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HER3 EGFRm NSCLC Care
HER3-Targeted Therapies for EGFRm NSCLC: Emerging Therapies and Challenges in Treatment

Released: October 09, 2024

Expiration: October 08, 2025

Karen Reckamp
Karen Reckamp, MD, MS
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Key Takeaways
  • HER3 overexpression is linked to resistance in EGFR-mutant (EGFRm) NSCLC, highlighting the need for newer HER3-targeted agents.
  • Patritumab deruxtecan is a HER3-targeted antibody–drug conjugate (ADC) in late-stage development that has shown positive results for patients with EGFRm NSCLC refractory to standard EGFR tyrosine kinase inhibitors (TKIs).
  • Treatment with patritumab deruxtecan requires careful monitoring due to unique toxicities by its different mechanism of action, including cytopenias and the potential risk of interstitial lung disease.

Targeting HER3 in Non-Small-Cell Lung Cancer
HER3 belongs to the human epidermal growth factor receptor (HER) family, which also includes HER2 and EGFR, though it is considered a nonfunctional receptor within the tyrosine kinase family of receptors. Despite its lack of intrinsic activity, HER3 is highly expressed in multiple tumors, especially in patients with EGFR-mutant (EGFRm) non-small-cell lung cancer (NSCLC). Overexpression of HER3 has been observed in cases of resistance to EGFR tyrosine kinase inhibitor (TKI) therapy, suggesting it has a role in the development of this therapeutic resistance. As a result, the development of HER3-targeting therapies has gained interest as a potential strategy to combat resistance in patients with EGFRm NSCLC.

Promising HER3 Therapy in NSCLC: Patritumab Deruxtecan and Other Emerging Options
Patritumab deruxtecan, a HER3-targeted antibody–drug conjugate (ADC), is currently the only HER3-directed agent in global, multicenter, phase III trials for NSCLC. This drug combines a HER3-targeting antibody with a cytotoxic payload and has been tested in several clinical trials, including the phase II HERTHENA-Lung01 trial, primarily in patients with highly refractory EGFRm NSCLC. Most of these patients had received multiple prior treatments, including various TKIs and systemic therapies, leaving them with limited remaining treatment options. Data from the phase III HERTHENA-Lung02 trial comparing patritumab deruxtecan vs pemetrexed and platinum chemotherapy in patients with NSCLC and an EGFR-activating mutation after 1-2 prior lines of EGFR TKI therapy will be presented at an upcoming medical meeting.

Other HER3-targeting antibodies are in earlier stages of development. BL-B01D1, also known as izalontamab brengitecan, inhibits both EGFR and HER3 and has promising phase Ia/Ib data for patients with solid tumors, including NSCLC. SHR-A2009F is a HER3-targeted ADC in phase II studies for previously treated advanced NSCLC as well as for patients with advanced solid tumors in general. Zenocutuzumab targets NRG1 fusions and is currently in phase II studies in patients with solid tumors harboring NRG1 fusion alterations. Thus, refractory EGFRm NSCLC represents a key area of exploration for HER3 ADC therapy, especially patritumab deruxtecan, based on efficacy seen in previous trials.

Sequencing Patritumab Deruxtecan in NSCLC Treatment
Currently, no HER3-targeted therapies, including patritumab deruxtecan, have received approval for clinical use. However, available trial data have shown promising results in patients with EGFRm NSCLC who have had prior treatment with EGFR TKIs and platinum-based doublet chemotherapy. These patients represent a highly treatment-resistant population. The sequencing of patritumab deruxtecan in the course of treatment is likely to occur following earlier therapies, including EGFR TKIs and cytotoxic agents. This succession of therapy is especially relevant given the evolving landscape of EGFRm NSCLC therapy, with approvals for treatments in the frontline setting such as osimertinib in combination with platinum-based chemotherapy or the combination of lazertinib and amivantamab, and recent second-line options such as chemotherapy and amivantamab. Osimertinib in combination with platinum-based chemotherapy as well as combination lazertinib and amivantamab therapy are indicated for first-line treatment of locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test. These patients often experience tumor progression and undergo extensive treatments, so additional therapeutic options are essential. Patritumab deruxtecan and other HER3-targeted ADCs could play a valuable role in managing previously treated, refractory patients later in the course of their disease.

Safety Profile and Adverse Events of Patritumab Deruxtecan
Patritumab deruxtecan is associated with both on-target and off-target toxicities due to its unique mechanism of action as an ADC. These toxicities can result from the interaction of the antibody with its intended target and the release of the cytotoxic payload into nontarget tissues. Although ADCs share some characteristics with both chemotherapy and targeted therapies, they also possess some unique toxicities of their own. Specifically, notable toxicities related to this agent include low-grade nausea and vomiting, which can require management, as well as cytopenias, particularly thrombocytopenia. Other cytotoxicity-related toxicities have been reported; however, there have been relatively few documented cases of pneumonitis or interstitial lung disease (ILD) associated with patritumab deruxtecan. Nevertheless, ILD remains a concern with HER2-targeted ADCs, such as trastuzumab deruxtecan, especially in patients with lung cancer. This situation necessitates careful monitoring as more data on patritumab deruxtecan become available.

Closing Thoughts
HER3-targeted agents, such as patritumab deruxtecan, are expected to be tested across various malignancies due to the significant expression of HER3 in multiple tumor types. This emerging class of therapies represents a promising area of development, particularly for patients with EGFRm NSCLC. Despite the increasing number of treatment options available, these patients still face persistent challenges related to resistance and refractory disease. Patritumab deruxtecan offers a novel therapeutic mechanism, making it a significant breakthrough and a valuable addition to existing treatment options. Its distinct mechanism of action may allow for easier sequencing with other therapies, potentially addressing the resistance that limits the effectiveness of current treatments. This holds great potential for improving outcomes in this patient population.

Your Thoughts
What are your biggest challenges in the care of your patients with advanced EGFRm NSCLC? Please answer the polling question and join the conversation by posting a comment in the discussion section.

For more information on the use of HER3-targeted therapy for the treatment of advanced EGFRm NSCLC, please check back as more information is added on this program page: “HER3-Targeted Therapies for EGFRm NSCLC: Key Evidence and Real-world Insights to Optimize Patient Care.”

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If HER3-targeted therapy were approved where you practice, would you incorporate these agents into your clinical practice?

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