HER2-Mutant NSCLC: Emerging Therapeutic Landscape and Clinical Implications

Session Overview and Presentation Highlights

Testing Recommendations for Diagnosing HER2 NSCLC

Dr Sabari described HER2 alterations in NSCLC, how they differ from those in breast cancer, and the clinical significance in NSCLC. The differences between HER2 mutation, amplification, and overexpression were explained along with corresponding testing recommendations from US and international organizations. Advisors were asked to share their current practices for identifying patients with HER2 mutations.

ADC Class Review for the Treatment of HER2 NSCLC

Study design and T-DXd efficacy and safety results from DESTINY-Lung trials were presented, and use of other ADCs in early clinical trials was mentioned. Advisors were asked to share their experience using T-DXd, managing adverse effects, and treating brain metastases in patients with HER2-mutant NSCLC. Insights into using T-DXd in the front line and treating patients after progression on T-DXd were also solicited.

TKIs in Development for HER2 NSCLC

Mechanisms of action and clinical trial efficacy and safety results for zongertinib and BAY 2927088 were presented. Advisors were asked to share their insights and perspectives on the trial results and how TKIs may fit into the treatment paradigm for individuals with HER2-mutant NSCLC. They discussed sequencing and early-line treatment preferences if ADCs and TKIs were approved in this patient population.

Discussion Themes/Summary

Faculty agreed that testing for HER2 should be a standard component when ordering NGS for newly diagnosed NSCLC patients and acknowledged that requesting both DNA- and RNA-based testing will improve the odds of catching other rare alterations.

Familiarity with T-DXd is widespread, and the panel members generally find T-DXd to be well tolerated. However, much of their experience comes from use in breast cancer. Nausea and cytopenias were highlighted as requiring more management; some faculty obtain quarterly ECGs to monitor for cardiotoxicity. The potential for interstitial lung disease (ILD) is not a major barrier to use, but it is a concern in the NSCLC population. In patients with HER2-mutant NSCLC, T-DXd is often used in a later line; however, there is strong interest in evaluating it for potential frontline use.

Treatment options for patients with brain metastases were identified as an unmet need, and referral to radiation oncology is often favored given current alternatives. TKIs typically have better central nervous system penetration than do ADCs; thus, if approved, zongertinib would be preferred over T-DXd in HER2-mutant NSCLC patients with brain metastases. Further, if use of multiple drug classes (eg, chemotherapy, immunotherapy, ADCs, and TKIs) is approved in that population, presence of brain metastases would drive sequencing of those agents.

Only 1 faculty member had used a HER2 TKI, but there was a very high level of enthusiasm for zongertinib given the overall response, progression-free survival, and safety data presented. In noting the “impressive” data, faculty anticipate that OS will also be positive. OS data are important and preferred, but the potential lack of OS data upon approval would not hinder its use. There was apprehension about whether the HER2/EGFR dual target of BAY 2927088 would increase the risk of toxicity and whether toxicity would limit its effective dosing.

There is a strong desire to test for HER2 more consistently in NSCLC and move T-DXd to an earlier line of treatment for patients harboring HER2 mutations. The potential for zongertinib in these patients was viewed very positively based on data presented and, if approved, would be preferred for the second line over T-DXd. Advisors urged that studies be done to inform sequencing and combination use as more options become available to manage these patients.

Unmet Needs and Recommendations

1. HER2 testing should be a standard component of tissue and plasma panels and should not rely upon a specific request.
2. The same provider should routinely monitor patients on T-DXd to pick up on subtleties of ILD.
3. ·Studies of ADCs and TKIs in the front line, head-to-head, and in combination are needed.
4. ·There is an unmet need for effective treatments in brain metastases.

References

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