Trastuzumab Deruxtecan Effective For HR-Positive, HER2-Low Breast Cancer Treatment After Endocrine Therapy

At the American Society of Clinical Oncology (ASCO) 2024 annual meeting in Chicago, Illinois, researchers presented study results from DESTINY-Breast06 (DB-06) (NCT04494425) that found trastuzumab deruxtecan (T-DXd) reduces cancer growth for patients with hormone receptor (HR)-positive, HER2-low, or HER2-ultralow metastatic breast cancer that increased in patients after endocrine therapy, published in the Journal of Clinical Oncology.¹

Antibody drug conjugates (ADCs), like T-DXd, combine monoclonal antibodies with cytotoxic payloads to selectively deliver potent cytotoxic drugs to cancer cells expressing specific surface antigens like HER2.² Patients with breast cancer have expressed effective treatment outcomes with ADCs as they aim to maximize efficacy and decrease the systemic toxicity linked to chemotherapy. These drugs have a wide range of potential, which is why research, development, and approvals of ADCs have occurred within the last decade.

Giuseppe Curigliano, MD, PhD, director of the early drug development division and current co-chair for the experimental therapeutics program at the European Institute of Oncology in Milano, Italy, said in his presentation of DB-06 at ASCO 2024, “This is for sure an unmet medical need because activity of treatment after CDK4/6 inhibitor is very poor. Median progression-free survival is 7 months with alpelisib in the post-CDK4/6 inhibitor, 5.5 months with capivasertib, and single-agent chemotherapy is no more than 7 months.”

Results from DB-06 follow the DESTINY-Breast04 (DB-04) study, previously presented at ASCO 2022, that found evidence of trastuzumab deruxtecan to reduce the risk of disease progression or death by 50% compared with chemotherapy for patients with HER2-low, HR-positive, and HR-negative breast cancers.³

Furthermore, AstraZeneca and Daiichi Sankyo announced results from the DB-06 phase 3 trial that found fam-trastuzumab deruxtecan-nxki displayed clinically meaningful progression-free survival (PFS) improvements among patients with HR-positive, HER2-low metastatic breast cancer after 1 or more forms of endocrine therapy.⁴

The DB-06 trial built upon these prior results and conducted a randomization trial for patients with HER2-low or HER2-ultralow to receive either 5.4 mg injections of T-DXd or a physician’s choice of chemotherapy.¹

Participants did not have any prior chemotherapy treatment for metastatic breast cancer. Additionally, they had to have more than or equal to 2 lines of endocrine therapy. Individuals who had 1 line of endocrine therapy could enroll if disease progression occurred less than or equal to 2 years of adjuvant endocrine therapy or less than or equal to 6 months of endocrine therapy with CDK4/6 inhibitors.

The primary end point of the study was PFS by blinded independent central review in HER2-low breast cancer. Some of the secondary end points included intent-to-treat, overall survival (OS), objective response rate, and safety.

By March 2024, a total of 866 patients were randomized to receive either T-DXd (n = 436) or a physician’s choice of chemotherapy (n = 430). Patients with HER2-low breast cancer (n = 713) and HER2-ultralow breast cancer (n = 153) were included. The study population consisted mainly of women and ranged from 28 to 85 years of age.

The majority of the patient population was previously treated with CDK4/6 inhibitors (90.4%). Patients apart of the chemotherapy group had physicians select either capecitabine (59.8%), nab-paclitaxel (24.4%), or paclitaxel (15.8%).

The highest confirmed objective response rates (ORR) were found in patients with HER2-ultralow breast cancer (61.8%) after T-DXd treatment, followed by patients with HER2-low breast cancer treated with T-DXd (56.5%). Both breast cancer groups treated with chemotherapy had lower ORRs (HER2-low, 32.2%; HER2-ultralow, 26.3%).

The complete response rates were 0 for both cancers treated with chemotherapy. However, patients with HER2-low breast cancer treated with T-DXd had a 2.5% complete response, and patients with HER2-ultralow had a 5.3% complete response.

Partial responses for each cancer group treated with T-DXd were similar for HER2-low (54%) and HER2-ultralow (56.6%). Patients with HER2-low breast cancer had a slightly higher partial response (32.2%) than HER2-ultralow (26.3%) when treated with chemotherapy.

Progression-free survival improved significantly among patients administered T-DXd compared with the patients treated with chemotherapy. On average, treatment lasted 11 months for the T-DXd group and 5.6 months for the chemotherapy groups because the T-DXd group experienced fewer severe adverse effects, allowing them to receive treatment for longer.⁵

Adverse events classified as grade 3 or higher were reported among the T-DXd group (40.6%) and the chemotherapy-treated group (31.4%). There were only 20.3% serious treatment emergent adverse events (TEAEs) found among the T-DXd group and 16.1% for the chemotherapy group.¹

Treatment discontinuation associated with TEAEs occurred in 14.3% of the T-DXd treated group and 9.4% of patients treated with chemotherapy. Pneumonitis was the most common TEAE that resulted in discontinuation for T-DXd (5.3%), and peripheral sensory neuropathy was most common for patients treated with chemotherapy (1.4%). Additionally, nausea was the most common TEAE associated with dose reduction for T-DXd (4.4%), and palmar-plantar erythrodysesthesia was found more frequently among patients treated with chemotherapy (16.5%).

Erica L. Mayer, MD, MPH, director of breast cancer clinical research, medical oncologist, and clinical investigator at Dana-Farber Cancer Institute, stated, “These data suggest that trastuzumab deruxtecan may become a preferred first-line treatment option for most patients with HR-positive metastatic breast cancer after progression on endocrine therapy.”

Patients with HR-positive, HER2-low, and HER2-ultralow metastatic breast cancers may benefit from T-DXd treatment after 1 or more lines of endocrine therapy and no prior chemotherapy, but researchers have noted the high levels of more serious toxicities T-DXd has displayed compared with traditional chemotherapy and advise this treatment may not be the best option for all patients.

References:

1. Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06). J Clin Oncol. 2024;42(17):1-1. doi:10.1200/JCO.2024.42.17

2. Mark C, Lee JS, Cui X, Yuan Y. Antibody-drug conjugates in breast cancer: current status and future directions. Int J Mol Sci. 2023;24(18):13726. doi:10.3390/ijms241813726

3. Caffrey M. Trastuzumab deruxtecan cuts risk of disease progression or death by 50% for patients with HER2-low metastatic breast cancer. AJMC. June 5, 2022. Accessed June 11, 2024. https://www.ajmc.com/view/trastuzumab-deruxtecan-cuts-risk-of-disease-progression-or-death-by-50-for-patients-with-her2-low-metastatic-breast-cancer

4. Santoro C. Destiny-Breast06 results offer new hope for patients with HR-positive, HER2-low metastatic breast cancer. AJMC. May 1, 2024. Accessed June 11, 2024. https://www.ajmc.com/view/destiny-breast06-results-offer-new-hope-for-patients-with-hr-positive-her2-low-metastatic-breast-cancer

5. American Society of Clinical Oncology. Trastuzumab deruxtecan significantly improves progression-free survival in breast cancer patients previously treated with endocrine therapy. ASCO. June 2, 2024. Accessed June 11, 2024. https://society.asco.org/about-asco/press-center/news-releases/trastuzumab-deruxtecan-significantly-improves-progression-free