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HER3 ADC commentary
HER3-Targeted Antibody–Drug Conjugates for Lung and Breast Cancers: Where We Are Today

Released: September 29, 2023

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Key Takeaways
  • HER3, a member of the EGFR family, plays a role in oncogenic signaling via heterodimerization with other receptor tyrosine kinases and may contribute to acquired resistance to treatments impacting these pathways.
  • The HER3-targeted antibody–drug conjugate patritumab deruxtecan has shown efficacy in patients with EGFR-mutated non-small-cell lung cancer after progression on osimertinib.
  • Responses to patritumab deruxtecan in breast and lung cancer do not appear to correlate with HER3 expression level.

In this commentary, Helena Yu, MD, of Memorial Sloan Kettering Cancer Center and Yuan Yuan, MD, PhD, of Cedars-Sinai Medical Center discuss the emerging area of HER3-targeted therapies and their potential to impact the care of patients with breast and lung cancers.  

Helena Yu, MD: HER3 is a unique member of the HER family, which also includes the more well-known receptors EGFR and HER2. In contrast to EGFR and HER2, HER3 itself has limited kinase activity but drives oncogenic signaling through heterodimerization with other HER family members. HER3 mutations are quite rare, but clinicians see HER3 overexpression and amplification across multiple tumor types, including breast and lung cancers. This HER3 overexpression and amplification seems to be associated with metastatic potential and decreased relapse‑free survival.

HER3 in Lung Cancer
Mechanisms of Treatment Resistance in EGFR-Mutated NSCLC 
Helena Yu, MD: Lung cancer is often characterized by driver mutations such as EGFR, ALK, and KRAS. HER3 expression is especially relevant in EGFR-mutant lung cancer due to the functional heterodimerization of these 2 receptor proteins. HER3 expression level is likely related to acquired resistance to EGFR tyrosine kinase inhibitors (TKIs), as an increase in HER3 expression is observed in patients after progression on these treatments. Mechanisms of resistance to osimertinib, the current standard first-line TKI for patients with the most common EGFR mutations, are quite diverse, but it is believed that targeting HER3 may be relevant across multiple genomic mechanisms of resistance. In this disease setting, on-target resistance usually involves acquired mutations in EGFR, and off-target resistance often presents as MET amplification or BRAF or KRAS alterations. Of interest, approximately half of patients do not seem to have any acquired genetic alteration driving resistance. 

HER3-Targeted Constructs 
HER3 monoclonal antibodies have been assessed in the past but found to have limited clinical activity. Recent investigation of HER3 as a therapeutic target has taken advantage of more advanced technology, namely, the antibody–drug conjugate (ADC). ADCs are monoclonal antibodies that are linked to a payload, which is typically a type of cytotoxic chemotherapy. Patritumab deruxtecan consists of a HER3 antibody (patritumab) linked to a topoisomerase based chemotherapy payload (deruxtecan). 

Clinical Data With Patritumab Deruxtecan in NSCLC
Clinical development of patritumab deruxtecan is most advanced in lung cancer. This agent was first evaluated in a phase I study in patients with EGFR-mutant lung cancer that had progressed on EGFR TKIs and chemotherapy. The recommended phase II dose was found to be 5.6 mg/kg every 3 weeks, and the drug was well tolerated in this patient population. Updated efficacy data including an overall response rate (ORR) of 40% and median progression free survival (PFS) of 6.4 months were presented at the Japanese Society of Medical Oncology annual meeting this year. Based on that phase I data, we embarked on the HERTHENA-Lung01 phase II study which was recently presented at the World Conference on Lung Cancer (WCLC), finding an ORR of 30% and a median PFS of 5.5 months in 225 patients treated with patritumab deruxtecan following targeted therapy with osimertinib and platinum based chemotherapy. In this disease setting, there are currently no targeted therapies that are approved post-osimertinib, and chemotherapies have very limited efficacy as salvage therapy. For comparison, we typically treat these patients with single-agent docetaxel, which has a response rate less than 10%. Patritumab deruxtecan would likely be used to fill the unmet need in this post-osimertinib, post-chemotherapy space where there are currently very few well-tolerated treatment options. Of note, patritumab deruxtecan appeared to be effective in patients with varying mechanisms of EGFR TKI resistance, such as the EGFR C797S mutation, other EGFR alterations, and MET amplification. Finding a targeted therapy that can transcend resistance mechanisms for a diverse group of patients is always beneficial. HER3 expression level did not seem to predict tumor response; almost all patients have some degree of HER3 expression, and it may be that by focusing on patients with EGFR-mutated cancer we are selecting for a population which already has widespread HER3 dependence. Looking forward, an important ongoing study is looking at patritumab deruxtecan in combination with osimertinib in patients who progressed on single-agent osimertinib and have not been treated with chemotherapy in the advanced disease setting. We look forward to data in this setting as well (NCT04676477).

HER3 in Breast Cancer
ADC Landscape in Breast Cancer
Yuan Yuan, MD, PhD: Multiple ADCs are available for the treatment of breast cancer (including trastuzumab deruxtecan targeting HER2 and sacituzumab govitecan targeting TROP2), so we have already faced questions regarding optimal ADC-after-ADC sequencing but still have not fully answered them. Studies have shown little or no correlation between immunohistochemistry (IHC) score and response to ADC treatment. For example, patients with low HER2 expression (IHC 1+) are included in the label indication for trastuzumab deruxtecan, and even patients with HER2-zero disease have shown a response rate of 30% with trastuzumab deruxtecan in clinical trials. This may be explained by the relatively high drug:antibody ratio for trastuzumab deruxtecan (8:1, meaning 8 molecules of deruxtecan are carried by each antibody), which may mean that relatively few molecules of bound ADC still allow sufficient introduction of the cytotoxic payload. The mechanisms of resistance to trastuzumab deruxtecan treatment are unclear as demonstrated by a recent rebiopsy study showing that HER2 expression levels largely persist in patients with breast or gastrointestinal cancers following treatment with this agent. If receptor downregulation is not the mechanism of resistance, it may be that some resistance develops to the payload, meaning that rechallenge with another ADC using the same payload or a similar topoisomerase inhibitor would be less efficacious. It is likely that both antibody-directed and payload-directed resistance may come into play in different patients or at different points in their treatment journey. These unanswered questions would apply to a novel HER3-targeted ADC and the addition of a new target would further complicate the issue of sequencing.

Clinical Data With Patritumab Deruxtecan in Breast Cancer
In contrast with lung cancer trials of patritumab deruxtecan which have focused on EGFR-mutated disease after failure of EGFR-directed therapy, clinical trials in breast cancer are exploring activity of this agent in multiple molecular subtypes and as neoadjuvant treatment as well as in more advanced treatment-resistant disease. Although only very early data are available in breast cancer at this point, they appear similar to data in lung cancer in that responses are seen in patients with all levels of HER3 expression. Responses are also seen in patient cohorts with both HER2-postive and -negative disease, which is interesting considering the functional relationship between HER2 and HER3. An agent with clinical activity in triple-negative breast cancer is particularly exciting because treatment options for those patients are relatively limited. In terms of safety, the incidence of interstitial lung disease thus far seems to be lower with patritumab deruxtecan than seen for trastuzumab deruxtecan, which is somewhat surprising because both have a drug:antibody ratio of 8:1 with the same cytotoxic payload. There may be a difference in HER2 vs HER3 expression levels in the lung epithelium which would impact the risk of pulmonary AEs. The future availability of mature data in the breast cancer space will provide more robust guidance on patient selection and optimal sequencing for this HER3-targeting ADC.

Learn More
To learn more about the rationale and clinical development of therapies targeting HER3 in multiple tumor types, visit our program with upcoming activities including an informative podcast and CME-certified microlearning text modules with downloadable slidesets.

Your Thoughts?
What questions do you have about HER3-targeted therapies and their potential use in the care of patients with cancer? Would you be comfortable discussing these agents with your patients who are interested in enrolling on a clinical trial? Leave a comment below and join in the discussion! 

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