Perseverance Is the Name of the Game With HER3 Research in Solid Tumors

Although the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTKs) plays a central role in the development of human cancers, efforts to target its activity therapeutically have focused thus far on 2 of its now famous members. Therapies aimed at the epidermal growth factor receptor (EGFR/ HER1) and HER2, renowned as major drivers of lung and breast cancer, respectively, were among the first targeted agents in the anticancer armamentarium.

Another member of this receptor family, HER3, has also been implicated in the development of a number of cancer types but was previously largely overlooked as a therapeutic target because of its lack of kinase activity. A growing appreciation of HER3 as the principal partner for HER2 in its oncogenic activities, and accumulating evidence implicating HER3 activation as a major cause of treatment failure, drove the development of numerous HER3-targeting monoclonal antibodies (mAbs) during the 2000s.

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Nevertheless, investigators have persevered, and new types of drugs have largely supplanted the first generation in clinical trials. These include bispecific antibodies targeting HER2 in addition to HER3 and a HER3-targeting antibody-drug conjugate (ADC). The latter, U3-1402, recently showed encouraging activity in heavily pretreated patients with HER3-overexpressing breast cancer and, in a separate trial, in patients with EGFR inhibitor—resistant, EGFR-mutant non—small cell lung cancer (NSCLC).^1,2

Meanwhile, the hunt continues for predictive biomarkers and appropriate partners for combination therapy. Recently, fusions involving the NRG1 gene, which encodes the HRG ligand, were identified in a small number of patients with a variety of tumor types. Clinical trials have already begun to enroll patients with these abnormalities.

A Pseudokinase

HER3 is one of 4 highly homologous RTKs that make up the HER family. Found predominantly on the surface of epithelial, mesenchymal, and neuronal cells, these receptors are key players in the transduction of intracellular signals that regulate normal cell growth and differentiation via binding of a wide range of different ligands.^3-5

Discovered 30 years ago,⁶ HER3 is unique among HER family members because it is a pseudokinase. Originally thought to be catalytically inactive, HER3 may possess a low level of kinase activity according to more recent studies, but it primarily signals through noncatalytic mechanisms.^3-5

Normally, upon ligand binding, RTKs pair up with either another receptor molecule of the same type (homodimerization) or a different kind of RTK (heterodimerization). This causes a conformational change in the second receptor molecule and triggers its tyrosine kinase activity. Because it has limited kinase activity, HER3 cannot signal through homodimers; its activity therefore relies on the formation of heterodimers with other members of the HER family, predominantly HER2.^3-5

In addition to forming heterodimers with HER family members, HER3 has been shown to partner with other RTKs, such as fibroblast growth factor receptor 2 and hepatocyte growth factor receptor.⁷

HER3 is activated by 2 ligands, HRG1 and HRG2, both members of the heregulin protein family. Heregulins are also interchangeably referred to as neuregulins (NRG1 and 2, respectively). Following ligand binding and heterodimerization, HER3’s kinase partner is activated and phosphorylates tyrosines within the intracellular domain of HER^3.8,9 These phosphorylated tyrosines form a binding platform for a host of key proteins that subsequently trigger downstream signaling cascades, including PI3K/AKT, MAPK, and JAK/STAT pathways (Figure).^3-5

HER3 contains the most phosphorylation sites of any of the HER family receptors and is therefore thought to play an important role as a signal amplifier for other receptors.³ This is exemplified by the fact that the PI3K pathway is activated downstream of HER2, but HER2 itself has only a weak affinity for PI3K.¹⁰ HER3, on the other hand, contains 6 tyrosines that, when phosphorylated, can bind to PI3K. Moreover, among all the possible HER receptor pairs, HER2/ HER3 heterodimers are the most potent activators of PI3K signaling.³

Oncogenic Double Act

Because HER receptors coordinate many important cellular processes, they are frequently found to be altered in cancer cells; such mutations promote many of the hallmark properties of oncogenesis, such as unchecked cell proliferation and survival. HER2 protein overexpression is found in a substantial proportion of breast tumors, for example, and activating mutations in the kinase domain of EGFR are well-established drivers of lung cancer.

HER3 is no exception to this trend; HER3 overexpression has been noted in many different types of cancer, including breast, gastric, colorectal (CRC), bladder, prostate, and ovarian, as well as NSCLC, head and neck squamous cell carcinoma (HNSCC), and melanoma.^4,5

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Data also indicate that HER3 overexpression may have prognostic significance. In a meta-analysis of 12 clinical trials that included patients with gastric, ovarian, pancreatic, breast, and cervical cancers, as well as melanoma, CRC, and HNSCC, HER3 overexpression was associated with poorer survival in patients with solid tumors, particularly those also overexpressing HER2. However, investigators said differences in the prevalence of HER3 overexpression depending on cells used for staining (combined cytoplasm and membrane vs either area alone) indicate that more reliable methods of evaluation are needed.¹²

HER3 mutations have also been identified in a small but significant number of cancers, ranging from around 2% of patients with breast cancer and NSCLC to >10% of patients with urothelial and bladder carcinomas.¹³ Although HER3 mutations have a low prevalence in primary estrogen receptor—positive breast cancers, they have been reported in up to 14% of metastatic cases.⁷ Mutations are most commonly described in the extracellular domain rather than the kinase domain, which makes sense given the limited kinase activity of HER3.¹⁴

HER3 may also play a major role in drug resistance and treatment failure.^3,11 Evidence shows that HER3 signaling is activated in HER2-positive breast cancers that are resistant to HER2-targeted therapies. Studies have found that in EGFR inhibitor—resistant NSCLC, HER3 activation (via phosphorylation) is increased and PI3K signaling is sustained.^15,16 HER3 signaling is also implicated in EGFR inhibitor resistance in HNSCC and pancreatic cancer, in platinum resistance in ovarian cancer, and in endocrine therapy resistance in hormone receptor—positive breast cancer and prostate cancer, among others.^3,4,11

The role of HER3 in facilitating treatment resistance may also be fostered through its partnerships with other, non-HER RTKs. For example, HER3, HER2, and insulinlike growth factor receptor 1 (IGF-1R) have been shown to form a heterotrimeric complex that confers resistance to trastuzumab in breast cancer cells.¹⁷

HRG ligands have also been shown to be aberrantly expressed across a number of tumor types, which may contribute to treatment resistance. In 2014, a research group identified fusions involving the NRG1 gene.¹⁸ These fusions, in which part of the NRG1 gene hybridizes with one of a number of genes, most commonly CD74, overexpress the HER3-binding domain of the NRG1 protein.

NRG1 fusions have subsequently been identified in a small percentage of patients across myriad tumor types. In a recent study, RNA sequencing was performed on 21,858 tumor specimens. The results showed a prevalence of 0.2% for NRG1 fusions, with one of the highest rates in NSCLC specimens.¹⁹

Clinical Trial Failures

Despite the rationale for HER3 inhibition as a therapeutic target, the numerous HER3-targeted drugs tested over the past decade have yet to bear fruit.

Table. Ongoing Clinical Development of HER3-Targeting Drugs (Click to Enlarge)

HER3 mAbs are reported to work via several mechanisms. They can lock the receptor in the inactive conformation, block binding by its ligand, prevent it from dimerizing with another receptor, trigger internalization of the receptor-mAb complex, and engage an immune response through antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity.

Among the most promising first-generation HER3 mAbs were patritumab (Daiichi Sankyo), lumretuzumab (Genentech/ Roche), and seribantumab (Merrimack Pharmaceuticals). Merrimack and Genentech were also developing the bispecific antibodies istiratumab (HER3 and IGF-1R) and duligotuzumab (EGFR and HER3), respectively.

Objective responses were limited when these drugs were tested as monotherapy, and attention was refocused on rational combinations.³ When combined with the EGFR inhibitor erlotinib, seribantumab failed to improve progression-free survival (PFS) in the overall cohort of patients with EGFR wild-type NSCLC. However, a retrospective analysis revealed that a subset of patients with detectable tumor heregulin (NRG1) mRNA expression had a significant PFS increase, consistent with data from similar trials in breast and ovarian cancers.^20,21 These results produced hope for heregulin as a biomarker for seribantumab response.

Seribantumab received orphan drug and fast track designation as a potential treatment for patients with advanced heregulin-positive NSCLC.²² It was studied in combination with docetaxel in the phase II SHERLOC trial (NCT02387216). The trial was halted in 2018, however, when Merrimack announced that it had not met its primary end point of improved PFS.²³ Merrimack subsequently announced that it was also discontinuing the SHERBOC trial of seribantumab in metastatic breast cancer (NCT03241810).^23,24

Patritumab was also studied in combination with erlotinib in 215 patients with advanced NSCLC. Overall, the combination yielded no significant differences in median PFS, which was 1.4 months (at patritumab 18 mg/kg) and 2.5 months (at patritumab 9 mg/kg) compared with 1.6 months for erlotinib alone.²⁵ In the subset with increased heregulin mRNA expression, the median PFS was significantly higher with the combination compared with erlotinib alone. The addition of patritumab conferred an increased risk of gastrointestinal toxicities but was well tolerated overall.

In a subsequent phase III study in previously treated patients with wild-type EGFR status and high heregulin mRNA expression, neither PFS nor overall survival (OS) was improved in the combination arm, and the trial was terminated prematurely.²⁶

Patritumab and lumretuzumab were tested in combination with paclitaxel and the HER2-targeted mAbs trastuzumab and pertuzumab (Perjeta), respectively, in patients with metastatic breast cancer. The patritumab combination was efficacious with a tolerable safety profile, whereas the utility of the lumretuzumab combination was limited by a narrow therapeutic window and high incidence of diarrhea.^27,28

Duligotuzumab was tested in patients with HNSCC and CRC, but development was hampered by limited efficacy and a high incidence of diarrhea and other gastrointestinal disorders.^29,30 Disappointing results were recently presented for the combination of duligotuzumab and folinic acid/fluorouracil/ irinotecan (FOLFIRI) in patients with RAS wild-type metastatic CRC. Compared with the combination of cetuximab and FOLFIRI, the duligotuzumab arm did not show improved PFS or OS.³¹

Merrimack discontinued istiratumab development in 2018 following missed end points in the phase II CARRIE trial (NCT02399137), in which it was combined with standard-of-care chemotherapy in patients with previously untreated metastatic pancreatic cancer. No statistically significant improvement in PFS, OS, or objective response rate (ORR) was observed.^32,33

No ongoing clinical trials are listed on the ClinicalTrials.gov website for any of these drugs or for several other HER3-targeted therapies that have been developed, including MM-111, AV-203, gemtuzumab, and REGN1400.

New Potential

Although the development of drugs targeting HER3 has proved daunting, investigators are evaluating several agents with novel mechanisms of action in early-phase clinical trials (Table).

Daiichi Sankyo, the developer of patritumab, has shifted its attention to its patritumab-based ADC, U3-1402, in which the HER3 mAb is conjugated to a topoisomerase I inhibitor. Several clinical trials are ongoing, and preliminary results were presented at recent conferences.

According to a presentation at the 2019 World Conference on Lung Cancer, 30 patients with advanced EGFR inhibitor—resistant, EGFR-mutant NSCLC have been enrolled in an ongoing phase I study of U3-1402 across 4 dose levels (3.2, 4.8, 5.6, and 6.4 mg/kg). Most patients had received prior treatment with osimertinib (Tagrisso), a third-generation EGFR inhibitor. Investigators noted 6 confirmed partial responses, including in patients with EGFR mutations that confer resistance to osimertinib, and antitumor activity was observed in patients with other mechanisms of resistance, including HER2 amplification. Treatment-emergent adverse events (TEAEs) were reported in 97% of patients, and dose-limiting toxicities (DLTs) included grade 3 febrile neutropenia and grade 4 platelet count decrease.²

Data from an ongoing trial in patients with HER3-overexpressing metastatic breast cancer were presented at the European Society for Molecular Oncology Breast Cancer meeting in May 2019. As of November 2018, 42 patients had received U3-1402 across dose-escalation (1.6-8.0 mg/kg) and dose-finding phases (4.8 or 6.4 mg/kg). The ORR was 42.9%, and the disease control rate was 90.5%. DLTs included decreased platelet count and increased aspartate aminotransferase/ alanine aminotransferase levels, and grade ≥3 TEAEs comprised thrombocytopenia, neutropenia, leukopenia, and anemia.¹

Zenocutuzumab (MCLA-128; Merus N.V.), a bispecific antibody targeting HER2 and HER3, is one of the drugs being developed in this space. The results of a phase I study in patients with advanced solid tumors positive for NRG1 fusions were presented at a recent conference. Patients (N = 29 across 8 tumor types, including pancreatic, lung, breast, sarcoma, prostate, gallbladder, unknown primary, and diffuse large B-cell lymphoma) were treated with zenocutuzumab 750 mg intravenously every 2 weeks. Three patients experienced dramatic tumor reduction, 2 with pancreatic ductal adenocarcinoma and 1 with NSCLC metastatic to the brain.³⁴

Two additional HER3 mAbs are still in development, CDX-3379 (formerly KTN-3379) and ISU104. In a first-in-human study of ISU104, patients with advanced solid tumors refractory to standard treatments were treated with escalating doses (1, 3, 5, 10, and 20 mg/kg daily for the first cycle and weekly thereafter). Among the 15 patients enrolled, no DLTs and only 2 grade 3 AEs were observed. The most common treatment-related AEs (TRAEs) included oral mucositis, diarrhea, pruritus, and fatigue. One patient experienced partial response (a patient with cancer of the hypopharynx), and 7 experienced stable disease (including those with head and neck, rectal, and breast cancers).³⁵

The results of a phase II study of CDX-3379 in combination with cetuximab in patients with previously treated HNSCC were presented at the 2019 meeting of the American Society of Clinical Oncology. Patients received CDX-3379 12 mg/kg intravenously every 21 days in combination with cetuximab at a loading dose of 400 mg/m², followed by a weekly dose of 250 mg/m². The trial was designed to enroll up to 30 patients in 2 stages; once 13 patients have achieved an objective response, more patients will be enrolled in stage 2. Stage 1 accrual is now complete: One patient experienced a confirmed complete response, and 7 experienced stable disease. TRAEs included diarrhea, hypokalemia, prolonged QT interval, and rash.³⁶

Jane de Lartigue, PhD, is a freelance medical writer and editor based in Gainesville, Florida.

References

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22. FDA grants orphan drug designation to seribantumab, an investigational treatment for heregulin-positive NSCLC. Oncology Nurse-APN/PA website. theoncologynurse.com/ton-web-exclusives/17410-fda-grants-orphan-drug-designation-to-seribantumab-an-investigational-treatment-for-heregulin-positive-nsclc. Updated February 19, 2019. Accessed December 14, 2019.
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Because HER3 has limited intrinsic kinase activity, small molecule kinase inhibitors are unlikely to be useful; the focus of drug development has been on HER3-targeted mAbs. However, because HER3 is phosphorylated by other kinases when it forms heterodimers with them, pan-HER or multikinase inhibitors could be useful because they indirectly inhibit HER3 signaling.⁴

The precise function of HER3 overexpression across these tumor types is not entirely clear; questions remain regarding whether and exactly how it might operate as a driver of cancer. The most solid evidence has been observed in breast and lung cancers, in which the tumor-promoting role of HER3 overexpression has been shown to be predominantly in its capacity as a partner for HER2 and EGFR, respectively.^3-5,11

However, after more than a decade of studies, none of these drugs have emerged triumphant from clinical trials, hampered by a lack of clinically meaningful efficacy. Despite a reasonable expectation that expression of HER3 and its ligand heregulin (HRG) would be predictive biomarkers for HER3-targeted therapy, their usefulness in clinical trials has been hit-and-miss.