Evaluation of Neoadjuvant Patritumab Deruxtecan With or Without Endocrine Therapy in Treatment-Naïve HR+/HER2- High-Risk Early Breast Cancer Patients

Trial ID: 2023-503403-28-00
Protocol: SOLTI-2103
Sponsor: Solti Group

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Diseases & Conditions

Hormone receptor positive HER2 negative breast cancer

Objectives

The primary objective of this phase 2 trial is to evaluate the **efficacy** of HER3-DXd at a dosage of 5.6 mg/kg, administered either alone or in combination with letrozole, as a neoadjuvant treatment for patients with operable early breast cancer. This is clinically relevant as it aims to determine the potential of HER3-DXd to improve treatment outcomes in high-risk HR+/HER2-negative breast cancer, a subgroup with significant therapeutic challenges.

Secondary objectives include:

Evaluating other parameters of the efficacy of HER3-DXd, alone or with letrozole, compared to chemotherapy.
Assessing long-term efficacy outcomes of HER3-DXd, alone or with letrozole, and chemotherapy.
Evaluating the CelTIL score at C1D21 and its predictive ability for pathological response at surgery and other response endpoints.
Assessing the predictive ability of HER3 receptor expression levels by IHC and ERBB3 mRNA expression level for pathological response at surgery.
Evaluating Ki67 IHC after 21 days of treatment and its predictive ability for pathological response at surgery and other response endpoints.
Describing the safety and tolerability of HER3-DXd with or without endocrine therapy versus chemotherapy in the neoadjuvant setting.
Assessing the quality of life of participants treated with HER3-DXd, either alone or in combination with letrozole, and chemotherapy.

Participants

The clinical trial involves a study population comprising both **male** and **female** participants, aged 18 years and older, who are treatment-naïve and diagnosed with HR+/HER2-negative high-risk early breast cancer. The trial includes individuals with histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast, specifically at Stage II to Stage IIIB, with no distant metastasis. Participants must have at least one lesion measuring 10 mm or more by MRI and exhibit an ER-positive and/or PgR-positive and HER2-negative tumor profile. The study population is characterized by a Ki67 IHC percentage of 20% or higher, or a high genomic risk as defined by specific gene signatures. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population was selected based on their eligibility for neoadjuvant chemotherapy and primary surgery, with the availability of pre-treatment tumor tissue samples for biomarker analysis. The sponsor has not provided the total number of participants involved in this trial. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **patritumab deruxtecan** as a neoadjuvant treatment for patients with high-risk HR+/HER2-negative early breast cancer. This is a phase II, randomized, double-blind, controlled study. The trial commenced on November 25, 2022, and is expected to conclude by October 17, 2029. Participants will be involved in the study for a maximum treatment period of 21 days, with the possibility of early termination if they do not meet the inclusion criteria or if adverse events occur that compromise their safety.

The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as adequate hematologic and end-organ function, and a negative serum pregnancy test for women of childbearing potential. Following the screening, participants will undergo treatment with patritumab deruxtecan administered intravenously at a dose of 5.6 mg/kg. Follow-up visits will be scheduled to monitor the participants' response to the treatment and to assess any adverse events. The end-of-study visit will evaluate the primary endpoint, which is the rate of pathological complete response in the breast and axillary lymph nodes at surgery.

Participants are expected to comply with trial procedures, including the use of effective contraception methods for both male and female participants, as specified in the protocol. Conditions that may lead to early termination from the study include non-compliance with trial procedures, withdrawal of consent, or the occurrence of severe adverse events. The trial aims to provide valuable insights into the potential benefits of patritumab deruxtecan in treating high-risk HR+/HER2-negative early breast cancer, contributing to the advancement of therapeutic options for this patient population.

Treatment

The clinical trial involves the administration of **Patritumab deruxtecan (U3-1402)**, an experimental medication formulated as a **lyophilized powder for preparation for injection**. This investigational drug is administered intravenously. The dosing regimen for Patritumab deruxtecan is set at a maximum daily dose of 5.6 mg/kg, with the treatment cycle repeating every 21 days. The active substance, Patritumab deruxtecan, is classified as a protein of other origin. The trial aims to evaluate the efficacy of this drug, either as a monotherapy or in combination with letrozole, in subjects with operable early breast cancer as a neoadjuvant treatment.

In addition to the experimental treatment, the study may include the administration of **letrozole**, a standard-of-care therapy, as part of the combination treatment arm. Letrozole is an aromatase inhibitor commonly used in the treatment of hormone receptor-positive breast cancer. The inclusion of letrozole in the treatment regimen is intended to assess the potential synergistic effects when combined with Patritumab deruxtecan. The dosing schedule and administration route for letrozole will follow standard clinical practice guidelines for its use in breast cancer therapy.

Participant compliance with the dosing regimen will be monitored throughout the trial to ensure adherence to the treatment protocol. This will involve regular assessments and documentation of drug administration, as well as any deviations from the prescribed dosing schedule. The trial is designed to maintain rigorous standards for data collection and analysis to accurately evaluate the safety and efficacy of the investigational treatment.

Efficacy

The efficacy of **Patritumab deruxtecan** in the clinical trial will be assessed using a range of primary and secondary endpoints. The primary endpoint is the rate of pathological complete response in the breast and lymph nodes (pCRBL), defined as the complete absence of invasive carcinoma in the breast and axillary lymph nodes on histological examination at surgery. Secondary endpoints include the rate of Residual Cancer Burden (RCB) category status assessed by a local pathologist, tumor overall objective response rate (ORR) as per RECIST v1.1, invasive disease-free survival (iDFS) rates at 3 and 5 years follow-up, and changes in CelTIL score from baseline to C2D1.

Additional secondary endpoints involve the correlation of CelTIL changes with pCR, RCB, ORR, and iDFS, as well as the correlation of pCR with HER3 receptor expression levels and ERBB3 mRNA expression levels. Changes in Ki67 IHC from baseline to C2D1 and their correlation with pCR, RCB, ORR, and iDFS will also be evaluated. The assessment of type, incidence, severity, and attribution of treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESI) will be conducted according to NCI CTCAE v. 5.0. Patient-reported outcomes will be measured using changes from baseline in EORTC QLQ-C30 and EORTC QLQ BR23 scores.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Signed ICF
Male/female . At least 18 years old
Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast untreated and recently diagnosed, Stage II to stage IIIB breast cancer, Absence of distant metastasis. At least 1 lesion ≥ 10 mm by MRI
ER-positive and/or PgR-positive and HER2-negative tumor
Ki67 IHC % ≥ 20% locally assessed and/or high genomic risk (defined by gene signature): Oncotype DX® RS ≥ 26, Mammaprint® = Risk of Recurrence High Endopredict® = High Risk or Prosigna® ROR ≥ 60.
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Breast cancer eligible for primary surgery.
Availability of pre-treatment tumor tissue sample of FFPE tumor block from primary tumor for biomarker analysis.
Eligible for neoadjuvant chemotherapy
Adequate hematologic and end-organ function
willing and able to comply with trial procedures.
Women of childbearing potential must have confirmed negative serum pregnancy test
Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the time of final study drug administration.
Women of CBP must be willing to use highly effective methods of contraception.
Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception and fetal protection for the duration of neoadjuvant treatment phase and after the last dose of treatment according to protocol.
Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and for at least 4 months after the final study drug administration.
Postmenopausal or pre-menopausal
Patients must have the ability to swallow oral medication.
Baseline LVEF ≥ 50%

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Exclusion Criteria

Metastatic (Stage IV) breast cancer.
Bilateral invasive breast cancer.
Any treatment for the currently diagnosed BC prior to enrollment.
Patients in whom a primary tumor excisional biopsy was performed
Prior treatment with a HER3 antibody, topoisomerase I inhibitor, with an ADC which consists of an exatecan derivative that is a topoisomerase I inhibitor (e.g., DS-8201) and with a govitecan derivative (e.g., IMMU- 132).
Patient has active cardiac disease or a history of cardiac dysfunction including any of the following:
Medical history of clinically significant lung diseases (e.g., interstitial pneumonia, pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis) or who are suspected to have these diseases by imaging at screening period.
Major surgical procedure or significant traumatic injury within 28 days prior to randomization.
Assessment by the investigator to be unable or unwilling to comply with the requirements of the protocol.
Patients with a history of any malignancy are ineligible (some exception detailed in protocol)
Current severe, uncontrolled systemic disease or other factors which in the Investigator's opinion makes it undesirable for the subject to participate in the study or which would jeopardize compliance with the protocol
Concurrent, serious, uncontrolled infections or current known infection with HIV or active hepatitis B and/or hepatitis C
History of significant co-morbidities that, in the judgment of the investigator, may interfere with the conduction of the study, the evaluation of response, or with ICF.
Known hypersensitivity to either the drug substance components or inactive ingredients in the drug product or history of severe hypersensitivity reactions to other monoclonal antibodies.
History of exposure to cumulative anthracycline
Any history of interstitial lung disease (ILD) (including pulmonary fibrosis or radiation pneumonitis), has current ILD, or is suspected to have such disease by imaging during screening.
Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement.
Has unresolved toxicities from previous anticancer therapy
Non-eligible for taxanes therapy.
Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to Cycle 1 Day 1.
Evidence of any leptomeningeal disease.
Has clinically significant corneal disease.
Female subject who is pregnant or breastfeeding or intends to become pregnant during the study.
Subjects who are currently receiving chloroquine or hydroxychloroquine. A washout period of > 14 days is required prior to randomization or Cycle 1 Day 1