Commentary
Trastuzumab deruxtecan is an antibody drug conjugate that consists of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase 1 inhibitor. This antibody drug conjugate is unique compared with prior antibody drug conjugates such as trastuzumab emtansine in that it has a high drug-to-antibody ratio (~8). Furthermore, there appears to be a unique bystander effect resulting in off-target cytotoxicity to neighboring tumor cells, enhancing the efficacy of this novel therapy. Prior studies of trastuzumab deruxtecan have shown durable activity in heavily pretreated patients with metastatic HER2-positive breast cancer.1
HER2-positive breast cancer represents approximately 20% of breast cancer cases in women.2 Historically, HER2 positivity has been defined by strong HER2 expression with IHC staining (ie, score 3+) or HER2 amplification through ISH. Conversely, HER2-negative disease has historically been defined as those with IHC scores of 0 or 1+. This group represents approximately 60% of HER2-negative metastatic breast cancer patients.3 These patients have limited targeted treatment options after progressing on primary therapy. Prior data has shown that patients with low HER2 expression represent a heterogeneous population and thus, the historic categorization of HER2 status as positive or negative may in fact not adequately characterize the proportion of patients who may derive clinical benefit from HER2-directed therapies. Nevertheless, there have been no data to date that have shown improved outcomes in low HER2 expressers with anti-HER2 therapies.
The current studies add to the rapidly growing body of literature outlining the efficacy of the novel antibody drug conjugate trastuzumab deruxtecan. The implications of the data presented in these 2 studies are immediately practice changing.
In the DESTINY-Breast03 trial, Cortéz and colleagues show that trastuzumab deruxtecan therapy significantly prolongs progression-free survival compared with trastuzumab emtansine in patients with HER2-positive metastatic breast cancer who have progressed on first-line trastuzumab and taxane-based therapy. With a hazard ratio of 0.28 for disease progression or death, the efficacy of trastuzumab deruxtecan highlighted in this trial clearly makes this the standard of care in the second-line setting for patients with metastatic HER2-positive breast cancer. The overall survival in this trial was immature at the time of this analysis, and thus continued follow-up to validate the results noted here are warranted.
The DESTINY-Breast04 trial by Modi et al expands the cohort of patients who benefit from trastuzumab deruxtecan profoundly. This study defines a population of patients with HER2-low metastatic breast cancer who will now be eligible for HER2-directed therapies. These data show that therapy with trastuzumab deruxtecan leads to a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with chemotherapy in patients with metastatic breast cancer with low expression of HER2. This benefit was seen in both the estrogen receptor–positive cohort as well as the entire population, including pre-treated triple-negative disease. Furthermore, this study does not define a threshold of HER2 expression by IHC that predicts benefit with trastuzumab deruxtecan. Patients with an IHC score of 1+ as well as those with a score of 2+/ISH negative both benefit to a similar extent from trastuzumab deruxtecan. Interestingly, in the DAISY trial, antitumor activity was noted with trastuzumab deruxtecan even in those without any detectable HER2 expression on IHC.4 Given the inconsistency and potential false negatives of IHC along with heterogeneous HER2 expression, further work is needed to better identify patients with low levels of HER2 expression who may benefit from this novel antibody drug conjugate. Thus, a reliable test to quantitatively assess the level of HER2 expression is needed in order to determine more accurately which patients will benefit from trastuzumab deruxtecan.
Last, trastuzumab deruxtecan has been associated with interstitial lung disease and pneumonitis. Interstitial lung disease and pneumonitis occurred in approximately 10% of patients who received trastuzumab deruxtecan in the DESTINY-Breast03 trial and about 12% of patients in the DESTINY-Breast04 trial. Most of these events were grade 1 and grade 2. Nevertheless, clinicians must be aware of this risk and monitor patients frequently for the development of pneumonitis or interstitial lung disease.