Johanna C. Bendell, MD: Let’s talk a little bit. Yelena, what’s your approach to the first-line treatment in terms of a choice of metastatic regimen? We’re going to talk a little bit about sequencing. Now we’re metastatic, so we’re not in a curative setting. So, we’re looking at first-line metastatic regimens. And tell me your thoughts in HER2-negative, then in HER2-positive disease—does that change where you’re going?

Yelena Y. Janjigian, MD: Absolutely. So, to Ian’s point, I think if the patient recurs within 6 months of receiving a 3-drug combination therapy, it’s a therapeutic challenge no matter what you said to do, and this patient’s disease is chemotherapy-refractory. And so, with that, we will put these patients in a separate therapeutic challenge, and I will focus on patients right now who present with de novo metastatic disease, which in the United States is a substantial percentage of our patients. I would say in my clinic, probably 50%, if not more, present with stage 4 disease at diagnosis. In the patient who is otherwise asymptomatic and has a relatively low-volume disease, for HER2-negative disease, I tend to prefer a 2-drug combination. And, again, to your point, it’s a marathon, it’s not a sprint, and the majority of these patients continue to work full time; they feel well. And, in fact, you probably saw, at the plenary session, Ethan Bash’s data presenting that with careful symptom management, tertiary nursing care, and early intervention, you can really get these patients through chemotherapy unscathed in terms of discontinuing therapy or dose reducing before they develop neuropathy, preventing need for growth-factor support with dose reductions and so on. So, the majority of the patients do well on that regimen.

For the HER2-positive patients, really the standard has become trastuzumab-based therapy, generally in combination with 5-FU and platinum chemotherapy. And, again, in my hands, oxaliplatin is better tolerated than cisplatin, and, generally, that’s what we prefer. For HER2-negative space, RAINFALL data will be coming out for the first-line use of VEGFR2 inhibition with ramucirumab. And, again, no one has really formally presented it, but it looks like it may be an option for us in the first-line setting.

When it comes to the second-line setting, what it comes down to is a combination of patient symptoms. That’s when it’s important to have the molecular signatures on hand and not rush through getting unstained slides, submitting things. It would be useful to start it in the first-line setting, so when the patient comes to second-line—particularly in an MSI patient—absolutely pembrolizumab should be done in standard practice setting. For HER2-positive patients, it’s a real challenge because—and these are data I presented a year ago, and now others from Asia observed the same—loss of HER2 expression and amplification occurs in up to 20% of these cases. Not only that, now more in-detail analysis shows that they’re activating other RTK pathways, so it’s no longer a simple HER2 tumor, but they acquire KRAS mutations, MET amplifications, and so on.

So, for the HER2 space, second-line is uncharted territory. T-DM1, unfortunately, did not show improvement in outcome compared to Taxol, and we really don’t have a HER2 agent in second-line that’s standard right now. And so, that’s where we are. For the majority of the patients in second-line therapy, outside of clinical trials and for MSS patients, paclitaxel and ramucirumab remain the standard. It will be impacted by the FLOT-4 data. To give my 2 cents, I don’t think use of paclitaxel- and docetaxel-resistant tumors should be recommended.

Johanna C. Bendell, MD: I’m going to tighten you down. What fluorouracil and platinum regimen do you use, and do you use an epirubicin?

Yelena Y. Janjigian, MD: We recently put out a consensus statement with the folks at MD Anderson, University of Chicago, and other academic centers across the United States in JCO saying that epirubicin should not be used in metastatic setting. So, epirubicin is out. First of all, it’s impossible to add biologic agents to 3-drug combinations. As for which fluoropyrimidines I use, in short, FOLFOX is the easiest—modified FOLFOX-6 is what you use. Capecitabine is also a good option, particularly for patients who don’t want to carry the pump and don’t want to carry a Mediport. But, generally, if I use that in a frail and a more immune-compromised patient, it’s capecitabine, 7 days on/7 days off, with oxaliplatin every other week. It’s not the XELOX-type of regimen, because those are still quite tough to use. I’ve attempted to use cisplatin, 80 mg/m², as part of several trials, and it’s not for the weakhearted. You get 3 hours of mannitol, you get renal insufficiencies in people with normal creatinine at baseline. These are fit 60- to 70-year-olds. Their kidneys have been through a lot, so I would not recommend it.

Johanna C. Bendell, MD: As you alluded to, one of the things that’s causing a little bit of a stir is the RAINFALL study saying in a press release that it’s met its primary endpoint, which is progression-free survival. It wasn’t overall survival, it was progression-free survival.

Yelena Y. Janjigian, MD: Right.

Johanna C. Bendell, MD: But, certainly, the suggestion is, are first-line therapies going to change sometime in the near future to add ramucirumab yet? But I think a lot of it still remains up in the air.

Transcript Edited for Clarity