The Evolving Role of Antibody Drug Conjugates
- While endocrine therapies remain a valuable tool in breast cancer treatment, Antibody Drug Conjugates (ADCs) could provide an effective alternative for specific patient populations.
- Some of the most promising ADCs include trastuzumab emtansine (brand name Kadcyla), trastuzumab deruxtecan (brand name Enhertu), and sacituzumab govitecan (brand name Trodelvy), each showing efficacy in HER2-positive, HER2-low, and triple-negative breast cancers.
- Enhertu, in particular, has demonstrated notable benefits, even in patients with HER2-low expression, with trials indicating improved progression-free survival (PFS) and overall survival (OS) compared to standard therapies.
- The clinical efficacy of ADCs in advanced breast cancer has led to discussions about whether they could be introduced earlier in the treatment sequence, potentially replacing endocrine therapies, but toxicities must be considered.
The evolving landscape of breast cancer treatment is exciting, with Antibody Drug Conjugates (ADCs) offering new hope for patients with various subtypes of the disease. While endocrine therapies remain a valuable tool, ADCs could provide an effective alternative for specific patient populations.
“I’m often now considering whether I should be moving those strategies up earlier on in the course of the disease rather than exhausting endocrine therapies with diminishing returns before considering those medications. So I think it’s really a field in flux at the moment. We’re learning and adapting as all this terrific new data is being reported,” Dr. Heather MacArthur, Director of Breast Cancer at UT Southwestern in Dallas, Texas, tells SurvivorNet Connect.
Endocrine Therapies for HR-Positive Breast Cancer
Endocrine therapies, such as tamoxifen and aromatase inhibitors, have been the backbone of treatment for hormone receptor-positive (HR+) breast cancer.
While effective, we know that resistance to endocrine therapies frequently develops, limiting long-term efficacy. For patients with HR+/HER2-negative metastatic breast cancer, CDK4/6 inhibitors have been added to first-line therapy, yet disease progression remains a significant challenge for many patients.
Introducing Antibody Drug Conjugates in Breast Cancer
Antibody Drug Conjugates (ADCs) combine the specificity of monoclonal antibodies with the potency of cytotoxic drugs. These agents work like a “Trojan horse,” delivering potent chemotherapy directly to cancer cells while sparing healthy tissues, thus minimizing systemic toxicity.
Some of the most promising ADCs include trastuzumab emtansine (brand name Kadcyla), trastuzumab deruxtecan (brand name Enhertu), and sacituzumab govitecan (brand name Trodelvy), each showing efficacy in HER2-positive, HER2-low, and triple-negative breast cancers. Enhertu, in particular, has demonstrated notable benefits, even in patients with HER2-low expression, with trials indicating improved progression-free survival (PFS) and overall survival (OS) compared to standard therapies.
Advantages of ADCs Over Traditional Therapies
The clinical efficacy of ADCs in advanced breast cancer has led to discussions about whether they could be introduced earlier in the treatment sequence, potentially replacing endocrine therapies. ADCs like Enhertu have shown a significant impact in both HER2-positive and HER2-low tumors, raising questions about whether endocrine therapies—often associated with resistance—should still be the preferred first-line treatment in HR+/HER2-low metastatic breast cancer.
Compared to endocrine therapies, ADCs offer the benefit of faster action and can be more effective in patients with visceral metastasis or rapidly progressing disease. Furthermore, ADCs do not rely on hormone sensitivity, a common limitation of endocrine therapies.
Clinical Trials Supporting ADCs
Clinical trials have underscored the potential of ADCs in breast cancer treatment.
For example, TROPICS-02, a trial involving sacituzumab govitecan (Trodelvy) in HR+/HER2-negative breast cancer, demonstrated improved PFS and OS compared to chemotherapy in patients with heavily pretreated disease.
Moreover, the DESTINY-Breast03 trial showed that Enhertu significantly improved progression-free survival and overall survival in patients with HER2-positive metastatic breast cancer compared to Kadcyla.
“The second line was previously TDM1 (Kadcyla) but now TDM1 has been displaced based on the DESTINY-Breast06 study, which looked at TDM1 going head to head against one of these more novel antibody drug conjugates Trastuzumab Deruxtecan (Enhertu), which is HER2 targeted antibody that’s linked to a topoisomerase payload,” Dr. MacArthur explains.
“There was a significant improvement in progression-free survival and overall survival in favor of the antibody drug conjugate (Enhertu). So that became for most patients a standard of care in the second line setting.”
Challenges and Considerations
While ADCs present a compelling alternative, there are several challenges to consider before moving them earlier in treatment protocols. ADCs can be associated with significant toxicities, including interstitial lung disease (ILD) in the case of Enhertu. Additionally, ADCs are costly, and there may be barriers to access for some patients.
It’s also important to weigh the risks of using potent therapies early in the treatment timeline. Endocrine therapies, despite their limitations, are generally well-tolerated and offer long-term disease control for many patients.
Should ADCs Be Moved Earlier?
Ultimately, the decision to move ADCs earlier in the treatment sequence should be guided by patient-specific factors, such as disease aggressiveness, tumor biology, and prior response to therapies.
In patients with rapidly progressing HR+/HER2-low metastatic breast cancer, especially those with visceral disease, introducing ADCs earlier could offer better disease control compared to traditional endocrine therapies. For others, endocrine therapies may still represent the most appropriate first-line approach.
