Long-term study results demonstrate significant benefits of treatment with Kadcycla (trastuzumab emtansine) versus Herceptin (trastuzumab) for patients with HER2-positive early breast cancer who have residual disease after initial treatment. The phase 3, open-label KATHERINE trial evaluated 1,486 patients with HER2-positive breast cancer who had residual invasive cancer identified at surgery after 6 cycles of neoadjuvant chemotherapy. In this study, 743 patients received Kadcycla and 743 patients received Herceptin.
Key findings:
- Improved survival: Patients who received Kadcycla had a 34% lower risk of death compared to those who received trastuzumab.
- Longer disease-free period: After 7 years, 80.8% of patients on Kadcycla were free from invasive disease, compared to 67.1% on trastuzumab.
- Overall survival benefit: 89.1% of Kadcycla patients were alive after 7 years, versus 84.4% of trastuzumab patients.
While Kadcycla did cause more side effects, most patients were able to complete their treatment.
About Kadcycla
Kadcycla has a unique mechanism as an antibody-drug conjugate:
- It uses trastuzumab to deliver a cytotoxic agent (emtansine) directly to HER2-positive cancer cells, potentially maximizing efficacy while minimizing damage to normal cells
- This targeted delivery allows Kadcycla to exert effects beyond just HER2 signaling blockade, including payload-mediated microtubule poisoning
Kadcycla is FDA approved for the treatment of patients with HER2-positive metastatic breast cancer who have previously received treatment with Herceptin and a taxane. The FDA approval is for patients who received prior therapy for metastatic disease or have developed disease recurrence during or within 6 months of completing adjuvant therapy. Kadcycla is also FDA approved for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and Herceptin-based treatment. The Kadcycla package insert includes a boxed warned for hepatotixicyt, cardiac toxicity, and embryo-fetal toxicity.
Limitations
Resistance to Kadcycla remains a clinical challenge, with various mechanisms of resistance identified. Key subgroups remain at risk for recurrence despite treatment with Kadcycla.
Emerging Comparisons
Recent studies have shown that newer HER2-targeted therapies may offer advantages over Kadcycla in certain contexts:
- Trastuzumab deruxtecan (Enhertu) has demonstrated superior progression-free survival (13.0 months) compared to Kadcycla (4.0 months) in patients who had failed previous HER2-targeted therapies.
- Enhertu may be more effective due to its higher drug-to-antibody ratio and its ability to affect neighboring cells, including those with lower HER2 expression.
While Kadcycla has shown significant benefits over some earlier HER2-targeted therapies, newer agents like Enhertu are emerging as potentially more effective options in certain clinical scenarios. The choice of therapy may depend on the specific patient context, prior treatments, and emerging resistance patterns.
More Reading
Understanding HER2 Positive Breast Cancer and Its Treatment
Enhertu (Trastuzumab Deruxtecan) Treatment of HER2+ Breast Cancer
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Reference:
Geyer CE Jr, Untch M, Huang CS, et al; KATHERINE Study Group. Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer. N Engl J Med. 2025 Jan 16;392(3):249-257.
Bardia A, Hu X, Dent R, Yonemori K, et al; DESTINY-Breast06 Trial Investigators. Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer. N Engl J Med. 2024 Sep 15.
Ji C, Li F, Yuan Y, Zhang H, et al. Novel Anti-HER2 Antibody-Drug Conjugates Versus T-DM1 for HER2-Positive Metastatic Breast Cancer After Tyrosine Kinase Inhibitors Treatment. Oncologist. 2023 Oct 3;28(10):e859-e866.
Hunter, F.W., Barker, H.R., Lipert, B. et al. Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer. Br J Cancer 122, 603–612 (2020).
