How has the availability of this ADC changed the treatment landscape for HER2-low metastatic breast cancer?
We now have a new generation of approved ADCs with a higher DAR and the ability to more efficiently and effectively deliver the toxin in advanced unresectable metastatic breast cancer. There are some drugs that have lower DAR values and still work in this situation. There is evidence that some efficacy can be seen in HER2-low metastatic breast cancer, a disease that is not HER2-positive by ASCO/CAP guidelines, but in which some HER2 is present on the cell surface.1 This led to U.S. Food and Drug Administration (FDA) approval of T-DXd in 2022, the first targeted therapy for unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer.4
This approval was based on results from the phase 3 DESTINY-Breast04 study (ClinicalTrials.gov identifier: NCT03734029), which found that the median progression-free survival (PFS) in patients treated with T-DXd compared to standard chemotherapy was 10.1 months vs. 5.4 months (hazard ratio for disease progression or death 0.51; 95% CI 0.40-0.64; P<0.001), with the median overall survival (OS) being 23 .9 months vs. 17.5 months increase (hazard). ratio for death: 0.64; 95% CI: 0.48-0.86; P = 0.003). In all treated patients regardless of HR status, T-DXd demonstrated a mean PFS of 9.9 months versus 5.1 months for chemotherapy (hazard ratio for disease progression or death 0.50; 95% CI 0.40-0.63; P<0.001). a median OS of 23.4 months for T-DXd compared to 16.8 months for the control arm (risk ratio for death 0.64; 95% CI 0.49-0.84; P=0.001).5 For DESTINY-Breast04, the PFS and OS for the primary endpoint – HR-positive, centrally determined, HER2-low disease – were impressive. That’s huge because now these patients are on T-DXd. We also find patients who do not respond because they would not have been eligible for the study. However, this is our new standard of care for this patient group. It is exciting that we have now been able to extend HER2-targeted therapy to a broader group of patients with HER2-low breast cancer. Having additional treatment options for these patients was a major advance and the improvement in survival of just over 5 to 6 months in this situation is tremendous. Some of them were HER2 positive according to the central test. So you have to be careful when testing for HER2 because we want to know who is HER2 positive. Whether you use the primary sample or a metastatic sample or even an older sample, research has predicted a benefit from T-DXd, which is really encouraging for clinical practice. Although the outcome in HR-positive disease was the primary endpoint and this was a large cohort, the study was not designed to evaluate outcomes in the HR-negative subgroup, which was relatively small.5 Consequently, we have to Define optimal treatment sequencing for the two subgroups. More patients in the T-DXd arm experienced adverse events leading to treatment discontinuation compared to the control arm (16.2% and 8.1%, respectively). Regarding toxicities, alopecia, nausea, vomiting, constipation, diarrhea, anemia, and thrombocytopenia were more common in the T-DXd arm, while neutropenia was more common in the chemotherapy arm. Drug-related interstitial lung disease (ILD) or pneumonitis occurred in 45 (12.1%) of patients who received T-DXd.5 Something we have learned and are still learning is how to monitor and treat patients with early ILD/pneumonitis. For patients with asymptomatic ILD, you need to withhold medication and consider low-dose steroids. Then, 3 weeks later, we repeat the non-contrast CT scan. I was able to successfully use the drug again in almost all patients. For symptomatic ILD, you must permanently stop the drug and start taking steroids immediately, and then begin evaluation. We need to learn how to treat these patients again in the safest way, so that we don’t abandon a very effective therapy. This also includes the considerable nausea caused by this drug. Overall, this is a drug that is fairly easy to administer to most patients and whose toxicity can be adequately controlled. We have yet to understand what to do and how well it works in patients with lower HER2 expression.
