Ian E. Krop, MD, PhD: At the 2019 San Antonio Breast Cancer Symposium we had the results of 3 different trials of novel agents in HER2-positive metastatic breast cancer. One of those trials was the DESTINY-Breast01 study, which evaluated a novel antibody-drug conjugate called trastuzumab deruxtecan. This was a conjugate that had several distinctive features over other currently used conjugates. Some of the most important points of trastuzumab deruxtecan are that it uses a topoisomerase I inhibitor payload.
This is a type of chemotherapy that’s not typically used in HER2-positive breast cancer, so there’s less potential likelihood that cancers will be resistant to this class of agent. There are 8 payload molecules per antibody, which is a higher drug-to-antibody ratio than is typically used in conjugates. Perhaps this drug can deliver more payload than other conjugates. And the payload is membrane permeable, which means it can defuse out of the target cell and kill neighboring cells regardless of their HER2 expression.
Based on those distinctive features, there was anticipation that perhaps this drug would have efficacy when other drugs had stopped working. There actually was a phase I trial that did demonstrate a response rate of almost 60% in patients who previously received T-DM1. So the DESTINY-Breast01 trial was designed to confirm the results of trastuzumab deruxtecan seen in the phase I study. The DESTINY-Breast01 study enrolled roughly 184 patients with centrally confirmed HER2-positive advanced breast cancer, all of whom had received T-DM1 [trastuzumab emtansine]. But there actually was no limit on the number of prior lines of therapy for this study. And in the treated population, the median number of prior lines of therapy in the metastatic setting was 6. This was a very heavily pretreated population.
Patients with stable, treated brain metastases also were allowed on the trial. The primary objective of the study was confirmed objective response rate by an independent review commission. And that primary end point of confirmed response in this study was 60.9%: 6% were complete responses, 55% were partial responses. So this was a very active drug. The clinical benefit rate at 6 months was 76%. And the median duration of response was over 14 months. Not only did the drug work in a large majority of patients, but the responses were durable. That’s reflected in the median progression-free survival, which was 16.4 months.
I think people felt that overall, this type of efficacy was substantially greater than what was expected or what’s been seen with other studies in this third- or later-line setting. In the past, historical data would suggest that studies have shown median progression-free survival is around 5 or 6 months with response rates of 20% or less. This did seem like a substantial increase in what was seen compared with historical control. But this was a single-arm study, so there was no built-in comparator. That’s an important caveat.
In terms of adverse effects of trastuzumab deruxtecan, as was seen in the phase I study, fatigue, nausea, and vomiting were common. They were almost all low grade. Neutropenia was also seen in about 35% of patients. But febrile neutropenia was very rare. And alopecia was seen in about half the patients.
One toxicity or risk of trastuzumab deruxtecan that was seen in the phase I study was also seen in the DESTINY-Breast01 study as well, and this was interstitial lung disease [ILD], or pneumonitis. This was seen in 13.6% of patients. The vast majority of those events were mild and reversible, but unfortunately 4 patients in the trial, or 2.2%, had fatal ILD or pneumonitis that was felt to be related to the drug. Clearly this is a risk of trastuzumab deruxtecan. And it is recommended—for patients being treated with trastuzumab deruxtecan—going forward that they be monitored closely for symptoms of ILD, which include dyspnea, cough, and fever. If ILD is suspected, the drug should be held or discontinued and corticosteroids are started promptly.
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.