My Treatment Approach: HER2-Mutant mNSCLC - Episode 11
Sequencing Treatment Options in HER2-Mutation mNSCLC
Panelists discuss how treatment sequencing for HER2-mutation non–small cell lung cancer (NSCLC) prioritizes zongertinib over trastuzumab deruxtecan in the second-line setting due to superior efficacy and tolerability, while noting that special populations like patients with baseline lung dysfunction (favoring zongertinib to avoid interstitial lung disease risk) or CNS (central nervous system) metastases (where zongertinib shows promising brain activity but may require concurrent radiation for larger lesions) require individualized, case-by-case management with close monitoring and early imaging follow-up.
Sequencing Treatment Options in HER2-Mutation Metastatic NSCLC
Treatment sequencing in HER2-mutated metastatic NSCLC requires careful consideration of approved indications and available clinical trial opportunities. For newly diagnosed patients, standard first-line treatment remains chemotherapy or chemotherapy plus immunotherapy, as neither zongertinib nor trastuzumab deruxtecan has FDA approval in the frontline setting. While off-label use may be considered after patient discussion, enrollment in ongoing phase 3 clinical trials represents the optimal approach, including Beamion LUNG-2 (zongertinib vs chemoimmunotherapy), Destiny LUNG-04 (trastuzumab deruxtecan vs chemoimmunotherapy), and SOHO-2/Bayer 292 (sevabertinib vs chemoimmunotherapy).
In the second-line setting, zongertinib emerges as the preferred choice for patients progressing on chemotherapy with or without immunotherapy who have HER2 exon 20 insertion mutations. This preference stems from best-in-class efficacy metrics, including superior response rates and duration of response, combined with a significantly better tolerability profile compared with antibody-drug conjugates. The treatment sequence would position zongertinib in second line followed by trastuzumab deruxtecan in third line. For patients who receive trastuzumab deruxtecan in second line, zongertinib retains efficacy in third line with approximately 50% response rate based on cohort 3 data from the Beamion LUNG-1 study.
Special patient populations require individualized management approaches, particularly those with baseline lung dysfunction or CNS metastases. For patients with preexisting lung dysfunction, zongertinib offers advantages due to the absence of interstitial lung disease risk, which is particularly important in patients with reduced pulmonary reserve or prior lung radiation exposure. CNS metastases management involves case-by-case decision-making with radiation oncology consultation. Zongertinib demonstrates promising intracranial activity, though data maturity remains limited compared with established agents like osimertinib. For small, asymptomatic CNS lesions, zongertinib monotherapy with short-interval MRI monitoring (4-6 weeks) represents a reasonable approach, while larger or symptomatic lesions may require up-front radiation therapy before systemic treatment initiation. The principle that effective systemic therapies translate to CNS efficacy supports zongertinib’s use in this challenging patient subset.
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