Emerging Therapies in HER 2-Positive Metastatic Breast Cancer - Episode 11
Ian E. Krop, MD, PhD: One of the toxicities of trastuzumab deruxtecan that was seen in both the phase I and DESTINY-Breast01 trials was ILD [interstitial lung disease], or pneumonitis. This was identified as an important toxicity and can be severe. Because of that, we have looked at what are the predictors of ILD in patients with HER2-positive advanced breast cancer? A couple of characteristics stood out in an analysis. One was the dose. Doses of trastuzumab deruxtecan higher than the now-recommended phase II dose of 5.4 mg/kg were associated with higher rates of interstitial lung disease, which is 1 of the main reasons why the dose of 5.4 mg/kg was selected to move forward. Patients from Japan seemed to have a higher rate of pneumonitis, or ILD, and that’s actually been seen with a number of other drugs as well, so I don’t think that was that unexpected.
There did also seem to be a strong trend for those patients who were heavily pretreated, with 10 or more prior lines of therapy, having higher rates of ILD. While these risk factors are certainly helpful, it is important to recognize that even patients who don’t have these risk factors still have the possibility of developing ILD or pneumonitis. It’s important, therefore, to be cognizant of that. Experts in ILD have recommended that patients be followed closely for the symptoms of ILD, which include dyspnea, cough, and fever; and that if they have those symptoms and ILD is suspected, that further evaluation is done, which includes high-resolution computed tomography [CT] scans, consultation with a pulmonary specialist, and that the trastuzumab deruxtecan be stopped and corticosteroids be started promptly.
Sarah A. Hurvitz, MD: The ILD issue is something that we have to pay close attention to. As discussed, there are a lot of parameters in place to help us catch this early, effectively manage this, and not allow it to progress to grade 3, 4, or 5 toxicity. This may have been a showstopper for an ordinary drug that’s demonstrated an objective response rate of 15% to 20% in a phase I or single-arm phase II study.
But this is a population of patients who have heavily pretreated—a huge area of unmet need—aggressive HER2-positive metastatic breast cancer, many of whom have visceral disease, some of whom had CNS [central nervous system] metastases. To see a response rate of over 60%, to see a progression-free survival well over a year, close to a year and a half, is truly extraordinary. I think this is going to lead many of us to feel comfortable with it becoming available, hopefully, to our patients soon as the standard of care, as long as the phase III clinical trials are run and conducted to help us better define how to detect and manage the development of ILD in some patients.
Ian E. Krop, MD, PhD: Whenever we make decisions regarding treatment of patients, we have to weigh the risk and benefit. In patients who have metastatic HER2-positive breast cancer, especially those who have cancers that have progressed on standard therapies, such as trastuzumab, pertuzumab, and T-DM1 [trastuzumab emtansine], it’s important to note that this is an incurable disease. The current standard options have relatively limited efficacy. The data from the DESTINY-Breast01 study would suggest that the efficacy of trastuzumab deruxtecan is substantially better than the current options for such patients. While trastuzumab deruxtecan does have several potential toxicities, which include generally manageable hematologic and GI [gastrointestinal] toxicity but also this important risk of pneumonitis or ILD, compared with the very encouraging efficacy profile, to me, it’s very clear that the benefits outweigh the risks for this patient population.
Transcript Edited for Clarity
Editor’s Note: This interview took place prior to the FDA approval on December 20, 2019 of fam-trastuzumab deruxtecan-nxki for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received ≥2 prior anti—HER2-based regimens in the metastatic setting.