The Future of Antibody Drug Conjugates

Educational Objectives

The goal of this program is to improve management of breast cancer using antibody drug conjugates. After hearing and assimilating this program, the clinician will be better able to:

1. Assess use of trastuzumab emtansine compared with trastuzumab in high-risk breast cancer patients as observed in the KATHERINE trial.
2. Explain the results using trastuzumab deruxtecan in patients with human epidermal growth factor receptor-low breast cancer, per the DESTINY-Breast04 trial.

Summary

Introduction: antibody drug conjugates (ADCs) consist of an antibody that binds to a specific target on cancer cells, a linker that connects the antibody to a chemotherapy agent, and the chemotherapy agent itself; the antibody binds to the cancer cell, and the chemotherapy agent is internalized, delivering a high level of cytotoxic agent

Evidence: the EMILIA trial by Dieras et al (2017) compared trastuzumab emtansine (T-DM1) vs standard treatment (lapatinib with capecitabine) for metastatic breast cancer; results showed significant improvement in overall survival (OS) and progression-free survival (PFS) with use of T-DM1; however, it failed to impress in earlier stage treatment (first-line, adjuvant, neoadjuvant); this led to some pessimism about the drug

The KATHERINE trial: by von Minckwitz et al (2021) compared T-DM1 vs trastuzumab in patients with high-risk breast cancer who were human epidermal growth factor receptor 2 (HER2) negative; initial results showed a significant improvement in disease-free survival (DFS) with T-DM1 (11% in 3 yr; hazard ratio [HR] of 0.5); this led to a shift in clinical practice; updated results (7 yr) revealed the DFS benefit with T-DM1 remained strong (increased to 14%); there was a statistically significant improvement in OS with T-DM1 (5% absolute difference at 7 yr)

Trastuzumab deruxtecan (TDXd): early results were very promising, especially considering the heavily pretreated patients involved; however, its role was met with some hesitation because of lung toxicity concerns; the DESTINY-Breast09 trial by Cortes et al (2022) compared TDXd with T-DM1; results showed significantly improved PFS and improvement in OS with use of TDXd (HR=0.28)

Sacituzumab govitecan (Trodelvy): targets trophoblast cell-surface antigen 2 (Trop-2); it carries a powerful payload (SN-38), which is the active compound of irinotecan and was effective in heavily pretreated patients with triple-negative breast cancer; Bardia et al (2021) showed significant improvement in PFS and OS compared with the control arm; it is also being explored for other breast cancer types because of Trop-2 expression across various subtypes; high levels of Trop-2 expression may not be necessary for sacituzumab govitecan to be effective; the medication is being tested in later-line and first-line treatment settings through multiple trials (ASCENT 3 and 4); trials with treatment depends on programmed death-ligand (PD-L1) status are ongoing; in patients who are PD-L1 negative sacituzumab govitecan vs physician's choice of treatment; in patients who are PD-L1 positive, sacituzumab govitecan with pembrolizumab vs physician's choice of chemotherapy with pembrolizumab; another trial evaluates sacitumab govitecan in patients with residual disease after neoadjuvant therapy

Datopotamab deruxtecan (Dato-DXd): targets Trop-2 and carries a different payload (DXd); initial studies (TROPION-Pan Tumor01; Bardia et al [2024]) showed promising activity in heavily pretreated patients with various tumor types, including triple-negative breast cancer; responses were durable; Dato-DXd is being investigated in the first-line setting for triple-negative breast cancer (TNBC) vs investigator's choice of treatment

Post-neoadjuvant setting: ongoing study evaluates Dato-DXd alone (without pembrolizumab) vs investigator's choice of chemotherapy for patients who received neoadjuvant pembrolizumab but still have residual disease after treatment; there is a third arm which includes both medications

Combination with durvalumab: is based on promising results from the BEGONIA study; the arm with Dato-DXd and durvalumab showed an 80% overall response rate in patients with TNBC; a longer follow-up from this study confirms sustained benefits

Enfortumab vedotin: targets nectin-4; it showed significant improvement in activity compared with chemotherapy for bladder cancer, and is being explored in the neoadjuvant setting TNBC; a trial is designed to replace the standard pembrolizumab regimen with enfortumab and durvalumab for patients with TNBC having non-pathological complete response

DESTINY-Breast04 trial: by Modi et al (2022) investigated TDXd for patients with HER2-low breast cancer; most HER2-low patients were hormone receptor-positive (ER+) and had received CDK4/6 inhibitors before; TDXd showed significant improvement in PFS for ER+ patients; positive response rates were observed in ER+ and ER- patients; OS benefit was also observed

Future directions: new ADC drugs will likely need to show a benefit in OS, not just PFS, to gain approval; medications targeting Trop-2 are being tested for ER+ breast cancer in addition to TNBC; ADCs are being combined with other treatment options, eg, endocrine therapy and checkpoint inhibitors; development is ongoing for improved linker technology, which is a crucial component of ADCs; some medications in development can target 2 different antigens or deliver 2 different chemotherapy agents

Readings

Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab Govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485; Bardia A, Krop IE, Kogawa T, et al. Datopotamab Deruxtecan in advanced or metastatic HR+/HER2- and triple-negative breast cancer: Results from the phase I TROPION-PanTumor01 study. J Clin Oncol. 2024;42(19):2281-2294. doi:10.1200/JCO.23.01909; Cortés J, Kim SB, Chung WP, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for breast cancer. N Engl J Med. 2022;386(12):1143-1154. doi:10.1056/NEJMoa2115022; Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): A descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial [published correction appears in Lancet Oncol. 2017 Aug;18(8):e433. doi: 10.1016/S1470-2045(17)30527-2] [published correction appears in Lancet Oncol. 2018 Dec;19(12):e667. doi: 10.1016/S1470-2045(18)30848-9]. Lancet Oncol. 2017;18(6):732-742. doi:10.1016/S1470-2045(17)30312-1; Hurvitz SA, Hegg R, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial [published correction appears in Lancet. 2023 Feb 18;401(10376):556. doi: 10.1016/S0140-6736(22)00045-9]. Lancet. 2023;401(10371):105-117. doi:10.1016/S0140-6736(22)02420-5; Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690; von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab Emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Geyer Jr. has received grant/research support from Astra Zeneca, Daichi Sankyo Inc., and Genentech. Members of the planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Geyer was recorded at the 11th Annual USC Multi-Disciplinary Breast Cancer Symposium, held on January 27, 2024, in Los Angeles, CA, and presented by the Keck School of Medicine of the University of Southern California. For more information about the upcoming CME activities from this presenter, please keck.usc.edu/cme. Audio Digest thanks the speakers and Keck School of Medicine of the University of Southern California for their cooperation in the production of this program.

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