Best practices for preventing and managing treatment-related adverse events associated with systemic therapies used to treat HER2-positive metastatic breast cancer.
Lisa A. Carey, MD, FASCO: That brings us to another issue that is germane for all of these, which is toxicity. V.K., as we play this out, what are your perceptions about how to integrate toxicity issues, safety management, and patient preferences in this arena?
Vijayakrishna Gadi, MD, PhD: I’ll start by saying I’ve been lucky enough to give all of these agents to patients in studies and as they’ve been approved. Having said that, these are all very recent approvals, so my total N [number of patients] for any 1 drug or agent is low, and I think that’s probably a true statement for most of us. Picking things like patient selection, age, what they’ve previously seen, what they’ve been intolerant to in the past, and so forth, matters. Some of these drugs come with other drugs, like capecitabine, and you must take that into consideration in terms of tolerance.
When I think about the major issues, the toxicities with these new drugs come down to 2 or 3 organ systems: the GI [gastrointestinal] tract, the lungs, and the skin and other tissues, for EGFR-mediated toxicities. For the GI tract, I think diarrhea is a big one that we worry about, and of the agents, neratinib might be considered the biggest offender. A lot of our experience, of course, comes from the adjuvant setting. I for one have gotten experienced with it. I do the dose escalation to get to the target dose.
Lisa A. Carey, MD, FASCO: The CONTROL trial taught us all, didn’t it?
Vijayakrishna Gadi, MD, PhD: Yes. That, I think, has helped inform how we can use this drug more effectively, and I’m migrating those same practices to the patients who have metastatic disease. So far, I’m seeing success in terms of getting the drug moved up.
Lisa A. Carey, MD, FASCO: Before you move on, V.K., I think that’s an important point for treating oncologists. The CONTROL trial escalated a half dose of neratinib up to a full dose over just a couple of weeks. Is that what you do?
Vijayakrishna Gadi, MD, PhD: Yes, that’s what I do. Typically, it’s 3 pills, then 4 pills, then 6 pills—they skip 5 for some reason. It takes anywhere from 3 to 4 weeks to get there, and most people seem to do well with that strategy. It’s something I’m finding myself doing with other drugs as well, but that can be a discussion for another day.
The other toxicities—again a lot of these drugs have capecitabine associated with them as a partnering agent. With capecitabine you have the conventional hand-foot syndrome and liver toxicities. Interestingly, if you look carefully, for example, at the HER2CLIMB data, patients are not only on tucatinib longer because it works, but they’re on the capecitabine longer because it works with the combination. When you’re on a drug 30% longer, like capecitabine, you’re going to see toxicities accumulate over time. Most of these trials had a very fixed way of giving the capecitabine, for example, 2 weeks on the medication, 1 week off. As you all probably do, that’s another dose that we can escalate, we can deescalate, we can do 1 week on, 1 week off, and there’s a lot of variability to how we can give the drug to make it tolerable. I find that, in general, for diarrhea and the rash, we’re pretty good at managing those.
The toxicity that hangs out there, and I’m learning more from my community colleagues, is the pneumonitis issues. For years these colleagues of ours have been treating pneumonitis with the checkpoint inhibitors and with lung cancer TKIs [tyrosine kinase inhibitors]. The call is here now; it’s on our doorstep with trastuzumab deruxtecan. Obviously, the trial showed that some patients died from this pneumonitis in some scenarios. We still don’t know why or who gets this, and we don’t have many patient stratification factors available to us. I get the sense that most of the serious adverse events related to pneumonitis were early in the study, and as we learned, we got better at identifying and stopping it. Now we have ways to mitigate, treat, and understand this, and we’re doing a better job. It will be interesting to see what this looks like in the phase 3 study.
Having said that, we are now in the COVID-19 world. I don’t know if somebody has had COVID-19 and had some low-level lung injury and developed chronic manifestations of COVID-19, I don’t know how they’re going to do on this drug. Even though we don’t have the data and I’m not going to be scared to prescribe it, it’s still in the back of my brain. I think with that drug, it’s still a little harder because it’s not settled out like some of the other toxicities with some of the other agents.
I’ll yield the floor to others. I’m still learning about this. Anybody else have thoughts on those toxicities?
Reshma Mahtani, DO: Yes. I would add that even though we have guidelines that obviously lay out this plan of how to sequence these therapies, it’s difficult, in my mind, to have a prescriptive approach of how to do this. I think we know that shared decision-making is an important factor, and what’s important to one patient, whether it’s IV [intravenous] vs oral therapy, or the frequency of follow-up and monitoring, all this factors in. I’ve had similar experiences with the HER2CLIMB regimen, of issues with diarrhea and hand-foot disease, and looking to modify the capecitabine dose as the first drug that we dose reduce. Most patients have done well with dose modifications. I haven’t had anyone who’s had to come off.
I share the concern that everybody has, about the ILD [interstitial lung disease], pneumonitis issue with trastuzumab deruxtecan. But I think we’re doing a lot to try to characterize that adverse effect and understand how to institute steroids early, dose hold or delay treatment, and decide whether to rechallenge based on the time it takes for the symptoms to resolve. I think a lot of this has helped us handle the adverse effects better, and to be aware and educate our patients on the importance of letting us know of any new symptoms.
Lee S. Schwartzberg, MD, FACP: Yes. I have a couple of things to add. I have had great success, mostly in the adjuvant setting, with starting at low doses with neratinib and working up, as opposed to adding additional antidiarrheal drugs, which as we know, are just antimotility drugs and aren’t fun for the patients to alternate constipation and diarrhea. So that works. But we don’t need to do that, at least I haven’t needed to do that,with using the HER2CLIMB regimen with tucatinib, starting at full dose and then, as both V.K. and Reshma said, adjusting first the capecitabine dose—because most of us tend to use a lower capecitabine dose anyway in the community setting. It’s easy to modify, and I haven’t had to stop anyone, or in my experience, reduce the dose of tucatinib to date.
The other point about not only COVID-19, but the other concern specific to breast cancer, is that we frequently see lymphangitic spread in the lung, and it can be difficult, in my experience, to determine low-grade ILD vs interstitial disease. That’s another concern when you’re thinking about which drug to pick.
Lisa A. Carey, MD, FASCO: That’s a good point. You mentioned something interesting. The CONTROL trial, as everybody knows, had a bunch of interventions, and some were layering all these antidiarrheal things, and dose escalation was the last arm. They all work to some degree, but dose escalation was the most effective. For the other ones, of course, you’re adding a bunch of drugs. I think most of us said, “I’m going to do that dose escalation.”
Reshma Mahtani, DO: One thing I’m curious about, in terms of experience for all of you with the dose escalation, is have you found that fewer patients are able to get up to the 6 tablets per day? Since I’ve employed that dose escalation strategy, I find that patients start to get to 4 or 5 tablets, and then they can’t get to 6. As opposed to how we used to do it, where we would add a lot of antidiarrheals up front, and then I had the experience that more patients were able to maintain 6-tablet dosing. Have any of you seen that?
Vijayakrishna Gadi, MD, PhD: I personally have been able to get to 6, but again, that’s in the adjuvant setting.
Reshma Mahtani, DO: Yes.
Vijayakrishna Gadi, MD, PhD: I haven’t had that experience in the metastatic setting.
Lee S. Schwartzberg, MD, FACP: Those patients tend to be highly motivated to do everything to reduce their chance of coming back. My experience has been like V.K.’s.
Transcript Edited for Clarity