ADCs, Biomarker-Driven Therapies Will Be Prominent at Breast Cancer Conference

Breast cancer diagnostics, therapeutics, and biomarker-driven therapy will be important focal points during the 22nd Annual School of Breast Oncology® conference, to be held November 7 to 9, 2024, according to Joseph A. Sparano, MD, a key presenter.

“Although we’re a decade or more into the use of biomarkers to help guide adjuvant therapies, we need more information to identify which biomarkers could benefit from CDK4/6 inhibitors,” Sparano, the Ezra M. Greenspan, MD, Professor in Clinical Cancer Therapeutics; chief, Division of Hematology Oncology; and deputy director, Tisch Cancer Institute at Icahn School of Medicine at Mount Sinai, in New York, New York, told Targeted Therapies in Oncology in an interview prior to the conference. “There have also been interesting developments in the use of biomarkers to help guide HER2-directed therapies,” he continued. These topics, as well as integrating molecular and genomic testing, expanding current and emerging imaging modalities, and developing best practices and strategies for locoregional management, will give attendees a comprehensive review of the most recent data on breast cancer biology.

Antibody-Drug Conjugates

The antibody-drug conjugate (ADC) class of agents in breast cancer has burgeoned with the successful combination of monoclonal antibodies and the potency of chemotherapy or other forms of toxic payload.

ADCs that target HER2 and TROP-2 mark a new era of development that explores specific linkers and combinations to enhance the bystander effect. This allows the drug from an ADC to kill neighboring cells, even if those cells don’t express the ADC target antigen.

“I think there is a tremendous amount of progress and promise for the future development of these agents,” Sparano said.

Results from the phase 3 TROPiCS-02 study (NCT03901339) led to the FDA approval of sacituzumab govitecan-hziy (Trodelvy) for the treatment of adult patients with unresectable, locally advanced or metastatic hormone receptor (HR)–positive, HER2-negative (immunohistochemistry [IHC] 0, IHC 1+ , or IHC 2+/ in situ hybridization negative) breast cancer who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting.¹

The approval led to the inclusion of sacituzumab govitecan-hziy as a category I approach in the 2023 National Comprehensive Cancer Network Guidelines for Breast Cancer and its recommendation as a second-line treatment for patients with HR-positive/HER2-negative breast cancer who have previously received endocrine therapy and CDK4/6 inhibitors.²

Another TROP-2–directed therapy, datopotamab deruxtecan (Dato-DXd), has had a biologics license application (BLA) filed with the FDA for patients with HR-positive, HER2-negative breast cancer who previously received systemic therapy.³

The BLA is supported by findings from the phase 3 TROPION-Breast01 trial (NCT05104866).

According to data presented at the 2023 European Society for Medical Oncology (ESMO) Annual Congress, Dato-DXd reduced the risk of disease progression or death by 37% compared with investigator’s choice of chemotherapy (HR, 0.63; 95% CI, 0.52-0.76; P < .001) as assessed by blinded independent central review.

The confirmed objective response rates (ORRs) were 36.4% and 22.9% for DatoDXd and chemotherapy, respectively.⁴ Ongoing evaluations of next-generation ADCs look promising. Advances in the various ADC components (ie, the antibody, linker, payload, and conjugation chemistry) will be key to improving the efficacy and safety of these agents.

In addition, several novel formats are being evaluated, including bispecific ADCs, probody-drug conjugates, immune-stimulating ADCs, protein-degrader ADCs, and dual-drug ADCs.⁵

Emerging CDK4/6 Inhibitors

“There are new-generation CDK4/6 inhibitors undergoing development that may have better antitumor activity,” Sparano said. “These may be even more selective in targeting CDK4, which is believed to mediate most of the antitumor effect,” he said.

The novel CDK4 inhibitor PF-07220060 in combination with endocrine therapy demonstrated a favorable safety profile and generated robust response rates in heavily pretreated patients with HR-positive, HER2-negative metastatic breast cancer whose disease progressed on prior CDK4/6 inhibitors, regardless of mutation status, according to updated findings from a phase 1/2a trial (NCT04557449) presented at the 2024 ESMO Breast Cancer Congress.⁶

At the data cutoff of November 1, 2023, investigators reported best responses of complete response (CR), partial response, stable disease, progressive disease (PD), and non-CR/non-PD in 3.0%, 21.2%, 42.4%, 18.2%, and 15.2% of patients, respectively, who were enrolled in parts 1B and 1C of the trial (n = 33).

According to investigators, the disease control rate was 81.8%, and the median progression-free survival was 8.1 months (95% CI, 5.3-10.9).⁶

Exploring Immunotherapy in TNBC

Sparano will make 2 presentations during the conference: “Considerations in Systemic Therapy for Early-Stage Triple-Negative Breast Cancer,” and, “The Art and Science of Managing Metastatic Breast Cancer” on November 8 and 9, respectively.

For his systemic therapy presentation, Sparano will provide evolving evidence supporting the use of immunotherapy for the treatment of localized triple-negative breast cancer (TNBC) based on findings from KEYNOTE-522 (NCT03036488).⁷

“I think the key challenge for the use of these agents in early-stage, localized disease is the spectrum of immune-related adverse events, some of which develop earlier in the course of treatment and can be potentially life-threatening, or others which occur later and can be chronic, requiring lifelong therapeutic interventions,” Sparano said.

KEYNOTE-522 data demonstrated that among patients with TNBC, the percentage of those with a pathological CR was significantly higher among patients who received pembrolizumab (Keytruda) plus neoadjuvant chemotherapy than those who received placebo plus neoadjuvant chemotherapy.⁷

Among the first 602 patients who were randomly assigned, the percentage of patients with a pathological CR was 64.8% (95% CI, 59.9%-69.5%) in the pembrolizumab-chemotherapy group and 51.2% (95% CI, 44.1%-58.3%) in the placebo-chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4%-21.8%; P < .001).⁷

After a median follow-up of 15.5 months (range, 2.7-25.0), 58 (7.4%) of 784 patients in the pembrolizumab-chemotherapy group and 46 (11.8%) of 390 patients in the placebo- chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or had died from any cause (HR, 0.63; 95% CI, 0.43-0.93).⁷

The objective of Sparano’s second presentation will be to focus on the agents that have established clinical activity in the treatment of patients with advanced disease and to focus on the mechanistic basis for their efficacy.

“I want to provide the rationale, so oncologists have a much better understanding of why these drugs are benefitting patients and an understanding of the adverse effects that are associated with them,” Sparano said.

Involvement in Ongoing Research

Sparano's work at the Merad Lab at the Mount Sinai School of Medicine, led by Miriam Merad, MD, PhD, director, Precision Immunology Institute at Mount Sinai School of Medicine in New York and the director, Mount Sinai Human Immune Monitoring Center, is particularly exciting.

The objective of the research carried out in the laboratory is to harness the understanding of the innate immune system to develop novel therapies against cancer and inflammatory diseases. The research focuses on innate immune sensors called dendritic cells and macrophages and their unique ability to sense and respond to tissue injury.

“We’re exploring the potential of immunotherapy to reverse the resistant [tumor] microenvironment and promote sensitivity to immunotherapy,” Sparano said. “We are currently in the process of developing clinical trials to evaluate agents that result in blockade of IL-4 signaling in combination with immune checkpoint blockade.”

REFERENCES:

1. FDA approves sacituzumab govitecan-hziy for HR-positive breast cancer. FDA. February 3, 2023. Accessed August 5, 2024. https://tinyurl.com/28ytcayw

2. Gradishar WJ, Moran MS, Abraham J, et al. NCCN Guidelines Insights: Breast Cancer, Version 4.2023. J Natl Compr Canc Netw. 2023;21(6):594-608. doi:10.6004/jnccn.2023.0031

3. Datopotamab deruxtecan biologics license application accepted in the US for patients with previously treated metastatic HR-positive, HER2-negative breast cancer. News release. AstraZeneca. April 2, 2024. Accessed August 5, 2024. https://tinyurl.com/mr4dj53s

4. Bardia A, Jhaveri K, Im S, et al. Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): primary results from the randomised phase III TROPION-Breast01 trial. Ann Oncol. 2023;34(suppl 2):S1254-S1335. doi:10.1016/S09237534(23)04149-2

5. Tsuchikama K, Anami Y, Ha SYY, Yamazaki CM. Exploring the next generation of antibody-drug conjugates. Nat Rev Clin Oncol. 2024;21(3):203-223. doi:10.1038/s41571-023-00850-2

6. Yap T, Sharma MR, Hamilton EP, et al. First-in-human phase I/IIa study of the first-in-class, next-generation CDK4-selective inhibitor PF-07220060 in combination with endocrine therapy (ET) in patients (pts) with HR+/ HER2– metastatic breast cancer (mBC) who progressed on prior CDK4/6 inhibitors (CDK4/6i): safety and efficacy update. Ann Oncol. 2024;9(suppl 4):1-47. doi:10.1016/esmoop/ esmoop103200

7. Schmid P, Cortes J, Pusztai L, et al; KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/ NEJMoa1910549