information. They should know, at least I would imagine.

Sam Klempner, MD: There are some tweaks to the data that we’re all comfortable with and I’ll make a comment specifically about the chemotherapy backbones. CIS [carcinoma in situ] and 5FU have been the global backbone for a lot of these trials, particularly the pembro [pembrolizumab (Keytruda)] studies and cisplatin and 5FU is certainly a global standard. But it’s transitioning definitely in Western countries, but even in Asian centers as well, to be 5FU and oxaliplatin. I don’t know about you, but I’m perfectly comfortable extrapolating a CIS [cisplatin]-5FU pembro data onto a 5FU-oxaliplatin backbone.

Daniel Catenacci, MD: Totally. Thankfully like the NCCN [National Cancer Comprehensive Network] guidelines and even FDA [Food and Drug Administration] overlooked the KEYNOTE-590, for example, which was CIS-5FU pembro and allowed either, or. That’s testament finally that oxaliplatin is considered a global standard and that it’s all of our preferred treatments. I haven’t met one oncologist who prefers cisplatin over oxaliplatin. It’s just more toxic and causes more problems than anything so I’m glad to hear that. How about triplet versus doublet? That’s a whole argument. I was going to say for me, that very akin to the arguments in colon cancer with the FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, and irinotecan] tribe stuff, that’s come out. I would use a triplet therapy in a select population of patients who I feel when they first get present. Like we’re talking about right now, HER2-negative tumors that have a heavy burden of disease. They have multiple symptoms. That’s the one that’s pretty desperate for our response. I might add in a third drug in that setting. My preferred is FOLFIRINOX [folinic acid, fluorouracil, irinotecan, and oxaliplatin] that’s standard more classic choice would be to add a taxane there with DCF [docetaxel, cisplatin, and 5-fluorouracil] or DOF [docetaxel, oxaliplatin, and 5‐fluorouracil] or FLOT [docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil]. I just find FOLFIRINOX is better tolerated, but that’s one indication I might consider. But for most patients, my preferred start is with FOLFOX [folinic acid, fluorouracil, and oxaliplatin].

Sam Klempner, MD: I agree, that’s consistent with the guidelines. It’s the backbone and control arm for the majority of our phase 3 trials. I agree that the data from Dr. Park’s FOLFIRINOX phase 2 [trial] is encouraging. We do see some improvements in response rates when you pound down more drugs, but it doesn’t always translate to harder clinical end point changes. I agree we both have the luxury of working in centers where we have multidisciplinary teams and a lot of ancillary support services. In young patients where we may be even considering surgical approaches aggressively, maybe those are the patients we might consider triplet therapies but outside of that, and ideally on study, I agree, little data to support a triplet over a doublet.

Daniel Catenacci, MD: I’ll also just add my plugin here about dropping the 5FU bolus. At least at our center, we’ve done that for most of our GI [gastrointestinal] cancers in the metastatic palliative setting. We find that it just adds more toxicity so it would be called modified FOLFOX-7 instead of modified FOLFOX-6 by just dropping out the bolus. It just becomes a much better tolerated approach. Of course, that’s part of the modified FOLFIRINOX, which is what I meant when I said FOLFIRINOX. I wouldn’t give them the classic parent FOLFIRINOX, and we genotype the irinotecan which makes it more tolerable. I agree with that. What’s your strategy now once you start your chemotherapy in terms of the so-called maintenance approach? Do you continue FOLFOX indefinitely? Are you dropping it, are you doing OPTIMOX say from colorectal space and extrapolating here? What’s your general approach there?

Sam Klempner, MD: I try to be internally consistent with this approach, but I have to say I’m not always that way. I do prefer an arbitrary 4-month period of 5-FU and oxaliplatin together and then if patients are not progressing, I have low threshold to drop the oxaliplatin. I do add it back if there’s not an explosion of their disease. This is where judgment and experience managing this patient population comes into play. Some patients can’t pick up progression relatively early from symptoms and radiographically and [in] those patients I don’t feel concerns about adding back oxaliplatin and seeing what happens. In the patient who’s developing multi-focal progression on 5-FU, it’s unlikely that oxali [oxaliplatin] is probably going to salvage that, although, it’s unreasonable to try. I’ve taken more of the approach of a predefined duration of FOLFOX as the backbone. Taking it one step further and I’ll ask your opinion too, now that the standard may be FOLFOX/nivo [nivolumab (Opdivo)] for some of the patients, in the same setting I envision my practice will be to continue the 5-FU with the nivo [nivolumab] in the backbone. It may be a mistake to stop chemotherapy entirely and continue nivo, which there’s a risk that that trend may happen in practice. I hope that it doesn’t.

Daniel Catenacci, MD: Yes. No, I agree with you wholeheartedly. Also, it’s very akin to say 5-FU/trastuzumab [Herceptin] maintenance after the platinum is dropped. I cringe sometimes too when I see just the trastuzumab alone without the chemotherapy part because that the chemotherapy, the 5-FU does help many of those patients stay controlled for longer. The same concept here, right. For me, it would be for patients above CPS [combined positive score] with 5 that are getting FOLFOX/nivo that then would go to 5-FU/nivo. The few patients that I might drop the 5-FU as well might be MSI-high [microsatellite instability high] tumors that are the ones who can have really remarkable outcomes and dramatic benefit. To the point where you can start peeling off the chemotherapy quickly and if they’re doing well then probably the immunotherapy is going to be enough. But most patients, I agree, they’re going to need the 5-FU there to bolster the control for longer.

Sam Klempner, MD: Yes.

Daniel Catenacci, MD: Right. The only other thing I would say is that occasionally I do build in complete chemotherapy holidays when patients are doing really, really well for 5 or 6 weeks, exactly like OPTIMOX and OPTIMOX2.

TRANSCRIPT EDITED FOR CLARITY