Early-phase data from the SOLTI TOT-HER3 and ICARUS-BREAST01 trials suggest that the novel HER3-directed antibody-drug conjugate patritumab deruxtecan may have beneficial activity in patients with hormone receptor–positive/HER2-negative and triple-negative breast cancer subtypes, according to research presented at the European Society for Medical Oncology (ESMO) Breast Cancer Annual Congress 2023.^1,2

Although further research is needed to clarify the significance of these findings and their potential impact on treatment options, authors of these studies called the findings significant given the key oncogenic role in breast cancer played by HER3, which has been associated with poor prognosis and resistance to various treatments.

Javier Cortés, MD, PhD

Mafalda Oliveira, MD, PhD

“The activity data are extremely provocative, with a promising response rate after just one dose of patritumab deruxtecan, and it is good to see preliminary activity in triple-negative breast cancer,” said Javier Cortés, MD, PhD, Head of Breast Cancer and Gynecological Tumors at the Ramón y Cajal University Hospital, Spain. “However, more data are required to confirm these preliminary results.”

Lead study author Mafalda Oliveira, MD, PhD, a medical oncologist at the Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology, Spain, who presented the results of SOLTI TOT-HER3 at the ESMO meeting, noted that HER3 has been a challenging target for researchers because of its association with poor prognosis and resistance to PI3K/AKT/mTOR inhibitors and endocrine therapy.

SOLTI TOT-HER3

The SOLTI TOT-HER3 trial is a window-of-opportunity study evaluating a single dose of patritumab deruxtecan in patients with treatment-naive HER2-negative early-stage breast cancer. Part A of the trial, which was previously reported, demonstrated the biologic and clinical activity of a single dose. Part B of the trial involved one dose of 5.6 mg/kg in 37 evaluable patients and showed a significant change in tumor cellularity and tumor-infiltrating lymphocyte score (CelTIL; P = .046).¹ The overall response rate was 32% (35% in triple-negative breast cancer and 30% in hormone receptor–positive/HER2-negative disease) and was associated with the absolute change in CelTIL (area under the curve = 0.693; P = .049).

The data showed no association between baseline ERBB3 levels and CelTIL change or overall response rate, said Dr. Oliveira, who noted that patritumab deruxtecan induced high expression of immune-related genes and suppressed proliferation-related genes.

ICARUS-BREAST01

Patritumab deruxtecan also demonstrated promising activity in the ICARUS-BREAST01 trial, a single-arm, phase II study in patients with hormone receptor–positive, HER2-negative/HER2-low advanced breast cancer, unselected for HER3 expression, with disease progression on cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, any line of targeted/endocrine therapy, and one line of chemotherapy. The study findings were presented at the ESMO meeting by Barbara Pistilli, MD, of the Breast Cancer Group at Gustave Roussy Cancer Center, Villejuif, France.²

Barbara Pistilli, MD

In the 56 evaluable patients, a partial response was observed in 16 patients (28.6%) after a median of eight cycles of patritumab deruxtecan, with stable disease in 30 patients and progressive disease in 10. The most common any-grade adverse events were nausea (76.8%) and fatigue (89.3%). Fatigue was also the most frequent grade 3 or greater adverse event (14.0%). 

DISCLOSURE: Dr. Cortés has served as consultant/advisor for Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies; has received honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, Daiichi Sankyo, and Astrazeneca; has received research funding from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman-La Roche, Guardanth Health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, and Queen Mary University of London; owns stock in MedSIR, Nektar Pharmaceuticals, and Leuko (relative); has received travel expenses from Roche, Novartis, Eisai, pfizer, Daiichi Sankyo, Astrazeneca, Gilead, and Merck Sharp & Dohme; and holds the following patents: Pharmaceutical Combinations of A Pi3k Inhibitor And A Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. Issued. Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés. US 2019/0338368 A1. Licensed. Dr. Oliveira reported financial relationships with AstraZeneca, Daiichi Sankyo/AstraZeneca, Gilead Sciences, Pierre Fabre, Roche, Seagen, iTeos, Relay Therapeutics, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Boehringer Ingelheim, GSK, Zenith Epigenetics, and Ayala Pharmaceuticals.

REFERENCES

1. Oliveira AM, Pascual T, Ortega PT, et al: Patritumab deruxtecan in hormonal receptor-positive/HER2-negative and triple negative breast cancer: Results of part B of SOLTI TOT-HER3 window of opportunity trial. ESMO Breast Cancer Annual Congress 2023. Abstract 124O. Presented May 12, 2023.

2. Pistilli B, Ibrahimi N, Lacroix-Triki M, et al: A phase 2 study of patritumab deruxtecan in patients with advanced breast cancer, with biomarker analysis to characterize response to therapy (ICARUS-BREAST01). ESMO Breast Cancer Annual Congress 2023. Abstract 189O. Presented May 12, 2023.