Promising Antibody-Drug Conjugates Have the Potential to Change Treatment Landscape for HER2-Negative Breast Cancer

Emerging and recently approved antibody-drug conjugates (ADCs) present the opportunity to change the treatment paradigm for patients with HER2-negative breast cancer, both in the metastatic and operable settings, according to a presentation from the 38th Annual Miami Breast Cancer Conference®.¹

Specifically, Kevin Kalinsky, MD, MS, director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University, described the data and prospective trials surrounding a number of ADCs, including sacituzumab govitecan (Trodelvy), ladiratuzumab vedotin, and trastuzumab deruxtecan (Enhertu), among others.

“While we have sacituzumab govitecan for patients with metastatic triple-negative breast cancer and trastuzumab deruxtecan in patients with HER2-positive disease, keep your eyes on ADC development as single agents, but also in combination with other therapies,” explained Kalinsky in his presentation. “I mentioned sacituzumab govitecan is being evaluated, for instance, with PARP inhibition. Then, there’s also a potential role for combining these ADCs with checkpoint inhibition.”

Sacituzumab govitecan, a humanized anti–Trop-2 antibody, was approved based on data from single-arm, open-label IMMU-132-01 trial (NCT01631552) investigating 110 patients with metastatic triple-negative breast cancer (mTNBC) who received 2 or more prior therapies.²

The data found that patients experienced a confirmed objective response rate (ORR) of 33.3% (36 of 108 patients), while 45.4% (49 of 108 patients) achieved a clinical benefit. This data led to the subsequent development of the phase 3 ASCENT trial (NCT02574455).

The ASCENT trial investigating sacituzumab govitecan for patients with mTNBC was halted early due to compelling evidence of efficacy, decided via a unanimous recommendation from the Data Safety Monitoring Committee (DSMC).³

Eligible patients for the ASCENT trial received 2 or more prior lines of treatment in the metastatic setting. The patient cohort was randomized 1:1 to receive either sacituzumab govitecan or physician’s choice of chemotherapy.⁴

The analysis found a median progression-free survival (PFS) of 5.6 months (95% CI, 4.3-6.3) for the sacituzumab govitecan group compared with 1.7 months (95% CI, 1.5-2.6) for the chemotherapy group (HR, 0.41; 95% CI, 0.32-0.52; P < .0001).

More, median overall survival (OS) was recorded at 12.1 months (95% CI, 10.7-14.0) among patients receiving sacituzumab govitecan compared with 6.7 months (95% CI, 5.6-7.7) for patients receiving chemotherapy (HR, 0.48; 95% CI, 0.38-0.50; P < .0001).

Kalinsky noted that there are also data supporting the use of sacituzumab govitecan for patients with hormone receptor–positive/HER2-negative breast cancer. The response rate was similar to that of patients with mTNBC.

“In my opinion, ADCs, as we’ve seen with sacituzumab govitecan, have the potential to change how we’re treating our patients with metastatic disease and hopefully for those patients in the operable setting as well,” explained Kalinsky.

Next, ladiratuzumab vedotin is an ADC that targets LIV-1, which is a transmembrane cell adhesion molecule highly expressed in metastatic breast cancer. A phase 1 trial (NCT01969643) was launched to investigate this drug for patients with breast cancer, including mTNBC.⁵

In a poster presentation at the 2017 San Antonio Breast Cancer Symposium, the data showed a confirmed ORR of 25% (15 of 60 patients), while also suggesting a recommended phase 2 dose of 2.5mg/kg intravenously every 3 weeks. The most common toxicities included alopecia, neutropenia, nausea, and transaminitis neuropathy.

Finally, Kalinsky discussed a trial in which trastuzumab deruxtecan is being used to treat non-amplified patients with HER2-low tumors (NCT02564900). Among both the IHC 2+ and IHC 1+ cohorts, the confirmed ORR was 37% (20 of 54 patients) with a median duration of response at 10.4 months.⁶

Looking ahead, the randomized DESTINY-Breast04 trial (NCT03734029) is awaiting results regarding trastuzumab deruxtecan versus physician’s choice of chemotherapy to treat patients with unresectable HER2-low breast cancer. The goal is to determine if there is a role for this molecule in the HER2-low setting.⁶

He concluded by stating that the future landscape for the treatment of these patients stands to see a large shift with the introduction of these newer ADCs

References:

1. Kalinsky K. Antibody-Drug Conjugates for HER2-Negative Breast Cancer. Presented at: 38th Annual Miami Breast Cancer Conference. March 4-7, 2021.

2. 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

3. Immunomedics Announces ASCENT Study to be Stopped for Compelling Efficacy. News release. Immunomedics, Inc. April 6, 2020. Accessed March 10, 2021. https://bit.ly/3rDeSpF

4. Bardia A, Tolaney SM, Loirat D, et al. LBA17 ASCENT: A randomized phase III study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2020;31(suppl4):S1142-S1215. 10.1016/annonc/annonc325

5. 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.

6. 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. 2020;38(17):1887-1896. doi: 10.1200/JCO.19.02318