HER2-Targeted Therapies Show Promise in CNS Involvement

Sara Hurvitz, MD

Senior Vice President and Director

Clinical Research Division

Professor

Clinical Research Division

Fred Hutchinson Cancer Center

Professor and Head Department of Medicine

University of Washington School of Medicine

Seattle, WA

From breakthroughs in the preclinical setting to changes in clinical paradigms, the breast cancer landscape is rapidly evolving, particularly in treating patients with HER2- positive disease. Although beneficial outcomes associated with HER2-targeted therapies have been reported, there remains a proportion of patients who develop resistance and eventually relapse. This makes the ongoing search for new antibodies, antibody-drug conjugates (ADCs), and novel targeted combinations paramount.¹

The standard first-line treatment for patients with HER2-positive metastatic breast cancer is pertuzumab (Perjeta) and trastuzumab (Herceptin), which are anti-HER2 antibodies, plus a taxane.² After progression, standard second-line treatment had been trastuzumab emtansine (Kadcyla), according to National Comprehensive Cancer Network guidelines and findings from the phase 3 EMILIA trial (NCT00829166).^3,4

But the emergence of the ADC trastuzumab deruxtecan (T-DXd; Enhertu), with its superior activity and clinical benefit compared with T-DM1, has moved it before T-DM1 as a new standard in the second line.⁵ Results from the phase 3 DESTINY-Breast03 trial (NCT03529110) showed that 75.8% of patients treated with T-DXd were alive without disease progression at 12 months (95% CI, 69.8%-80.7%) compared with 34.1% of patients treated with T-DM1 (95% CI, 27.7%-40.5%). The HR for progression or death from any cause was 0.28 (95% CI, 0.220.37; P < .001).⁵ Investigators reported that an overall response, either a complete or partial response, was observed in 79.7% (95% CI, 74.3%84.4%) of the patients who received T-DXd and in 34.2% (95% CI, 28.5%-40.3%) of those who received T-DM1.⁵

“I think the big question that remains is how do we best treat patients whose disease progresses after T-DXd?” asked Sara Hurvitz, MD, senior vice president, director, and professor, Clinical Research Division at the Fred Hutchinson Cancer Center, Seattle, Washington. That, and other clinical questions, will be discussed during the 23rd Annual International Congress on the Future of Breast Cancer® West (IBC West), sponsored by Physicians’ Education Resource® (PER®), LLC, July 12 and 13, 2024, in San Diego, California.

“Conferences such as IBC West are important to help oncologists keep up with the rapid pace of data,” Hurvitz, cochair of the conference and professor and head, Department of Medicine, University of Washington School of Medicine in Seattle, Washington, said during an interview with Targeted Therapies in Oncology (AGENDA). Joining her as the other cochair is Joyce O’Shaughnessy, MD, the Celebrating Women Chair in Breast Cancer Research, Baylor University Medical Center, and director, Breast Cancer Research Program, Texas Oncology, US Oncology, in Dallas, Texas.

CNS Involvement

In the HER2-positive setting, one interesting development is related to the activity of T-DXd and brain metastases. “There was a pooled analysis6 presented at the ESMO [European Society for Medical Oncology] Congress 2023 looking at the data from 3 studies evaluating T-DXd that showed significant central nervous system [CNS] objective response rates and progression-free survival rates versus comparator arms,” Hurvitz said.

In the analysis, 148 patients with HER2-positive unresectable or metastatic breast cancer had received 1 or more anti–HER2-based regimens. Patients from DESTINY-Breast-01 (DB-01; NCT03248492), -02 (DB-02; NCT03523585), and -03 (DB-03; NCT03529110) were evaluated. Patients in DB-01 and DB-02 were previously treated with T-DM1, whereas patients in DB-03 were treated with trastuzumab and a taxane. The end points were intracranial (IC) objective response rates, IC duration of response, CSN progression-free survival, and safety. A summary of efficacy responses is provided in the TABLE.⁶

Median treatment duration was 12.7 months (range, 0.7-45.1) with T-DXd and 5.6 months (range, 0.1-43.0) for the comparator. The investigators reported that in the T-DXd cohort, the rate of any-grade drug- related treatment-emergent adverse events (TEAEs) was 94.5%, drug-related grade 3 or greater TEAEs was 43.2%, and serious drug-related AEs was 13.0%. In the comparator arm, these rates were 94.0%, 36.1%, and 7.2%, respectively.

Although the patient numbers were small and not statistically tested, these responses are “challenging our paradigm thinking that bulky [ADCs] cannot get past that blood brain barrier and impact cancer in the brain,” Hurvitz said. “Clearly, there are benefits seen in multiple trials of ADCs,” she said. “We need a better understanding of whether we can be sequencing ADCs after ADCs,” Hurvitz continued. The breast cancer setting enjoys a very active research setting, Hurvitz said. She noted that agents such as neratinib (Nerlynx), lapatinib (Tykerb), or margetuximab-cmkb (Margenza), which have limited use, may play a larger role in the post–T-DXd setting. Other novel agents that target HER2 are undergoing development such as zongertinib (BI 1810631) and the bispecific antibody, zanidatamab.⁷ “Zanidatamab is undergoing evaluation8 in combination with CDK4/6 inhibitors and endocrine therapy in patients with hormone receptor- positive breast cancer,” Hurvitz added.

“This is a rapidly evolving field,” Hurvitz said. To keep advancing, “we need our patients to enroll in clinical trials and help be part of the acquisition of new knowledge to help guide our treatment in the future,” Hurvitz concluded.

REFERENCES:

1. Escrivá-de-Romaní S, Saura C. The change of paradigm in the treatment of HER2-positive breast cancer with the development of new generation antibody-drug conjugates. Cancer Drug Resist. 2023;6(1):45-58. doi:10.20517/cdr.2022.52

2. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-119. doi:10.1056/NEJMoa1113216

3. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 2.2024. Accessed May 2, 2024. https://tinyurl.com/4hfywr7c

4. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-1791. doi:10.1056/NEJMoa1209124

5. Cortés J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):1143-1154. doi:10.1056/NEJMoa2115022

6. Hurvitz SA, Modi S, Li W, et al. A pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) with brain metastases (BMs) from DESTINYBreast (DB)-01,-02, and-03. Ann Oncol. 2023;34(suppl 2):S335-336. doi:10.1016/j.annonc.2023.09.554

7. Lee K-S, Wang, X, Im YH, et al. Zanidatamab (zani), a HER2-targeted bispecific antibody, in combination with docetaxel as first-line (1L) therapy for patients (pts) with advanced HER2-positive breast cancer: Preliminary results from a phase 1b/2 study. J Clin Oncol. 2022;40(suppl 16):1031-1031. doi: 10.1200/JCO.2022.40.16_suppl.1031

8. Escrivá-de-Romani S, Cejalvo JM, Alba E, et al. Primary results from a phase 2a study of zanidatamab (zani) + palbociclib (palbo) + fulvestrant (fulv) in HER2+/HR+ metastatic breast cancer (mBC). Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract LBO1-04.