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FAQs: Targeting HER3 in NSCLC
FAQs: Novel Antibody–Drug Conjugates and Other Agents Targeting HER3 in NSCLC

Released: May 25, 2023

Yasushi Goto
Yasushi Goto, MD, PhD
Helena Yu
Helena Yu, MD
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Key Takeaways
  • ADCs targeting HER3 have shown promising activity in early-stage clinical trials in patients with advanced NSCLC and EGFR-activating mutations who progressed on EGFR TKI therapy.
  • Ongoing studies are exploring optimal positioning of HER3-targeted agents and other novel targeted therapies in treatment sequencing and combination therapy for patients with advanced NSCLC.

In this commentary adapted from a discussion between Yasushi Goto, MD, PhD, and Helena Yu, MD, during a live webinar titled “From Congress to Clinic: A Post-JSMO Update on Novel Antibody–Drug Conjugates and Other Agents Targeting HER3 in NSCLC” on April 6, 2023, the experts answer questions from the audience about emerging clinical trial data for HER3-targeted agents and their potential impact on clinical practice in the treatment of patients with advanced non-small-cell lung cancer (NSCLC).

In your experience, how prevalent is overlap between EGFR-activating mutations and other mutations, such as NRG1 gene fusion, in NSCLC?

Helena Yu, MD:
The Memorial Sloan Kettering Cancer Center participated in the eNRGy (NCT02912949) study enrolling patients with NRG1-positive solid tumors for treatment with zenocutuzumab, as well as the trials of patritumab deruxtecan in EGFR-mutated NSCLC. We largely have not seen overlap between driver mutations in NSCLC. The major exception to this is in the acquired resistance setting, where acquired oncogene mutations such as ALK or RET fusions sometimes are seen in patients with previously treated EGFR-mutated lung cancer. NRG1 fusions are exceedingly rare, having less than 1% incidence in NSCLC. We were able to recruit patients with NRG1-positive tumors with no other treatment options for the eNRGy trial, but they did not have EGFR mutations.

Other than patients with EGFR mutations, is there any subgroup of patients with NSCLC for whom HER3-targeted therapy might be useful?

Helena Yu, MD:
This introduces an important question: What level of expression is needed for a targeted therapy to be effective? For HER3- or TROP-2–targeted antibody–drug conjugates (ADCs), the answer may be that very little expression is sufficient. The initial phase I study of patritumab deruxtecan included a wild-type arm, which did seem to show efficacy in patients with no driver mutations, including EGFR, KRAS, and ALK. Clinical development initially focused on EGFR-mutated lung cancer because that mutation seemed to lead to inherent enrichment in HER3 expression, but patritumab deruxtecan likely could be explored in other NSCLC populations, as well.

How would you compare the adverse event profile of patritumab deruxtecan with other ADCs or treatments? Specifically, what has been your experience with interstitial lung disease (ILD) or pneumonitis?

Yasushi Goto, MD, PhD:
Patritumab deruxtecan largely demonstrates off-target toxicity, which means the toxicity is due to the deruxtecan payload. Gastrointestinal toxicities such as nausea and stomatitis are the most frequent and are relatively tolerable when managed with preemptive antiemetic treatments.

ILD is a substantial problem in Japan not only with HER3-targeted antibodies, but also with other agents, such as trastuzumab deruxtecan and osimertinib. In Japan, 10% of patients who receive osimertinib experience some kind of ILD, which can be fatal, so we are very vigilant and experienced in management of this adverse event. Prompt diagnosis is very important. In Japan, many patients with lung cancer are treated by respiratory specialists who perform a chest x-ray at every visit, which is sometimes useful in ILD diagnosis—but not always. Patient symptoms—such as shortness of breath during exercise, which usually indicates respiratory desaturation—are the most important signs for detection of ILD. I always tell patients to try to walk or exercise as much as they were accustomed before the treatment so any change of symptoms can be compared. However, because this is a lung disease, many patients feel better with treatment, and comparison can be difficult. We typically use steroids to treat ILD if it does occur.

Helena Yu, MD:
We also hold the treatment and administer steroids in the case of ILD.

If patritumab deruxtecan is approved for the treatment of EGFR-mutated NSCLC, where would you place it in treatment sequencing?

Yasushi Goto, MD, PhD:
Ongoing clinical studies are attempting to answer this question. For patients with NSCLC and EGFR-activating mutations, osimertinib is the first-line standard of care, but there is no clear best treatment following the development of resistance to EGFR tyrosine kinase inhibitor (TKI) therapy. The role of HER3 in EGFR TKI resistance led to its development as a therapeutic target, and phase I data show that patritumab deruxtecan may be efficacious in this setting regardless of the mechanism of resistance. So, this unmet need potentially may be filled, depending of course on efficacy and safety data that are yet to come. We are looking forward to the results of the phase III HERTHENA-Lung02 study (NCT05338970) to show whether second-line treatment with HER3-targeted therapy or platinum-based chemotherapy is preferable in this setting.

What outcomes do you predict for the phase II and III HERTHENA-Lung trials of patritumab deruxtecan? What do you see as the future for HER3-targeted agents in EGFR-mutated NSCLC?

Helena Yu, MD:
Currently we have no approved targeted therapies in the United States or globally for patients with EGFR-mutated NSCLC post osimertinib. Given the efficacy that patritumab deruxtecan has demonstrated to date, I am hopeful that it could be approved for later-line use. As with all drug development, an agent approved in the later-line setting may be expanded into earlier-line use if warranted by the outcomes of additional trials. In this case, patritumab deruxtecan might be an option before chemotherapy or in combination with an EGFR TKI in the first-line setting. The patritumab deruxtecan plus osimertinib combination study (U31402-A-U103; NCT04676477) will be very interesting for patients with brain metastases that are well maintained with osimertinib, because we would be reluctant to discontinue that to start a new targeted therapy in the setting of well-controlled brain metastases. The phase II HERTHENA-Lung01 study (NCT04619004) has completed enrollment, so we will first see those results comparing fixed-dose vs uptitration of patritumab deruxtecan in patients previously treated with osimertinib, and for the future we can anticipate potential approvals and use for our patients.

How do you think ADCs directed against TROP-2 or other targets will fit into treatment strategies for EGFR-mutated NSCLC?

Yasushi Goto, MD, PhD:
That’s a very good question. Our institution has participated in trials of TROP-2–targeted ADCs, which are promising emerging agents for patients with EGFR-mutated NSCLC. Ideally, in the future we might be able to differentiate patients who would benefit most from HER3- or TROP-2–targeted therapy with biomarker testing. Until then, toxicity likely will be a major factor influencing patient preference between these categories of agents.

Helena Yu, MD:
Having multiple targeted options for patients would be a good position in the future, so we look forward to having the opportunity to determine individualized treatment strategies.

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