Antibody-Drug Conjugates Make Headway in TNBC

Aditya Bardia, MD, MPH

The development of antibody-drug conjugates (ADCs) represents a promising strategy for patients with metastatic triple-negative breast cancer (TNBC), with early clinical trial results suggesting that novel agents could eventually change the landscape for this patient population, according to Aditya Bardia, MD, MPH.

The potential for ADCs shows the need to rethink the characterization of TNBC, Bardia said during a presentation at the 36th Annual Miami Breast Cancer Conference® (MBCC) Friday. "Triple-negative breast cancer, as we know, is a mixed bag,” he said. “It's a diagnosis of exclusion—it's defined by something it does not have, rather than something that it has… But there are actionable targets in triple-negative breast cancers.”

The need for new therapies is pressing. For patients with relapsed/refractory TNBC, Bardia said, there is no standard chemotherapy regimen, responses to treatment are usually short in duration and followed by rapid relapse, and visceral and brain metastases are common. The median progression-free survival (PFS) with chemotherapy ranges from 1.7 months to 3.7 months; the median overall survival (OS) from the onset of metastasis is 10 months to 13 months, Bardia said.

Against this backdrop, investigators are exploring strategies for drugs that take aim on targets in TNBC. Bardia said these targeted approaches fall into 3 main categories: oncogenes such as BRCA and PIK3CA, intercellular signaling pathways such as the PI3K/AKT/mTOR and androgen receptor networks, and cell surface markers for selective drug delivery with ADCs.

The components of ADCs are “important considerations that could impact the efficacy—toxicity ratio” of an individual drug, Bardia said. These agents are composed of an antibody with a high affinity and specificity to the tumor antigen, a payload such as a microtubule inhibitor or a DNA- damaging agent, and a linker that is capable of releasing the payload.

In addition to direct cytotoxic effects on cells that express the target antigen, ADCs appear to have a “bystander” effect, Bardia said. “Some of the payload leaks from the cancer cell and affects cells that do not express that antigen,” he said.

The precedent for ADC activity in breast cancer was set in 2013 with the FDA approval of ado-trastuzumab emtansine (Kadcyla), a HER2-targeted antibody and microtubule inhibitor conjugate approved for patients with HER2-positive, metastatic breast cancer who previously received trastuzumab (Herceptin) and a taxane.

Sacituzumab Govitecan

During his presentation, Bardia reviewed data for 3 emerging ADCs: sacituzumab govitecan (IMMU132), which targets TROP-2; ladiratuzumab vedotin, which targets LIV1; and trastuzumab deruxtecan (DS-8201), which targets HER2.In terms of the ADC pipeline, sacituzumab govitecan has reached the most advanced stage of development. Sacituzumab govitecan combines SN-38, the active metabolite of irinotecan, with a humanized immunoglobulin G antibody targeted against TROP-2, an epithelial antigen expressed on metastatic TNBC and many solid cancers. In preclinical studies, the conjugate has been shown to deliver up to 136-fold more SN-38 than irinotecan, Bardia said.

In a single-arm, phase II trial, sacituzumab govitecan elicited a confirmed objective response rate (ORR) of 33.3% in the study population of 108 patients, including 1 male. The median PFS with sacituzumab govitecan was 5.5 months (95% CI, 4.1-6.3) and OS was 13.0 months (95% CI, 11.2 to 13.7).¹

The median duration of response was estimated at 7.7 months (95% CI, 4.9-10.8) and the median time to onset of response was 2.0 months (range, 1.6-13.5). Notably, patients were able to remain on sacituzumab govitecan longer than they had on prior therapies, suggesting a lack of cross-resistance, said Bardia, who is the lead investigator on the study.

In terms of adverse events (AEs), Bardia said the most frequently reported all-grade AEs were nausea (67%), neutropenia (64%), anemia (50%), diarrhea (62%), and fatigue and asthenia (55% each). Grade 3 events included neutropenia (26%), anemia (11%), fatigue and asthenia (11%), diarrhea (8%), and nausea (6%). Grade 4 neutropenia was reported in 16% of participants.

Importantly, Bardia said, there were no reports of peripheral neuropathy, probably because the drug does not affect the microtubules. That may be a noteworthy attribute if the drug is tested in combination with other therapies that cause neuropathy.

The ADC is now being explored in the multicenter phase III ASCENT trial (NCT02574455) in patients with TNBC previously treated with at least 2 systemic chemotherapy regimens.

Although sacituzumab govitecan was being evaluated under the FDA's priority review program, the agency made a decision to delay approval, raising questions regarding chemistry, manufacturing, and control matters, according to Immunomedics, the company developing the drug. The company said it is working with the FDA to resolve the issues.

Ladiratuzumab Vedotin and Trastuzumab Deruxtecan

In response to a question, Bardia said no problems have been raised concerning the clinical data and pending trials have not been interrupted.The target for ladiratuzumab vedotin is LIV1, a transmembrane cell adhesion molecule highly expressed in metastatic breast cancer. The drug employs monomethyl auristatin E microtubule disrupting agent for its payload.

The drug is being evaluated in an ongoing phase I study in patients with metastatic TNBC who have received ≥2 cytotoxic regimens in the unresectable, locally advanced, or metastatic setting (NCT01969643).

In findings presented at the 2017 San Antonio Breast Cancer Symposium, the ORR was 25% (15 of 60 patients). The median PFS was 11.0 weeks (6.1-12.1) and the median duration of response was 13.3 weeks (95% CI, 5.3-19.1). All-grade AEs included alopecia (40.7%), neutropenia (24.7%), vomiting (23.5%), and peripheral neuropathy (19.8%).²

The third ADC under study that Bardia highlighted is trastuzumab deruxtecan (DS-8201), which targets HER2 but has shown efficacy among patients with low HER2 expression. In a phase I study, the drug demonstrated an ORR of 50.0% in patients with HER2-low breast cancer (17 of 34 patients), defined as immunohistochemistry (IHC) 2+/in situ hybridization (ISH) negative or IHC 1+/ISH-negative.³

Trastuzumab deruxtecan is being developed under a breakthrough therapy designation for patients with HER2-positive, locally advanced, or metastatic breast cancer who have been treated with trastuzumab (Herceptin) and pertuzumab (Perjeta) and have disease progression after T-DM1.

References

1. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med. 2019;380(8):741-751. doi: 10.1056/NEJMoa1814213.
2. Modi S, Pusztal L, Forero A, et al. Phase 1 study of the antibody-drug conjugate ladiratuzumab vedotin (SGN-LIV1A) in patients with heavily pretreated triple-negative metastatic breast cancer. Poster presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Poster PD3-14. sabcs17.posterview.com/nosl/p/PD3-14.
3. Modi S, Tsurutani J, Tamura K, et al. Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-low expressing breast cancer: updated results of a large phase 1 study. Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract Abstract P6-17-02. abstracts2view.com/sabcs/view.php?nu=SABCS18L_486&terms=.

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