The Next-Generation Promise of ADCs and SERDs in Breast Cancer

In 2022, development of novel targeted therapies has focused on antibody-drug conjugates (ADCs) and selective estrogen receptor degraders (SERDs). Both classes of agents have shown mixed efficacy over time. The generation in development offers reasons for excitement about improved outcomes for patients with breast cancer.

Novel and Promising ADCs

In a presentation at the 40th Annual CFS®, Neelima Vidula, MD, an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts, explained that ADCs consist of an antibody, a cytotoxic payload, and a linker. The antibody binds to an antigen on a cancer cell, triggering endocytosis, and the drug is released from the linker, allowing selective delivery of the treatment to the cancer cells. ADCs also induce antitumor immunity and can trigger a bystander effect on neighboring cancer cells.¹

ADCs have shown considerable benefit for patients with breast cancer, with several agents approved for use including the HER2-directed trastuzumab emtansine (Kadcyla) and trastuzumab deruxtecan (Enhertu), and the TROP2-directed sacituzumab govitecan (Trodelvy). Trastuzumab emtansine, which Vidula called the prototype of ADCs in breast cancer, is approved for patients with HER2-positive early breast cancer as an adjuvant therapy following neoadjuvant treatment as well as for patients with HER2-positive metastatic breast cancer. Trastuzumab deruxtecan is approved for the treatment of adult patients with previously treated HER2-low advanced breast cancer as well as for adult patients with previously treated HER2-positive breast cancer. Sacituzumab govitecan is approved for previously treated patients with locally advanced or metastatic triple-negative breast cancer (TNBC), where TROP2 is often highly expressed. It is undergoing FDA review for an indication for hormone receptor–positive, HER2-negative breast cancer.

Novel ADCs also are in development, building upon the success of earlier agents in this class with modifications resulting in more effective therapies. “We have come a long way since the development of trastuzumab emtansine,” Vidula commented. “Next-generation [ADCs] have cleavable linkers, a higher drug-to-antibody ratio, and increased membrane permeability, which likely explains their increased efficacy.”

One of the more promising agents in clinical trials is datopotamab deruxtecan, a TROP2-directed ADC with a topoisomerase I inhibitor and a cleavable linker, resulting in DNA damage and apoptosis and subsequent tumor regression. Results presented at the 2021 San Antonio Breast Cancer Symposium from the basket phase 1 TROPION-PanTumor01 trial (NCT03401385) showed that in a cohort of patients with HER2-negative breast cancer, datopotamab deruxtecan led to antitumor activity in patients with previously treated advanced or metastatic TNBC.²

At a median follow-up of 7.6 months (range, 4-13), the objective response rate (ORR) in the cohort was 34%, including 1 confirmed complete response and 14 confirmed partial responses. The disease control rate was 77%.

With extended follow-up of 8.8 months, an ORR of 52% was observed in patients who had not received prior treatment with a topoisomerase I inhibitor–based ADC. The median duration of response (DOR) was not reached. Vidula suggested that the data indicated there could be a role for this agent after progression on a prior TROP2 ADC, such as sacituzumab govitecan. As of data cutoff, 30% of patients remained on treatment and 70% had discontinued treatment.

Treatment-emergent adverse events (TEAEs) were reported in 98% of patients, with the most common being nausea, stomatitis, vomiting, and fatigue. Grade 3 or higher treatment-related AEs were observed in 23% of patients. No cases of treatment-related interstitial lung disease were reported, and no AEs were considered fatal.

The agent is being investigated further in the ongoing randomized, open-label, phase 3 TROPION-Breast02 trial (NCT05374512) in patients with locally recurrent, inoperable, or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibition in the first-line setting; it will be compared with investigator’s choice of chemotherapy. Additionally, the agent is being explored in combination with durvalumab (Imfinzi) in the phase 1b/2 BEGONIA study (NCT03742102) in patients with locally advanced or metastatic TNBC.

Patritumab deruxtecan is an ADC consisting of an anti-HER3 monoclonal antibody, a topoisomerase I inhibitor, and a cleavable tetrapeptide-based linker. HER3 is overexpressed in approximately 30% to 50% of breast cancers.

In the phase 1/2 U31402-A-J101 (NCT02980341) study presented at the 2022 American Society of Clinical Oncology Annual Meeting, patritumab deruxtecan showed promising efficacy in patients with HER3- expressing metastatic breast cancer.3 At a median follow-up of 31.9 months, an ORR of 30.1% (95% CI, 21.8%-39.4%) was observed in patients with HER3-high or HER3-low, hormone receptor–positive, HER2-negative metastatic breast cancer. Patients in this cohort had a median DOR of 7.2 months (95% CI, 5.3-not evaluable [NE]). The median progression-free survival (PFS) was 7.4 months (95% CI, 4.7-8.4) and the median overall survival (OS) was 14.6 months (95% CI, 11.3-19.5).

Specifically, among patients with HER3- high, HER2-positive metastatic breast cancer, the ORR was 42.9% (95% CI, 17.7%- 71.1%) with a median DOR of 8.3 months (95% CI, 2.8-26.4). The median PFS was 11.0 months (95% CI, 4.4-16.4) and median OS was 19.5 months (95% CI, 12.2-NE).

In those with HER3-high metastatic TNBC, the ORR was 22.6% (95% CI, 12.3%-36.2%) with a median DOR of 8.3 months (95% CI, 2.8-26.4). The median PFS was 5.5 months (95% CI, 3.9-6.8) and the median OS was 14.6 months (95% CI, 11.2-17.2).

In all patients treated with patritumab deruxtecan (N = 182), TEAEs of grade 3 or higher were reported in 65.9% of all patients and led to treatment discontinuation in 9.9%. Common TEAEs included neutrophil count decrease, platelet count decrease, white blood cell count decrease, anemia, alanine aminotransferase increase, aspartate aminotransferase increase, decreased appetite, nausea, fatigue, diarrhea, malaise, stomatitis, and vomiting. Treatment-related interstitial lung disease/pneumonitis was only observed in 12 patients (6.6%), including 3 grade 3 events and 1 grade 5 event.

Novel SERDs

Patients with estrogen receptor (ER)– positive breast cancer are typically treated with endocrine therapy and CDK4/6 inhibition but tend to develop resistance to this regimen, often through the development of acquired ESR1 mutations. Following resistance, current practice recommends further endocrine therapy for these patients, including the first-generation SERD fulvestrant (Faslodex).⁴ Novel, oral SERDs are associated with a higher bioavailability compared with fulvestrant, which results in greater efficacy.

Elacestrant was the first oral SERD to show a significant survival improvement over standard-of-care (SOC) therapy in patients with ER-positive, HER2-negative advanced breast cancer in a phase 3 study.

In the open-label, randomized EMERALD trial (NCT03778931), patients with ER-positive, HER2-negative advanced breast cancer who were previously treated with 1 or 2 lines of endocrine therapy, a CDK4/6 inhibitor, and up to 1 chemotherapy received treatment with elacestrant or SOC endocrine monotherapy of fulvestrant, anastrozole, letrozole, or exemestane.⁵

At 6 months, the PFS rate in all patients was 34.3% (95% CI, 27.2%-41.5%) with elacestrant and 22.3% (95% CI, 15.2%-29.4%) at 12 months compared with 20.4% (95% CI, 14.1%-26.7%) and 9.4% (95% CI, 4.0%-14.8%), respectively, with SOC (HR, 0.70; 95% CI, 0.55-0.88; P = .0018).

Comparatively, the 6-month and 12-month PFS rates with fulvestrant were 22.9% (95% CI, 15.15%-30.57%) and 10.2% (95% CI, 3.4%- 16.9%), respectively (HR, 0.68; 95% CI, 0.52- 0.90; P = .0049) (TABLE⁵).

In patients with ESR1 mutations, the PFS rate at 6 months was 40.8% (95% CI, 30.1%- 51.4%) and 26.8% (95% CI, 16.2%-37.4%) at 12 months with elacestrant compared with 19.1% (95% CI, 10.5%-27.8%) at 6 months and 8.2% (95% CI, 1.3%-15.1%) at 12 months with SOC (HR, 0.55; 95% CI, 0.39-0.77; P = .0005).

With fulvestrant specifically, the 6-month and 12-month PFS rates were 20.8% (95% CI, 10.68%-30.83%) and 8.4% (95% CI, 0.2%- 16.6%), respectively (HR, 0.50; 95% CI, 0.34-0.74; P = .0005). Interim OS results also showed a trend favoring elacestrant (HR, 0.75; 95% CI, 0.54-1.04; P = .08).

AEs were reported in 92.0% of patients in the elacestrant arm compared with 86.0% of the SOC arm, and grade 3/4 AEs were observed in 27.0% and 20.5%, respectively. The most common AEs with elacestrant were nausea, fatigue, vomiting, decreased appetite, and arthralgia. Findings from EMERALD support the FDA’s priority review for a new drug application for elacestrant as a treatment for patients with ER-positive, HER2-negative advanced or metastatic breast cancer.⁶

Camizestrant is another next-generation oral SERD that was investigated in the phase 2 SERENA-2 trial (NCT04214288) showing meaningful efficacy and tolerability compared with fulvestrant in postmenopausal patients with ER-positive locally advanced or metastatic breast cancer who were previously treated with endocrine therapy for advanced disease.⁷ Updated results from SERENA-2 will be presented at the 2022 San Antonio Breast Cancer Symposium. The agent is also being investigated further in the pivotal phase 3 SERENA-6 (NCT04964934) and phase 3 SERENA-4 (NCT04711252) trials.

_REFERENCES:

_{1. Vidula N. Current and emerging antibody-drug conjugates (ADCs) for breast cancer. Presented at: 40th Annual Chemotherapy Foundation Symposium; November 8-10, 2022; New York, NY.}

_{2. Krop I, Juric D, Shimizu T, et al. Datopotamab deruxtecan in advanced/metastatic HER2- breast cancer: results from the phase 1 TROPION-PanTumor01 study. Cancer Res. 2022;82(suppl 4):GS1-05. doi:10.1158/1538-7445.SABCS21-GS1-05}

_{3. Krop IE, Masuda N, Mukohara T, et al. Results from the phase 1/2 study of patritumab deruxtecan, a HER3-directed antibody-drug conjugate (ADC), in patients with HER3-expressing metastatic breast cancer (MBC). J Clin Oncol. 2022;40(suppl 16):1002. doi:10.1200/ JCO.2022.40.16_suppl.1002}

_{4. Sanchez KG, Nangia JR, Schiff R, Rimawi MF. Elacestrant and the promise of oral SERDs. J Clin Oncol. 2022;40(28):3227-3229. doi:10.1200/JCO.22.00841}

_{5. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor–positive, human epidermal growth factor receptor 2– negative advanced breast cancer: results from the randomized phase III EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/ JCO.22.00338}

_{6. Menarini Group’s elacestrant granted priority review by the U.S. FDA for patients with ER+/HER2- advanced or metastatic breast cancer. News release. Menarini Industrie Farmaceutiche Riunite. August 11, 2022. Accessed November 22, 2022. https://prn.to/3bQQfD9}

_{7. Camizestrant significantly improved progression-free survival vs. Faslodex in SERENA-2 phase II trial in advanced ER-positive breast cancer. News release. AstraZeneca. October 26, 2022. Accessed November 22, 2022. https://bit.ly/3zhO1Fw}