Recent advances in HER2-targeted therapies are showing promising results in addressing treatment resistance for patients with HER2-positive breast cancer, offering new hope for those who have progressed on standard therapies. These developments, discussed at the 2024 San Antonio Breast Cancer Symposium (SABCS), highlight several innovative approaches to targeting HER2-positive disease.
Novel ADC Shows Remarkable Efficacy
The investigational antibody-drug conjugate (ADC) SHR-A1811 has emerged as a particularly promising candidate in the treatment landscape. In a phase 1 umbrella trial, this HER2-targeted ADC achieved an impressive overall response rate of 76.3% in patients with HER2-positive breast cancer. The drug, which utilizes a topoisomerase inhibitor payload, has demonstrated comparable efficacy to established treatments like trastuzumab deruxtecan (T-DXd) while potentially offering an improved safety profile with lower rates of interstitial lung disease.
Further supporting its potential, SHR-A1811 showed strong results in the neoadjuvant setting, achieving a pathologic complete response rate of 63.2% in the phase 2 FASCINATE-N trial. These findings suggest the drug could become an important addition to the therapeutic arsenal for HER2-positive breast cancer.
Bispecific Antibody Combination Shows Promise in Resistant Disease
A notable advancement in addressing treatment-resistant disease comes from the combination of zanidatamab, a bispecific antibody targeting two distinct HER2 epitopes, with evorpacept (ALX148), a CD47-blocking agent. This combination demonstrated significant activity in heavily pretreated patients who had previously received T-DXd, achieving a confirmed response rate of 55.6% in patients with centrally-confirmed HER2-positive disease.
This finding is particularly significant given the limited effective treatment options available for patients who have progressed on T-DXd. The dual mechanism of action – targeting HER2 while enhancing antibody-mediated phagocytosis – represents an innovative approach to overcoming treatment resistance.
Understanding Resistance Mechanisms
Recent research has also provided valuable insights into resistance mechanisms, which could help guide future treatment strategies. Scientists have identified upregulation of topoisomerase I alterations in some patients who progressed on T-DXd treatment, potentially explaining one mechanism of resistance to these therapies.
Additionally, studies have revealed that tumors with HER2 gene loss demonstrate poor prognosis and reduced response to HER2-directed therapies. This finding, while intuitive, provides concrete evidence for the importance of maintaining HER2 expression for treatment efficacy and suggests the need for alternative approaches in patients with HER2 gene loss.
Clinical Implications and Future Directions
"The outcomes of patients with HER2-positive disease are now much better than they used to be," notes Dr. Ian Krop, director of the Clinical Trials Office at Yale Cancer Center. "However, there are still patients whose cancer has become resistant to standard therapies, and we're not good at identifying which patients are going to benefit from which of the different types of drugs."
These emerging therapies and insights into resistance mechanisms represent significant progress in addressing the ongoing challenges in treating HER2-positive breast cancer. As research continues, the focus remains on developing more effective treatments and better understanding how to match patients with the most appropriate therapeutic options.
