Patritumab Deruxtecan Demonstrates Meaningful Activity in HR+/HER2– Advanced Breast Cancer

Patritumab deruxtecan (HER3-DXd) elicited responses and showcased an acceptable toxicity profile in patients with hormone receptor–positive, HER2-negative advanced breast cancer whose disease progressed after 2 or more lines of therapy, including a CDK4/6 inhibitor, according to additional data from the phase 2 ICARUS-BREAST01 study (NCT04965766).1

The findings were shared in a poster during the 42nd Annual Miami Breast Cancer Conference (MBCC), and showed that the antibody-drug conjugate elicited a confirmed objective response rate (ORR) of 53.5% (95% CI, 43.2%-63.6%) in evaluable patients (n = 99), comprised a complete response rate of 2.0% and a partial response rate of 51.5%. Additionally, 37.4% of patients had stable disease, 7.1% experienced progressive disease (PD), and 2.0% were not evaluable. The clinical benefit rate (CBR) was 62.6% (95% CI, 52.3%-72.1%).

Notably, 90 of the 99 patients experienced tumor shrinkage with treatment. Moreover, the median duration of response (DOR) was 8.7 months (95% CI, 8.1-12.5) and the median progression-free survival (PFS) was 9.4 months (95% CI, 8.1-13.4).

“The efficacy and safety profile of HER3-DXd makes this ADC an optimal candidate for further, larger trials in patients with hormone receptor–positive, HER2-negative advanced breast cancer after failure of CDK4/6 inhibitors,” Barbara Pistilli, MD, chair of the breast cancer unit in the Department of Medical Oncology at Gustave Roussy in Villejuif, France, and colleagues, wrote.

ICARUS-BREAST01: Background and Basics

Although the combination of endocrine therapy and CDK4/6 inhibition has improved clinical outcomes in patients with hormone receptor–positive, HER2-negative advanced breast cancer, there are limited effective options for those who experience PD. Patritumab deruxtecan is comprised of an anti-HER3 monoclonal antibody that is conjugated to a topoisomerase I inhibitor via a cleavable peptide linker, and the ADC has demonstrated activity spanning breast cancer subtypes in previous phase 1 and 2 studies.

The multicenter, single-arm, investigator-initiated, phase 2, ICARUS-BREAST01 study was conducted at 11 clinical sites in France and included patients with hormone receptor–positive, HER2-negative, unresectable locally advanced or metastatic breast cancer that had progressed on CDK4/6 inhibition with endocrine therapy and 1 previous chemotherapy for advanced disease. Patients were able to have prior exposure to PI3K/AKT/mTOR inhibition but could not have previously received fam-trastuzumab deruxtecan-nxki (Enhertu).

Study participants were administered patritumab deruxtecan at a dose of 5.6 mg/kg every 3 weeks until PD or intolerable toxicity. Investigator-assessed confirmed ORR served as the study’s primary end point, and key secondary end points included DOR, PFS, CBR, overall survival, and safety/tolerability.

Investigators also examined predictors of response or resistance, HER3 expression dynamics before and following treatment, and circulating tumor cell levels during treatment.

Patients were required to have a tumor biopsy and provide blood. On April 21, 2022, HER3 expression prescreening was removed by amendment.

Patient Demographics, Baseline Characteristics, Disposition, and Treatment Exposure

The data cutoff date for the data shared at MBCC was April 16, 2024, and the median follow-up was 15.3 months (95% CI, 13.0-17.2). In the 99 patients enrolled, the median age was 57.0 years (range, 48.0-66.0) and all were female. The majority had estrogen receptor­–positive disease (94.9%). The median number of systemic treatments received for advanced breast cancer was 2, with a range of 1 to 4. Almost all patients (99.0%) previously received a CDK4/6 inhibitor for a median duration of 13.7 months (range, 6.5-19.7); 35.4% of patients previously received a PI3K/AKT/mTOR inhibitor and all had prior chemotherapy for advanced disease.

“High levels of baseline HER3 membrane expression were observed,” the study authors wrote. “Most patients had HER2 immunohistochemistry [IHC] 0/1+ breast cancer, with less than 10% of patients reporting IHC ≥2+.” The median membrane H-score for HER3 expression was 180 (interquartile range [IQR], 144-215). For almost half of patients (49.4%), overall membrane positivity at 10x magnification was 75% or higher.

At the time of data cutoff, 19.2% of patients were still receiving patritumab deruxtecan. The most common reason for treatment discontinuation was PD (64.6%), followed by adverse effects (AEs; 8.1%) and other (7.1%). Patients had received a median of 11.0 cycles of the ADC (IQR, 6.0-18.0) for a median duration of 251.0 days (IQR, 144.5-402.0). Moreover, 32.3% of patients required at least 1 dose modification.

Safety Spotlight

The ADC was found to have a manageable safety profile. Any-grade treatment-emergent AEs (TEAEs) were observed in 98.0% of patients, with 54.5% of these effects grade 3 or higher in severity. TEAEs led to dose interruption or reduction for 26.3% and 20.2% of patients, respectively; they led to discontinuation of the ADC for 11.1% of patients. One patient experienced a TEAE in the form of massive pleural effusion that proved fatal, although this was not determined to be related to study treatment.

Any-grade treatment-related AEs occurred in 98.0% of patients, with 50.1% of those effects grade 3 or higher. Thirteen cases of interstitial lung disease were identified as suspected during treatment, and 7 of them were adjudicated as related to the ADC; 2 resulted in treatment discontinuation. The most common TRAEs observed in 10% or more of patients included fatigue (any grade, 82.8%; grade ≥3, 10.1%), nausea (74.7%; 14.1%), diarrhea (52.5%; 10.1%), alopecia (40.4%; 0%), constipation (21.2%; 0%), vomiting (18.2%; 3.0%), anorexia (16.2%; 1.0%), decreased neutrophil count (14.1%; 12.1%), abdominal pain (11.1%; 0%), stomatitis (10.1%; 0%), and anemia (10.1%; 0%).

Additional Analyses

Investigators performed IHC analysis on tumor samples at baseline and did not find any significant difference in HER3 membrane expression between responders and nonresponders with HER3 H-score (P = .8) and membrane positivity at 10x magnification (P = .4). “HER3-DXd activity was observed across a range of tumor HER3 and HER2 membrane expression in tumors by IHC,” the study authors noted.

They also performed whole-exome sequencing on 43 tumor samples at baseline and identified 73 genes of interest. When looking at genomic alterations, they found that TP53, PIK3CA, and ERBB3 alterations were more common in those who responded to the ADC vs not (53.8% vs 20.4%; 38.5% vs 17.6%; 11.5% vs 5.9%, respectively). Conversely, more patients who did not respond to patritumab deruxtecan were found to have ESR1 mutations vs those who did respond (52.9% vs 23.1%).

“Despite the limitations of the small sample size, exploratory biomarker analyses suggests that further evaluation is warranted to determine if the distribution of HER3-DXd in the tumor may play a role in determining a better treatment response,” the study authors concluded. “Following HER3-DXd treatment, upregulation of genes involved in the immune response, particularly interferon a and y, was significantly enriched in the entire cohort and among responders.”

Reference

Pistilli B, Pierotti L, Lacroix-Triki M, et al. Effiacy, safety, and biomarker analysis of ICARUS-BREAST01: A phase 2 study of patritumab deruxtecan (HER3-DXd) in patients with HR+/HER2– advanced breast cancer. Presented at: 42nd Annual Miami Breast Cancer Conference. March 6-9, 2025; Miami, Florida. Poster 82.