Erika Hamilton, MD, on T-DXd for Metastatic Breast Cancer: Clinical Considerations

Following ASCO 2022, we are increasingly seeing trastuzumab deruxtecan being used in earlier settings, specifically with DESTINY-Breast03, trastuzumab deruxtecan beating T-DM1 head to head in the second line, HER2-positive metastatic setting. We've learned some practical tips in how to manage this drug over the past several years. Certainly, we saw in DESTINY-Breast03 that nausea, vomiting, as well as alopecia or hair loss was more common with trastuzumab deruxtecan than it was with T-DM1, and really fatigue was quite similar between the arms of T-DM1 and trastuzumab deruxtecan. It's important to note that in DESTINY-Breast03, there were no mandatory prophylactic antiemetics and this really was recommended and acknowledged that trastuzumab deruxtecan is moderately emetogenic partway through the study. And so now, in subsequent trials with trastuzumab deruxtecan, there are in fact prophylactic antiemetics specifically what's recommended and what's now included in the label. And I think what many of us, at least, in the United States are doing is a three drug antiemetic regimen, so this is a 5HT3 dexamethasone, as well as an NK1 antiemetic. So with this, I really think that we are cutting down the rates of nausea and particularly cutting down any more severe nausea that really gets in the way of how our patients feel. It's also important to note that in the safety analysis, we saw that the nausea really peaks in early cycles and stays about study throughout the entire treatment duration. And what we know from trastuzumab deruxtecan, is that patients really can be on this treatment for quite some time. So I really keep the antiemetics on board as well. Certainly if someone's having no nausea, we can think about peeling them back. If they're still struggling with nausea, we can add something on, but I typically do start with that three drug antiemetic regimen. Additionally, the alopecia, I think initially with trastuzumab deruxtecan was a little bit surprising. Some of our other antibody drug conjugates, such as TDM one, we don't see as much alopecia. So I think it's important when speaking to our patients that a, we make sure that they know upfront that they can see alopecia. With antibody drug conjugates, unfortunately, we don't think that cold capping or a lot of the hair preservation techniques are really as effective as they are with more shorter half life chemotherapy. Certainly the half life of antibody drug conjugates are longer. And therefore things like cryotherapy for neuropathy, which is not a prominent symptom of this particular antibody, drug conjugate, or alopecia with the antibody drug conjugates. It's harder to do the cold capping or the cryotherapy and really make a difference in what we're seeing for our patients in terms of hair loss. Finally, I think one other side effect that we've been very closely following is ILD or pneumonitis. And that was based on the initial study, Destiny-Breast01, showing some cases of fatal pneumonitis with treatment with trastuzumab deruxtecan. I think this all gave us a little bit pause, particularly as we're removing it into the earlier line settings, but now with Destiny-Breast03 and more education around this and recommendations of what to do, would we've been able to completely eliminate grade four and grade five ILD pneumonitis and even grade three, ILD pneumonitis and Destiny-Breast03 is only 0.8%. So less than 1%. Really again, reminding that the recommendations here are to permanently discontinue trastuzumab deruxtecan for any grade two pneumonitis or greater. And even with grade one pneumonitis, which is asymptomatic pneumonitis found only incidentally on a screening scan, et cetera, we would recommend holding the drug and if it resolves restarting within four weeks. So with those increased recommendations, educating our patients, that pneumonitis ILD is a possible side effect and holding if we see any. Again, we've been able to make sure that these patients are now doing well, certainly with no grade four, grade five and grade three, less than 1%. I think we all feel much more comfortable moving this drug into the earlier lines of therapy. So this will not be the last we'll see of clinical trials reporting results with trastuzumab deruxtecan certainly trastuzumab deruxtecan is in first line metastatic evaluations versus a current standard of care, as well as neoadjuvant treatment and even adjuvant treatment for residual disease and a so called Katherine indication, going head to head with TDM one and that space as well. So it's very important. What we've learned from trastuzumab deruxtecan, educating our patients about the ILD possibility educating them about the alopecia. So that's not a surprise and really, us, as providers doing a better job, making sure that prophylactic antiemetics are on board from the beginning to make sure that nausea is as manageable as possible for our patients.