Novel antibody-drug conjugates that target actionable cell-surface markers in metastatic breast cancer will soon expand the utility of the class that already includes ado-trastuzumab emtansine (T-DM1), according to two speakers at the 2020 Miami Breast Cancer Conference. These new agents were described by Aditya Bardia, MD, MPH, Director of Precision Medicine at the Center for Breast Cancer, Massachusetts General Hospital Cancer Center, and Assistant Professor of Medicine, Harvard Medical School,1 and Sara Hurvitz, MD, Director of the Breast Cancer Clinical Research Program; Co-Director, Santa Monica UCLA Outpatient Hematology/Oncology Practice; and Associate Professor of Medicine at the David Geffen School of Medicine at UCLA.2
Aditya Bardia, MD, MPH
Sara Hurvitz, MD
Antibody-drug conjugates consist of a high-affinity antibody linked to a cytotoxic payload. They bind to a target antigen and are internalized by the cell, where the linker is degraded by the lysosome to release the payload within the cell and exert its anticancer effect.
“Different antibody-drug conjugates targeting different antigens could even redefine the molecular classification of breast cancer,” Dr. Bardia predicted.
One antibody-drug conjugate far along in development is sacituzumab govitecan, which targets Trop-2 (a pan-epithelial cancer antigen) to release SN-38, the active metabolite of irinotecan. “The advantage of this agent as compared with the parent compound irinotecan is that it can deliver 136 times more SN-38 to the cancer cells in preclinical models.” It also has a bystander effect, thus impacting surrounding cells in the tumor microenvironment not expressing Trop-2, he added.
Sacituzumab govitecan produced durable responses in a phase I/II single-arm study of 110 patients with pretreated metastatic triple-negative breast cancer.3 More than one-third of patients had a confirmed radiologic response as per Response Evaluation Criteria in Solid Tumors, with a median duration of response of 7.7 months by independent review and 9.1 months by central review, and a clinical benefit rate of 45.4%, according to Dr. Bardia, who led the study. The response rates are generally “more than double that of standard chemotherapy in this setting,” he noted.
The median progression-free survival was 5.5 months, and the 12-month progression-free survival was 15.1%. The median overall survival was 13.0 months, and the 12-month estimated survival was 51.3%. Myelosuppression and gastrointestinal disorders were the most common side effects, but peripheral neuropathy was not seen. “The absence of peripheral neuropathy provides an advantage for this agent, especially in heavily treated patients who have received taxanes as well as platinums and might have residual neuropathy,” commented Dr. Bardia.
In December 2019, the U.S. Food and Drug Administration (FDA) accepted a biologics license application for sacituzumab govitecan for patients with metastatic triple-negative breast cancer who have received at least two prior therapies. The phase III (confirmatory) ASCENT trial comparing sacituzumab govitecan with treatment of physician choice in 529 patients with metastatic triple-negative breast cancer has been completed.
Fam-trastuzumab deruxtecan is an antibody-drug conjugate with three components: a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab; a topoisomerase I inhibitor payload; and a tetrapeptide-based cleavable linker. This novel anti-HER2 agent was approved in December 2019 for the treatment of patients with unresectable or metastatic HER2-positive breast cancer who have received at least two prior anti–HER2-based regimens, based on the phase II DESTINY-Breast01 trial.
In that study, fam-trastuzumab deruxtecan induced responses in 60.3% of patients, including a 4.3% complete response rate and a 56% partial response rate; the clinical benefit rate reached 97.3%.4 Responses were consistent across subgroups, including patients with prior pertuzumab treatment and those with at least three prior regimens. The median duration of response was 14.8 months, and the median progression-free survival was 16.4 months overall and 18.1 months in patients with brain metastases. The median overall survival was not reached.
“The waterfall plot showing responses was remarkable,” Dr. Hurvitz noted. “Almost everyone had disease shrinkage with this novel antibody-drug conjugate. This is very exciting for patients with heavily pretreated disease.”
Dr. Bardia added that the subgroup of patients with tumors that had low HER2 expression (ie, 1+/2+, not meeting the traditional criteria for HER2 positivity) also derived “impressive activity.”5 He considered it might be due to a bystander effect seen with the agent, and additional research is needed to understand this better.
The toxicity of concern was interstitial lung disease, observed in 13.6% of patients (grade ≥ 3 in 2.7%) and leading to some treatment discontinuations. However, the median time to onset of more than 6 months “allows for monitoring and intervention,” Dr. Hurvitz added. “Education and guidelines about managing interstitial lung disease are underway.”
The confirmatory phase III DESTINYBreast02 trial (ClinicalTrials.gov identifier NCT03523585) is currently randomly assigning patients to fam-trastuzumab deruxtecan or physician’s choice of capecitabine plus either trastuzumab or lapatinib.
Ladiratuzumab vedotin consists of an anti–LIV-1 antibody connected to a microtubule-disrupting agent via a protease-cleavable linker. LIV-1 is a transmembrane cell adhesion molecule highly expressed in metastatic breast cancer. In a phase I study of 60 patients, the response rate was 25%, the median progression-free survival was 11.0 weeks, and the median duration of response was 13.3 weeks.6 Some peripheral neuropathy, possibly due to the toxic payload with a microtubule inhibitor, is being observed in clinical trials with this agent, noted Dr. Bardia.
HER3 overexpression in breast cancer is associated with diminished survival, currently an effective targeted agent is lacking. An ongoing phase I/II study is exploring the safety and efficacy of the investigational agent U3-1402 in 42 patients with HER3-overexpressing breast cancer.7 The response rate was 42.9%, rising to 60% among the cohort treated at a dose of 6.4 mg/kg; the disease control rate was 90.5% and 100%, respectively. The duration of response was not reached, and the median progression-free survival across doses was 8.3 months (range, 1.2–15.8 months), Dr. Bardia reported.
ARX788 and SYD985
Dr. Hurvitz discussed two novel HER2-targeting antibody-drug conjugates: ARX788 and SYD985. In a phase I study of 51 Chinese patients treated with ARX788, objective responses increased with dose escalation, reaching 63% among patients treated with 1.5 mg/kg.8 Eight cases (15.7%) of drug-related pulmonary toxicities were observed; some cases of interstitial lung disease were reported, one of which was grade 3.
“It is important to monitor for interstitial lung disease with ARX788,” said Dr. Hurvitz. “There have been no grade 5 events, but there is pneumonitis, so this will have to be monitored closely.”
SYD985 produced a response rate of 33% in the ongoing phase III TULIP randomized trial.9 In January 2018, SYD985 was granted Fast Track designation by the FDA for pretreated HER2-positive metastatic breast cancer.
Looking Farther Down the Road
“Moving forward, the question is how can we further increase response rates,” Dr. Bardia said. “Can we improve them to 60%, 70%, 80%?”
Such rates might be possible with combination therapy, targeted patient selection, and the use of antibody-drug conjugates in other settings and in other breast cancer subtypes. For instance, at the 2019 San Antonio Breast Cancer Symposium, findings were presented from a phase Ib/II study for the combination of ladiratuzumab vedotin and pembrolizumab with locally advanced or metastatic triple-negative breast cancer.10 In 26 patients with follow-up of at least 3 months, the response rate was 54%, and more than 90% of patients had tumor shrinkage.
“It does appear that combination therapy results in higher response rates,” said Dr. Bardia. This combination will be further assessed in a phase I/II study enrolling 97 patients.
Another strategy is to identify biomarkers that can predict which patients will have excellent outcomes with single-agent therapy alone—and biomarker interrogation is better accomplished in the neoadjuvant setting than in the metastatic setting, according to Dr. Bardia. For example, the NeoSTAR study will evaluate sacituzumab govitecan in neoadjuvant triple-negative breast cancer and might shed light on important predictive biomarkers.
Finally, expansion of antibody-drug conjugates in other disease settings that express the target antigen needs to be considered. “For example, sacituzumab govitecan is also being evaluated in hormone receptor–positive metastatic disease, since these tumors also express Trop-2,” said Dr. Bardia. In a phase I trial, he and his colleagues saw a response rate of 31%, a clinical benefit rate of 48%, and tumor shrinkage in 63%.11 Such promising activity suggests the potential of antibody-drug conjugates needs to be capitalized on further for patients with breast cancer.
DISCLOSURE: Dr. Bardia has served as a consultant or advisor to Pfizer, Novartis, Genentech/Roche, Radius Health, Merck, Immunomedics, Sanofi, Daiichi Sankyo/AstraZeneca, Eli Lilly, and Phillips and has received research funding from bioTheranostics. Dr. Hurvitz has received institutional research funding from Ambryx, Amgen, Arvinas, Bayer, BioMarin, Cascadian Therapeutics, Daiichi Sankyo, Dignitana, Genentech/Roche, GlaxoSmithKline, Immunomedics, Lilly, MacroGenics, Merrimack, Novartis, OBI Pharma, Pfizer, Pieris, Puma Biotechnology, Radius, Sanofi, and Seattle Genetics.
1. Bardia A: Antibody-drug conjugates: present and future. 2020 Miami Breast Cancer Conference. Invited Lecture. Presented March 6, 2020.
2. Hurvitz SA: Novel therapies for advanced HER2-positive breast cancer. 2020 Miami Breast Cancer Conference. Invited Lecture. Presented March 6, 2020.
3. Bardia A, Mayer IA, Vahdat LT, et al: Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med 380:741-751, 2019.
4. Modi S, Saura C, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 382:610-621, 2020.
5. Modi S, Park H, Murthy RK, et al: Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: Results from a phase Ib study. J Clin Oncol. February 14, 2020 (early release online).
6. Modi S, Pusztai L, Forero A, et al: Phase I study of the antibody-drug conjugate SGN-LIV1A in patients with heavily pretreated triple-negative metastatic breast cancer. 2017 San Antonio Breast Cancer Symposium. Abstract PD3-14. Presented December 7, 2017.
7. Masuda N, Yonemori K, Takahashi S, et al: Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in HER3-overexpressing metastatic breast cancer: Updated results of a phase I/II trial. 2018 San Antonio Breast Cancer Symposium. Abstract PD1-03. December 6, 2018.
8. Hu X, Zhang J, Ji D, et al: A phase I study of ARX788, a HER2-targeting antibody-drug conjugate, in patients with metastatic HER2-positive breast cancer. 2019 San Antonio Breast Cancer Symposium. Abstract P1-18-16. Presented December 11, 2019.
9. Saura C, Thistlethwaite F, Banerji U, et al: A phase I expansion cohort study of SYD985 in heavily pretreated patients with HER2-positive or HER2-low metastatic breast cancer. 2018 ASCO Annual Meeting. Abstract 1014. Presented June 2, 2018.
10. Han H, Diab S, Alemany C, et al: Open label phase Ib/II study of ladiratuzumab vedotin in combination with pembrolizumab for first-line treatment of patients with unresectable locally advanced or metastatic triple-negative breast cancer. 2019 San Antonio Breast Cancer Symposium. Abstract PD1-06. Presented December 11, 2019.
11. Bardia A, Diamond JR, Vahdat LT, et al: Efficacy of sacituzumab govitecan (anti-Trop-2-SN-38 antibody-drug conjugate) for treatment-refractory hormone-receptor positive/HER2- metastatic breast cancer. 2018 ASCO Annual Meeting. Abstract 1004. Presented June 3, 2018.