HERTHENA-PanTumor01: a phase II study of patritumab deruxtecan (HER3-DXd) in previously treated advanced solid tumors.

1.
Introduction
1.1.
Background and rationale
1.1.1.
HER3 is a promising target
Human epidermal growth factor receptor (HER) 3 is a member of the HER family of receptor tyrosine kinases [1]. HER3 preferentially forms dimers with HER family members HER2 and epidermal growth factor receptor (EGFR) but can also dimerize with non-EGFR proteins such as MET proto-oncogene receptor tyrosine kinase and fibroblast growth factor receptor 2 [2]. The ligands of HER3 are neuregulins 1 through 4 [1–3]. Upon ligand binding and heterodimerization, downstream intracellular signaling through phosphoinositide 3-kinase and mitogen-activated protein kinase promotes cancer cell survival and proliferation [2].
HER3 messenger RNA and protein expression has been observed in many tumor types, including melanoma [4–8], gastric and gastroesophageal junction (GEJ) cancer [8–11], human papilloma virus (HPV)-associated and HPV-negative head and neck squamous cell cancer (HNSCC) [8,12–14], ovarian cancer [8,15], cervical cancer [15,16], endometrial cancer [8,15], bladder cancer [8,17], esophageal squamous cell carcinoma (ESCC) [8,18], pancreatic cancer [8,19], and prostate cancer [20], as shown in Table 1. In many of these cancers, HER3 expression has been associated with poor clinical outcomes, including decreased survival [4–7,9,10,14–17,19–25]. HER3 expression has also been implicated in treatment resistance to EGFR inhibitors in HNSCC in preclinical models [26]. Additionally, low HER3 expression (H-score ≤50) has been associated with an increased progression-free survival benefit with afatinib, an EGFR tyrosine kinase inhibitor, compared with methotrexate [27]. Despite these observations, there is currently no HER3-directed antibody-drug conjugate approved for the treatment of any cancer.

1.1.2.
Key attributes of HER3-DXd and previous HER3-DXd data
HER3-DXd is an investigational HER3-directed antibody-drug conjugate composed of a fully human anti-HER3 immunoglobulin G1 monoclonal antibody (patritumab) covalently linked to a topoisomerase I inhibitor payload (deruxtecan, an exatecan derivative) via a stable tetrapeptide-based cleavable linker [28–33]. HER3-DXd selectively binds to HER3 on the surface of tumor cells and is internalized by the cell [29,31]. After internalization, HER3-DXd is trafficked to lysosomes, where the linker is selectively cleaved by lysosomal enzymes upregulated in tumor cells [29,32,34]. The deruxtecan payload is released and enters the cell nucleus, where it causes DNA damage that leads to tumor cell death [29,32,33]. The membrane permeability of the deruxtecan payload allows for a bystander antitumor effect that can result in cell death in neighboring cells, including those that lack HER3 expression [33].
HER3-DXd has demonstrated meaningful and durable efficacy in previously treated, EGFR-mutated non-small cell lung cancer (NSCLC). Antitumor efficacy was observed across a range of baseline HER3 expression levels in NSCLC [35,36]. In patients with EGFR-mutated NSCLC, antitumor activity was observed in those with tumors harboring diverse genomic alterations associated with EGFR tyrosine kinase inhibitor resistance [35,36]. HER3-DXd demonstrated clinically meaningful and durable intracranial responses in patients with EGFR-mutated NSCLC with central nervous system (CNS) metastases that had not been previously irradiated [36]. In EGFR-mutated NSCLC, HER3-DXd demonstrated clinical effectiveness across a range of HER3 expression levels [35,36]. The safety profile of HER3-DXd was manageable and tolerable in patients with NSCLC, with rates of treatment discontinuation due to adverse events ranging from 7% to 10% [35,36]. Previous trials of HER3-DXd have also assessed translational endpoints; however, mechanisms of resistance to HER3-DXd and the role of HER3 as a biomarker for determining treatment efficacy are poorly characterized.
Treatment with HER3-DXd resulted in clinically meaningful efficacy in HER3-expressing, unresectable advanced or metastatic breast cancer (BC). Antitumor activity has been demonstrated in heavily pretreated patients across major BC subtypes (hormone receptor positive/HER2 negative, triple negative, and HER2 positive) across a range of HER3 expression [37,38]. Similar to results in NSCLC, HER3-DXd treatment in BC was considered manageable and tolerable, with rates of treatment discontinuations attributed to adverse events in the range of 10% to 13% [37,38].
In preclinical studies, HER3-DXd has demonstrated antitumor activity in patient-derived xenograft (PDX) and cell-line models of melanoma, gastric cancer, and prostate cancer (Table 1). HER3-DXd treatment once weekly for 2 weeks in a CM-3 mouse tumor model of melanoma was associated with significant inhibition of tumor growth compared with the control treatment [28]. In a PDX model of gastric cancer, HER3-DXd once weekly for 3 weeks demonstrated significant antitumor activity compared with control [29]. Finally, HER3-DXd treatment once weekly for 5 weeks resulted in durable (up to 60 days after the last injection) antitumor activity in the CP50-PDX mouse model of HER3-expressing, previously treated prostate cancer [20].

1.1.3.
Tumor selection
As mentioned previously, HER3 expression has been found in melanoma, gastric and GEJ cancer, HNSCC, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, ESCC, pancreatic cancer, and prostate cancer. Additional criteria for the selection of tumors for investigation, including evidence of topoisomerase I inhibitor sensitivity [39–46], are shown in Table 1. Each of the tumor types included in the study has an unmet medical need in the advanced or refractory setting with no satisfactory alternative treatment options following progression on standard therapy.

1.2.
Objectives and trial design
HERTHENA-PanTumor01 (NCT06172478) is an ongoing global, multicohort, signal-seeking, phase II trial assessing the efficacy and safety of HER3-DXd in patients with relapsed or refractory locally advanced or metastatic solid tumors including melanoma, HNSCC, gastric/GEJ cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, ESCC, pancreatic cancer, and prostate cancer (Figure 1). Patients are being enrolled at trial sites in Asia (Japan, Republic of Korea, and Taiwan), Australia, Europe (Belgium, France, Spain, and the United Kingdom), and North America (the United States). Patient enrollment began in February 2024, with the first patient receiving the first dose of HER3-DXd in March 2024. HERTHENA-PanTumor01 has an estimated completion date of 30 April 2026.

2.
Methods
2.1.
Study design
All patients must sign the study informed consent form, including consent for the provision of tumor tissue. During the screening period, patients must provide a pretreatment tumor biopsy from ≥1 lesion that was not previously irradiated or archival tumor tissue from a biopsy obtained at the time of disease progression while on or after the previous systemic treatment. Patients undergo baseline tumor imaging, including a brain magnetic resonance imaging (MRI) or computed tomography (CT) scan, during the screening period. After all screening procedures, patients begin the study treatment, which continues until the time of disease progression, unacceptable toxicity, death, loss to follow-up, withdrawal of consent, or other reason for discontinuation. An optional end-of-treatment tumor biopsy is performed at the time of progression or discontinuation from HER3-DXd. An end-of-treatment visit occurs approximately 7 days after the final dose of HER3-DXd or after the decision to stop treatment. Approximately 40 days after treatment discontinuation, a safety follow-up visit occurs, and follow-up for antidrug antibodies (if the patient was previously positive for antidrug antibodies) and survival continues every 3 months.

2.2.
Enrollment criteria
Approximately 40 patients will be enrolled into each tumor-specific cohort to receive HER3-DXd 5.6 mg/kg intravenously once every 3 weeks. Patients must be adults (aged 18 years or local age of consent) with locally advanced unresectable or metastatic disease not curable by surgery or radiation. Patients must have ≥1 measurable lesion on CT or MRI scan by investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; patients with prostate cancer and bone-only disease may also be eligible. Participants must have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 and adequate bone marrow reserve and organ function within 14 days prior to cycle 1 day 1. Patients with clinically inactive or treated brain metastases who are asymptomatic (without neurological signs or symptoms and not requiring treatment with corticosteroids or anticonvulsants) may be included.
Patients who have a history of interstitial lung disease (ILD) and/or pneumonitis requiring corticosteroid treatments, current ILD, or suspected ILD based on imaging during screening or clinically severe respiratory compromise resulting from intercurrent pulmonary illnesses are excluded. Those who require use of chronic systemic corticosteroids >10 mg/day (prednisone or equivalent) are not allowed. Additionally, patients who have evidence of clinically active spinal cord compression or brain metastases, defined as being symptomatic or untreated or requiring therapy with corticosteroids or anticonvulsants, or any history or current evidence of leptomeningeal disease are not eligible. Prior treatment with an anti-HER3 antibody and/or antibody-drug conjugate containing an exatecan derivative that is a topoisomerase I inhibitor (eg, trastuzumab deruxtecan) or previous treatment with irinotecan in the advanced or metastatic setting is not allowed.
Key eligibility criteria specific to the 10 tumor cohorts are shown in Table 2.

2.3.
Outcome measures and endpoints
The primary objective of this trial is to investigate the antitumor activity of HER3-DXd in patients with previously treated solid tumors, measured by the primary endpoint of objective response rate as assessed by the local investigator per RECIST 1.1 in all cohorts except for prostate cancer. In the prostate cancer cohort, the primary endpoint is the prostate-specific antigen (PSA) 50 response rate, defined as the proportion of patients achieving a ≥ 50% decrease in PSA from baseline to any post-baseline PSA amount, confirmed by a consecutive PSA measurement ≥3 weeks later. Both primary endpoints will be presented with a 2-sided 95% confidence interval using the Clopper-Pearson method, and the data will be summarized by cohort.
Secondary endpoints include safety, additional efficacy endpoints, pharmacokinetic endpoints, and assessment of the relationship between baseline HER3 expression and HER3-DXd efficacy. Due to the high incidence of CNS metastases in patients with melanoma, affecting up to 33% of patients at the time of diagnosis [47], an exploratory CNS response endpoint has been included for this cohort. All study endpoints, including specific secondary and exploratory endpoints for the prostate cancer and melanoma cohorts, are summarized in Table 3. This study is collecting required pretreatment and optional end-of-treatment tumor samples to evaluate potential associations between HER3 expression or other factors and efficacy.

2.4.
Study procedures
The treatment period begins after the informed consent form is signed and screening procedures, including collection of a pretreatment tissue sample, are completed. Dosing with HER3-DXd starts on day 1 of cycle 1 and is repeated every 21 days until the end of treatment. Baseline tumor assessments must be performed within 35 days before randomization. For patients in the prostate cancer cohort, a blood sample must be collected within 28 days prior to cycle 1 day 1. Radiographic tumor assessments are performed per RECIST 1.1 every 6 weeks for the first 48 weeks of treatment and then every 12 weeks until disease progression, death, loss to follow-up, or withdrawal of consent. All patients must have a contrast-enhanced brain MRI or CT scan done as part of baseline assessments. Patients in the melanoma cohort and those in non-melanoma cohorts with evidence of inactive brain metastases at baseline will also have a contrast-enhanced brain MRI or CT scan done during serial tumor assessments. Objective response will be assessed by the investigator, with all responses requiring confirmation ≥4 weeks after the initial response is observed.
Safety is assessed in all patients after signing of the informed consent form and up to 47 days after the last dose of HER3-DXd by physical examination, clinical laboratory tests, cardiac evaluation, ECOG PS, and ophthalmologic examination. Adverse event monitoring and toxicity grading are in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. An independent ILD adjudication committee reviews all potential cases of ILD, and all cases of ILD will be monitored until resolution regardless of severity or seriousness.
Blood samples for pharmacokinetic analyses are collected from all enrolled patients throughout the study to investigate serum concentrations of HER3-DXd, total anti-HER3 antibody, and released payload and the presence of neutralizing antidrug antibodies. Exploratory biomarkers are being assessed in all patients using blood samples collected at multiple time points and tissue samples acquired prior to treatment (a new core biopsy or archival sample) and at the end of treatment.
As a further exploratory endpoint, qualitative interviews that characterize the impact of treatment are conducted at baseline and during cycle 4 of treatment. A total of 15 patients from each cohort will be asked open-ended questions regarding the experience of treatment, the timings of treatment- and disease-related symptoms, and how these symptoms impact overall functioning and quality of life.

2.5.
Data collection, management, and statistical analysis
An electronic case report form, which is created for any patient who signs an informed consent form and undergoes a screening procedure, is reviewed by the investigator. Data are vetted electronically and manually to ensure quality; all adverse events are coded using the Medical Dictionary for Regulatory Activities, and all concomitant medications and prior cancer therapies are coded using the World Health Organization Drug Reference Dictionary. For each of the 10 cohorts, an interim analysis will be performed. The primary analysis for each cohort will occur when all patients in a cohort have either had a minimum of 9 months of follow-up or have discontinued from the trial at an earlier time point. This date will be used as the data cutoff for the primary analysis in the individual cohort.

2.6.
Data monitoring and auditing
Regular inspections of facilities and various study records are performed to ensure protocol adherence, accuracy of the data, and adherence to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline for Good Clinical Practice E6 and local regulatory requirements for the conduct of clinical research. All adverse events are reported in the electronic case report form and include the investigator’s assessment of seriousness, severity, and causality to study treatment.

3.
Ethics and dissemination
The HERTHENA-PanTumor01 protocol is approved by the institutional review board at each participating institution. This study is being conducted in compliance with the protocol, the ethical principles of the Declaration of Helsinki, the International Council for Harmonisation Guideline for Good Clinical Practice E6, and local regulatory requirements. Informed consent is obtained from all patients and is documented in the patients’ electronic medical records.

4.
Conclusion
Ten solid tumor types were chosen for inclusion in the HERTHENA-PanTumor01 trial based on HER3 expression, evidence of clinical activity of topoisomerase I inhibitor therapy, and in some cases preclinical activity of HER3-DXd. Results from the HERTHENA-PanTumor01 study will provide greater insight into the antitumor efficacy and safety profile of HER3-DXd in solid tumors, potentially informing additional clinical investigation.

Supplementary Material

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