Clinical Response to Seribantumab, an Anti–Human Epidermal Growth Factor Receptor-3 Immunoglobulin 2 Monoclonal Antibody, in a Patient With Metastatic Pancreatic Ductal Adenocarcinoma Harboring an NRG1 Fusion

Introduction

Neuregulin-1 (NRG1) fusions are rare oncogenic driver alterations found in 0.2%-0.5% of solid tumors.^1,2 In an analysis of approximately 22,000 solid tumors, 70% of tumor types harboring NRG1 fusions were adenocarcinomas.¹ The frequency of NRG1 fusions identified in the pancreatic cancer subset was 0.5%¹; however, other studies suggest enrichment (6%) in KRAS wild-type (wt) pancreatic ductal adenocarcinoma (PDAC). Most NRG1 fusion partners contain a transmembrane domain and sequester high levels of the NRG1 ligand with an intact epidermal growth factor receptor–like tyrosine kinase–binding domain near its primary receptor, the human epidermal growth factor receptor (HER)3/ERBB3.^3,4 This results in overactivation of HER3 and downstream signaling pathways including the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) pathways.² In patient-derived xenograft (PDX) models harboring an NRG1 fusion, inhibition of ligand-dependent activation of HER3 by seribantumab resulted in blockade of the HER family and downstream signaling, producing tumor regression.⁵ Tumors harboring NRG1 fusions do not respond well to currently available therapies.^1,2,6-10

Outcomes with PDAC are dismal with high mortality rates and a 5-year survival rate of < 10%.^11-14 Chemotherapy with gemcitabine-based regimens or folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) is recommended for patients with advanced PDAC.^15-17 However, these regimens have shown limited efficacy^18,19 and are often associated with toxicities that negatively affect patients' quality of life.^11,19,20

The Cancer Molecular Screening and Therapeutics (MoST) program is an Australian precision oncology program using DNA- and RNA-based sequencing to identify targetable genomic alterations in treatment-refractory advanced cancers.^21,22

Seribantumab is a fully human anti-HER3 IgG2 monoclonal antibody that blocks the ligand-dependent activation of HER3 and HER3-HER2 dimerization.⁵ This leads to reduced phosphorylation across the ERBB family and inhibition of the PI3K/AKT and MAPK downstream signaling pathways, resulting in tumor regression in preclinical models harboring an NRG1 fusion.^5,23 Seribantumab dose-dependently inhibited phosphorylation of key signaling pathways in human pancreatic ductal epithelial cells expressing an ATP1B1-NRG1 fusion and inhibited tumor growth in a PDX model of PDAC harboring an APP-NRG1 fusion.²⁴ Although preclinical data^5,24 and case reports^8,25-27 have previously described NRG1 fusions as a biomarker for other HER2-/HER3-directed therapies and there is active clinical investigation with seribantumab in this molecular subset,²⁸ to our knowledge, this case report is the first characterization of seribantumab's clinical activity in an Australian patient with an ATP1B1-NRG1 fusion, treated through compassionate access.

Case Report

A 38-year-old woman was diagnosed with stage IV PDAC with metastases to the liver and peripancreatic lymph nodes in 2019. She presented with biliary obstruction, requiring biliary stenting. The patient received first-line treatment with FOLFIRINOX from October 2019 until January 2020 when she developed acute gangrenous cholecystitis, managed with cholecystectomy. Upon recommencement of the same regimen, she developed multiple allergic reactions to oxaliplatin requiring omission. The patient continued on folinic acid, fluorouracil, and irinotecan (FOLFIRI) with intermittent delays in treatment because of cumulative toxicities until June 2020. The patient then received gemcitabine/nab-paclitaxel as second-line treatment from June to August 2020, when she developed progressive disease in the liver. FOLFIRI was reinitiated with multiple dose interruptions because of myelotoxicity.

In November 2020, comprehensive genomic profiling through the MoST program (Fig 1) revealed an ATP1B1-NRG1 fusion in the RNA component joining ATP1B1 (exon 2) to NRG1 (exon 2). This fusion retains the immunoglobulin (Ig) domain of NRG1 and all downstream domains including the epidermal growth factor–like domain, as previously described.²⁹

FIG 1.

Clinical course of a patient with PDAC harboring an ATP1B1-NRG1 fusion. ATP1B1, ATPase Na+/K+ transporting subunit beta 1; FOLFIRI, fluorouracil, leucovorin, and irinotecan; FOLFIRINOX, folinic acid, fluorouracil, irinotecan, and oxaliplatin; KRAS, Kirsten rat sarcoma; NRG1, neuregulin-1; PDAC, pancreatic ductal adenocarcinoma; wt, wild-type.

A gain-of-function frameshift mutation in the oncogene JUN was the only other pathogenic genomic alteration identified. KRAS mutations were absent in this tumor (KRAS wt), consistent with mutual exclusivity of NRG1 fusions and other oncogenic drivers.³⁰

On the basis of emerging preclinical data for seribantumab and clinical case reports of effective targeting of ATP1B1-NRG1 with anti–HER2-/HER3-directed therapies,^27,31-33 access to seribantumab was pursued, requiring a collaborative effort with Elevation Oncology Inc to provide seribantumab compassionately through the Special Access Scheme (SAS) program. SAS allows patients to access treatments that are not included on the Australian Register of Therapeutic Goods³⁴; with seribantumab only under clinical investigation in the United States at that time, and no appropriate clinical trials available in Australia. Approval to administer seribantumab required evidence from clinical case reports demonstrating effective targeting of NRG1 fusions with comparable agents in patients with pancreatic cancer (Table 1).^25,32,33,35 In December 2020, the patient began seribantumab therapy.

TABLE 1.

Previous Studies/Case Reports Evaluating HER-Targeted Therapies in Patients With Pancreatic Cancer Harboring NRG1 Fusions

Clinical response was observed within the first week of treatment; carbohydrate antigen 19-9 (CA 19-9) decreased from 1,143 IU/mL to 818 IU/mL. Initial tumor assessment on seribantumab therapy revealed a 14% tumor reduction in target liver lesions (Fig 2). After 3 months of treatment, CA 19-9 levels reached a nadir of 60 IU/mL and, at 4 months, imaging demonstrated a partial response per Response Evaluation Criteria in Solid Tumors version 1.1, with a 39% reduction in target lesions (Fig 2). There was a gradual increase in CA 19-9 level to 85 IU/mL.

FIG 2.

Seribantumab clinical activity in a patient with KRAS wt PDAC harboring an ATP1B1-NRG1 fusion. Plot of CA19-9 tumor marker (blue line) and sum of target lesions (red line). Dot represents time point of measurement. ATP1B1, ATPase Na+/K+ transporting subunit beta 1; CA 19-9, carbohydrate antigen 19-9; KRAS, Kirsten rat sarcoma; NRG1, neuregulin-1; PDAC, pancreatic ductal adenocarcinoma; PR, partial response; SD, stable disease; wt, wild-type.

The patient initiated treatment with seribantumab following the dosing schema explored in the ongoing CRESTONE study consisting of a loading dose of seribantumab 3,000 mg administered as a single 1-hour intravenous (IV) infusion once on week 1, followed by 2,000 mg, 1-hour IV infusion once weekly (week 2-4), and then maintenance dosing consisting of a fixed dose of 3,000 mg IV once every 2 weeks. Given the favorable safety and tolerability profile of seribantumab and to align with the updated dosing regimen of the CRESTONE study, in April 2021, the patient was transitioned to seribantumab 3,000 mg IV once weekly. At the June 11, 2021, data cutoff, imaging showed further tumor shrinkage with a 53% reduction in the target lesions within the liver (Figs 2 and 3), reflecting disease control of 6 months and a duration of response of 2 months, which is ongoing.

FIG 3.

Confirmed partial response in a patient with KRAS wt PDAC harboring an ATP1B1-NRG1 fusion: (A) target lesion 1 and (B) target lesion 2, at baseline and after 6 months on treatment with seribantumab. ATP1B1, ATPase Na+/K+ transporting subunit beta 1; KRAS, Kirsten rat sarcoma; NRG1, neuregulin-1; PDAC, pancreatic ductal adenocarcinoma; wt, wild-type.

Seribantumab was generally well tolerated. She reported improved energy levels, which allowed resumption of social activities and hobbies. During treatment with seribantumab, the patient reported intermittent grade 1/2 diarrhea, managed with loperamide. Diarrhea may have been confounded by a new diagnosis of type II diabetes requiring initiation of metformin before commencing seribantumab treatment and metformin uptitration during seribantumab therapy. The patient experienced a flare of her pre-existing seasonal fungal rash over the axilla, breast, and umbilicus, which resolved with topical antifungal treatment. This was the presumed cause for the reactive axillary lymph node enlargement seen on imaging. Six months after starting seribantumab, the patient experienced a grade 2 rise in ALT and grade 1 rise in AST. This was in the context of two courses of oral antibiotics for paronychia of the big toe. As a precautionary measure, the seribantumab dose was reduced by 25% (2,250 mg for one dose for 1 week) followed by a 1-week treatment delay. ALT and AST levels returned to baseline, and the patient resumed seribantumab treatment at full dose once weekly. There were no other adverse events.

The authors obtained informed consent to publish the report and clinical images from the patient.

Patient Consent

The authors obtained informed consent to publish the report and clinical images from the patient. This case study treatment falls under research exemption policies and thus, no ethics committee/institutional review board approval was required.

Discussion

This case report demonstrates proof of clinical activity of seribantumab in a patient with a treatment-refractory, metastatic KRAS wt PDAC harboring an ATP1B1-NRG1 fusion.^1,33,36 The patient was treated with seribantumab under the SAS program following the dosing schema used in the CRESTONE study. When the study was amended to evaluate a weekly dosing regimen, the patient transitioned to the new dosing frequency, which may have contributed to continued clinical benefit. After 6 months of treatment, the patient's tumor continues to show radiologic response and good tolerability with only grade 1/2 adverse events, even on a weekly dosing regimen. This was consistent with the previously established safety profile of seribantumab monotherapy and combination therapy.³⁷ The patient also reported improved energy levels and had resumed some of her normal activities, suggesting improvements in quality of life, which is remarkable for a patient with treatment-refractory advanced cancer.^38,39

In this case study, standard-of-care therapies had been exhausted before the patient's tumor was sequenced through the MoST program. The patient benefited from biomarker-based therapy with seribantumab on the basis of the NRG1 fusion, highlighting the importance of comprehensive genomic profiling at diagnosis, including an RNA component that is particularly crucial for detecting gene fusions.^40-42 Earlier testing provides an opportunity to ensure appropriate targeted treatments are initiated without delay.^42-44

Although only 7%-10% of pancreatic cancers are KRAS wt, this is more common in patients younger than 50 years.³⁶ This case study provides rationale for further evaluation of HER3-directed therapies such as seribantumab in these patient subsets, with the added advantage of less toxicities compared with standard therapies.^2,11,19,20

Several studies are underway to assess the efficacy of HER3-targeting therapies in tumors harboring NRG1 fusions.^2,28,45,46 The phase II CRESTONE (ClinicalTrials.gov identifier: NCT04383210) study of seribantumab is enrolling patients with solid tumors harboring an NRG1 fusion. The confirmed overall response rate (ORR) across tumor types was 33% including two complete responses and a disease control rate of 92%.⁴⁷ Similarly, zenocutuzumab, a HER2/HER3 bispecific antibody, demonstrated an ORR of 34% across tumor types and 42% in PDACs, with no complete responses and 76% of patients maintaining an objective response at 6 months.³⁵ The CRESTONE study is enrolling patients in Australia in collaboration with the University of Sydney and Omico through MoST CRESTONE.

AUTHOR CONTRIBUTIONS

Conception and design: Subotheni Thavaneswaran, Ray Asghari, Valerie M. Jansen, David M. Thomas

Financial support: David M. Thomas

Provision of study materials or patients: Subotheni Thavaneswaran, Ray Asghari

Collection and assembly of data: Subotheni Thavaneswaran, Wei Yen Chan, John P Grady, David M. Thomas

Data analysis and interpretation: Subotheni Thavaneswaran, Wei Yen Chan, John P Grady, Maegan Deegan, Valerie M. Jansen, David M. Thomas

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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