Breast cancer is the most-commonly diagnosed malignant tumor in women in the world. Most people with early stage breast cancer can be treated successfully, however, once it turns into metastatic breast cancer (mBC), the death rate will rise sharply.
Chemotherapeutic drugs commonly used in clinical practice can kill tumor cells while damaging normal tissue cells, with obvious toxic side effects and easy to develop drug resistance. Antibody drug conjugates (ADCs), as emerging therapeutic agents, have created a new treatment paradigm by reducing systemic toxicity while improving efficacy.
Trastuzumab deruxtecan (Enhertu), trastuzumab emtansine (Kadcyla), and sacituzumab govitecan (Trodelvy) are three ADCs approved by the U.S. Food and Drug Administration (FDA) for the treatment of breast cancer. Here, we will analyze the three FDA approved ADCs for the HER2-positive, HER2-low, and HER2-negative breast cancers.
ADCs for HER2-positive Breast Cancer
HER2-positive breast cancer accounts for about 20% of all breast cancer subtypes, and HER2 amplification or overexpression predicts poor prognosis.
Previous anti-HER2 targeted therapies have significantly improved the survival of patients with HER2-positive breast cancer, but the challenge of primary or secondary drug resistance still exists, and ADC drugs targeting HER2 have to some extent broken the bottleneck of longer survival benefit in HER2-positive mBC.
1.1 ado-Trastuzumab emtansine (T-DM1; Kadcyla)
In 2013, the FDA approved T-DM1 for metastatic HER2-positive breast cancer, becoming the first ADC approved for HER2+ mBC patients. Lately in 2019, T-DM1 was also approved in the adjuvant setting for patients with the residual invasive disease following the neoadjuvant paclitaxel and trastuzumab therapy.
In the global EMILIA clinical trial, 991 eligible patients were enrolled and randomly assigned to either trastuzumab emtansine (n=495) or capecitabine and lapatinib (control; n=496) [2]. The results showed that the median progression-free survival was 9.6 and 6.4 months, respectively, and the median overall survival was 30.9 and 25.1 months, respectively. T-DM1 caused a number of side effects in patients, such as nausea, fatigue, diarrhea, elevated liver enzymes, and thrombocytopenia.
Figure 1. EMILIA clinical trial PFS & OS [2]
1.2 fam-trastuzumab deruxtecan-nxki (T-DXd; DS-8201; ENHERTU®)
T-DXd was the second ADC approved by FDA to treat patients with HER2-positive, unresectable or metastatic BC following two or more prior anti-HER2-based regimens in December 2019 and was officially approved as a second-line drug on May 4, 2022.
In the phase 3 DESTINY-Breast03 trial, 261 patients were treated with T-DXd and 263 patients were treated with T-DM1. 75.2% of patients treated with T-DXd did not experience disease progression at 12 months. In contrast, only 33.9% of patients treated with T-DM1 had no disease progression. The median progression-free survival of patients treated with T-DXd and T-DM1 was 28.8 months and 6.8 months, respectively.[3]
Figure 2.Kaplan-Meier estimates of progression-free survival and overall survival (A) Progression-free survival by blinded independent central review. (B) Overall survival. [3]
The DESTINY-Breast02 trial evaluated the efficacy of T-DXd in patients who experienced disease progression following T-DM1 use.
A total of 608 patients with metastatic HER2-positive breast cancer and disease progression to T-DM1 (and prior trastuzumab) were randomly assigned (2:1) to receive T-DXd or a physician's choice of therapy. The primary endpoint was progression-free survival (PFS). The study results showed that at a median follow-up of 21.5 months, patients receiving T-DXd had a median PFS of 17.8 months compared with 6.9 months in the physician's choice group (HR 0.36, 95% CI 0.28-0.45; P < 0.0001), a significant improvement in PFS. Similarly, overall survival (OS) was significantly improved (39.2 months vs 26.5 months; HR 0.66, 95% CI 0.50-0.86; P = 0.0021).
ADCs for HER2-low Breast Cancer
fam-trastuzumab deruxtecan-nxki（T-DXd；DS-8201；ENHERTU®)
HER2 low expression is a subtype of breast cancer in which the cancer cells have low levels of HER2 on their surface. Based on the results of the DESTINY-Breast04 trial, T-DXd was approved by the FDA for the treatment of HER2-low breast cancer. The study randomized 373 patients to T-DXd and 184 to physician's choice of treatment (capecitabine, paclitaxel, gemcitabine, eribulin, or albumin-bound paclitaxel) [5]. 331 (88.7%) T-Dxd group patients and 163 (88.6%) chemotherapy group patients, respectively, were qualified for the hormone receptor–positive cohort.
Among hormone receptor-positive patients, median progression-free survival was 10.1 months for patients treated with T-DXd versus 5.4 months for patients treated with physician's choice therapy. In the entire patient population, patients treated with T-DXd had a median progression-free survival of 9.9 months, compared with a median progression-free survival of 5.1 months for patients receiving physician-selected therapy. The drug successfully reduced the risk of death or disease progression by 50 percent compared to physician-selected treatments for hormone receptor-positive and hormone receptor-negative cancers.
Figure 3. Kaplan–Meier Analysis of Progression-free Survival in the Hormone Receptor–Positive Cohort and among All Patients. [5]
Among hormone receptor-positive patients, median overall survival was 23.9 months for those treated with T-DXd and 17.5 months for those treated with physician's choice therapy. In the entire patient population, the median overall survival was 23.4 months for patients treated with T-DXd and 16.8 months for patients treated with physician's choice therapy.T-DXd significantly improved the overall survival of patients with breast cancer, regardless of whether or not they were hormone receptor-positive.
Figure 4. Kaplan–Meier Analysis of overall survival in the Hormone Receptor–Positive Cohort and among All Patients. [5]
ADCs for HER2-negative Breast Cancer (targeting Trop2)
3.1 sacituzumab govitecan-hziy （Trodelvy®）
Sacituzumab govitecan (Trodelvy®) is an FDA-approved ADC targeting TROP2, which has a cytotoxic payload of SN-38, a topoisomerase I inhibitor and active metabolite of irinotecan. Trodelvy can be used in patients with metastatic HR-positive/ HER2-negative breast cancer patients.
In the global phase III TROPiCS-02 clinical trial, patients with HR+/HER2- breast cancer previously treated with CDK4/6 inhibitors, paclitaxel, and endocrine therapy were randomized to sacituzumab govitecan and a physician's choice of treatment regimen (gemcitabine, eribulin, capecitabine, or vinorelbine) [6]. The median progression-free survival for patients receiving sacituzumab govitecan and physician's choice therapy was 5.5 months and 4.0 months, respectively. Similarly, the median overall survival for patients receiving sacituzumab govitecan and physician's choice therapy was 13.9 months and 12.3 months, respectively. The clinical benefit of receiving sacituzumab govitecan versus the physician's choice of regimen was statistically significant.
Sacituzumab govitecan has been approved by the FDA for patients with triple-negative breast cancer who have received two or more treatments. Triple-negative breast cancer is an aggressive subtype of breast cancer that does not express HER2, progesterone receptors, or estrogen receptors. Women with BRCA1 mutations who are younger than 40 years old have a high chance of developing triple-negative breast cancer. In the phase 3 trial, 235 patients with triple-negative breast cancer were treated with Sacituzumab govitecan, and an additional 233 patients received physician-selected chemotherapy [7]. Progression-free survival was 5.6 months for patients treated with Sacituzumab govitecan and 1.7 months for those who received chemotherapy.Sacituzumab govitecan significantly improves survival in patients with triple-negative breast cancer who have limited treatment options.
3.2 Datopotamab deruxtecan（Dato-DXd）
Datopotamab deruxtecan (Dato-DXd) consists of an anti-TROP2 monoclonal antibody, a cleavable linker and a topoisomerase I inhibitor payload.
On July 3, 2023, AstraZeneca and Daiichi Sankyo jointly announced that the Phase III TROPION-lung 01 study of Dato-DXd (datopotamab deruxtecan, DS-1062) in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) who have received at least one prior treatment met the progression-free survival (PFS) primary endpoint, with data on the other primary endpoint, overall survival (OS), yet to be matured, marking the first Phase III clinical results for Dato-DXd.
In addition to NSCLC, Dato-DXd has shown promising efficacy in triple-negative breast cancer.
On December 10, 2022, AstraZeneca, in conjunction with Daiichi Sankyo, announced the latest trial results of datopotamab deruxtecan (Dato-DXd) in patients with metastatic triple-negative breast cancer (TNBC) treated with a large number of up-front treatments. The data show that Dato-DXd reached a 32% objective response rate (ORR). Additionally, in a trial of the combination regimen of Dato-DXd with the PD-L1 inhibitor Durvalumab (Imfinzi) as first-line therapy in patients with metastatic TNBC, the combination therapy reached an ORR of an impressive 73.6%.
Conclusion
Patients with advanced breast cancer have limited treatment options. ADC has emerged as a powerful therapeutic approach to improve patient survival and quality of life. ADC has shown promising efficacy in the treatment of metastatic breast cancer, and we look forward to new breakthroughs with ADC in more difficult-to-treat solid tumors.
References:
[1] Narayan, P., Osgood, C. L., Singh, H., Chiu, H. J., Ricks, T. K., Chiu Yuen Chow, E., Qiu, J., Song, P., Yu, J., Namuswe, F., Guiterrez-Lugo, M., Hou, S., Pierce, W. F., Goldberg, K. B., Tang, S., Amiri-Kordestani, L., Theoret, M. R., Pazdur, R., & Beaver, J. A. (2021). FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 27(16), 4478–4485. https://doi.org/10.1158/1078-0432.CCR-20-4557
[2] https://www.kadcyla-hcp.com/metastatic-breast-cancer/efficacy/clinical-trial-results.html
[3] 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]. Lancet. 2023;401(10371):105-117. doi:10.1016/S0140-6736(22)02420-5
[4] André, F., Hee Park, Y., Kim, S. B., Takano, T., Im, S. A., Borges, G., Lima, J. P., Aksoy, S., Gavila Gregori, J., De Laurentiis, M., Bianchini, G., Roylance, R., Miyoshi, Y., Armstrong, A., Sinha, R., Ruiz Borrego, M., Lim, E., Ettl, J., Yerushalmi, R., Zagouri, F., Krop, I. (2023). Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet (London, England), 401(10390), 1773–1785.
[5] Modi, S., Jacot, W., Yamashita, T., Sohn, J., Vidal, M., Tokunaga, E., ... & Cameron, D. A. (2022). Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer.New England Journal of Medicine, 387(1), 9-20.
[6] Rugo, H. S., Bardia, A., Marmé, F., Cortes, J., Schmid, P., Loirat, D., ... & Tolaney, S. M. (2022). Primary results from TROPiCS-02: a randomized phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (Pts) with hormone receptor–positive/HER2-negative (HR+/HER2-) advanced breast cancer.
[7] Bardia, A., Hurvitz, S. A., Tolaney, S. M., Loirat, D., Punie, K., Oliveira, M., ... & Rugo, H. S. (2021). Sacituzumab govitecan in metastatic triple-negative breast cancer.New England Journal of Medicine, 384(16), 1529-1541.
[8] Krop, I., Juric, D., Shimizu, T., Tolcher, A., Spira, A., Mukohara, T., ... & Bardia, A. (2022). Abstract GS1-05: Datopotamab deruxtecan in advanced/metastatic HER2-breast cancer: Results from the phase 1 TROPION-PanTumor01 study.Cancer Research, 82(4_Supplement), GS1-05.
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