CNS Control and Daily Tolerability Guide Treatment Sequencing in HER2-Mutated NSCLC

With 2 HER2-directed TKIs and an antibody-drug conjugate (ADC) now available for the treatment of patients with HER2-mutated non–small cell lung cancer (NSCLC), the main question facing the field has shifted from whether to target HER2 to how to choose the optimal treatment for patients based on intracranial disease control and day-to-day tolerability.¹

“We often think about the principle of using our best drugs up front,” Jacqueline Aredo, MD, of Mass General Brigham Cancer Institute in Boston, Massachusetts, said during a recent OncLive^® Scientific Interchange and Workshop.

Moderated by Sandip Patel, MD, FASCO, of the University of California (UC) San Diego Moores Cancer Center, the panel of hematology/oncology fellows and junior faculty worked through 2 cases: a treatment-naive patient and a patient progressing after frontline chemoimmunotherapy.

How should HER2 alterations be identified at NSCLC diagnosis?

The panelists described the importance of concurrent tissue and liquid biopsy next-generation sequencing at diagnosis, with HER2 immunohistochemistry (IHC) added on at several centers, and generally waited for results before treating clinically stable patients.

“We want to test. We are not guessing,” Patel said, adding that the testing bottleneck has shifted from sequencing to IHC because diagnostic specimens are often exhausted by histologic workup.

Christopher Grant, MD, of the UC San Diego Moores Cancer Center, noted that referral centers often struggle to retrieve tissue biopsied at outside facilities, which becomes harder to replace at later progressions.

Which agent should lead in the frontline HER2-mutated NSCLC setting?

For a 69-year-old never-smoker with a HER2 exon 20 YVMA insertion and a PD-L1 tumor proportion score of 10%, the panel uniformly chose zongertinib (Hernexeos), which received FDA accelerated approval in February 2026 for use as early as the frontline setting for the treatment of adult patients with unresectable or metastatic nonsquamous NSCLC whose tumors harbor HER2 tyrosine kinase domain (TKD) activating mutations, as detected by an FDA-authorized test.² In evaluable previously untreated patients in the phase 1b Beamion LUNG-1 trial (NCT04886804; n = 72), zongertinib produced an objective response rate (ORR) of 76% (95% CI, 65%-85%).³ Among patients with active brain metastases (cohort 4; n = 30), the intracranial ORR was 47% (95% CI, 30%-64%).

Additionally, in cohort F of the phase 1/2 SOHO-01 trial (NCT05099172; n = 73), sevabertinib (Hyrnuo) yielded an ORR of 75% (95% CI, 64%-85%) and a median progression-free survival (PFS) of 13.5 months (95% CI, 10.0-not evaluable [NE]) in treatment-naive patients, with grade 3 diarrhea in 5% of patients and no interstitial lung disease (ILD).⁴ Data from SOHO-01 supported the September 2026 FDA accelerated approval of sevabertinib for the treatment of adult patients with locally advanced or metastatic nonsquamous NSCLC with tumors harboring HER2 TKD mutations, as detected by an FDA-authorized test.⁵

Tolerability separated the 2 agents. “The diarrhea adverse effects that [patients] get with sevabertinib are real. Those are going to affect a patient every single day that they’re [receiving] the drug,” Grant said.

Aredo added that when her patients progress on zongertinib, the brain is often the first site of metastasis. For asymptomatic brain metastases, most panelists would start zongertinib with early radiation oncology referral and reserve stereotactic radiosurgery for residual disease.

What are best practices for treatment sequencing in previously treated, HER2-mutated NSCLC?

The second case involved a 64-year-old former smoker with a HER2 exon 20 YVMA insertion and PD-L1 expression of 75% who progressed systemically, with 1 new asymptomatic brain metastasis, after 12 months of carboplatin, pemetrexed, and pembrolizumab (Keytruda). The panel again favored zongertinib. However, Olivia Fankuchen, MD, MS, of Weill Cornell Medicine in New York, New York, said that liver function abnormalities would be her main reason to choose sevabertinib instead; Fawzi Abu Rous, MD, of Henry Ford Health in Detroit, Michigan, placed that threshold at grade 2 elevation.

In previously treated patients with HER2 TKD mutations, zongertinib generated an ORR of 71% (95% CI, 60%-80%) and a median PFS of 12.4 months (95% CI, 8.2-NE) in Beamion LUNG-1 cohort 1 (n = 75) and an ORR of 48% (95% CI, 32%-65%) after a prior HER2-directed ADC (cohort 5; n = 31).⁶ Sevabertinib produced ORRs of 64% (95% CI, 53%-75%) in HER2-directed therapy–naive patients (cohort D; n = 81) and 38% (95% CI, 25%-52%) after a HER2-directed ADC (cohort E; n = 55) in SOHO-01.⁷ In the phase 2 DESTINY-Lung02 trial (NCT04644237), fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) at 5.4 mg/kg (n = 102) produced a confirmed ORR of 50.0% (95% CI, 39.9%-60.1%), with adjudicated drug-related ILD reported in 14.9% of patients (n = 101) vs 32.0% of those who received T-DXd at 6.4 mg/kg (n = 50).⁸

“I would consider zongertinib followed by an ADC until we have more data on a TKI after a TKI,” Abu Rous said. Patient comorbidities also shaped treatment selection. The panelists noted that they would avoid T-DXd in patients with pre-existing anemia or pneumonitis and use caution with sevabertinib after recent immunotherapy because of colitis risk.

Adverse effect monitoring practices varied widely among the experts.

“There’s a huge discrepancy in checking for cardiac toxicity and even ILD,” said Ramya Muddasani, DO, MS, of City of Hope in Duarte, California, contrasting main-campus support with community network sites.

What unmet needs exist for HER2-mutated NSCLC management?

Intracranial control remains the central treatment gap, according to the panelists, with intracranial ORRs of approximately 30% to 50% and stereotactic radiosurgery still needed to avoid whole-brain radiotherapy. The faculty called for repeat tissue and liquid biopsy at each progression to characterize treatment resistance. They also emphasized the importance of conducting clinical trials investigating combinations, such as a TKI plus chemotherapy or an ADC.

Additionally, emerging agents, including the central nervous system–penetrant TKIs NVL-330 and IAM1363 and the next-generation ADCs CGT4255 and trastuzumab rezetecan (SHR-A1811), drew interest, as did better molecular characterization of HER2 amplification.

References

1. Advancing precision care in HER2-mutated NSCLC: personalized treatment and strategic sequencing. An OncLive Scientific Interchange and Workshop. OncLive. July 23, 2026. Accessed September 30, 2026.
2. FDA grants accelerated approval to zongertinib for unresectable or metastatic non-squamous non-small cell lung cancer. FDA. February 26, 2026. Accessed September 30, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-unresectable-or-metastatic-non-squamous-non-small-cell
3. Heymach JV, Yamamoto N, Girard N, et al. First-line zongertinib in advanced HER2-mutant non-small-cell lung cancer. N Engl J Med. 2026;394(17):1675-1684. doi:10.1056/NEJMoa2516969
4. Loong HH, Le X, Prelaj A, et al. SOHO-01: updated safety and efficacy of sevabertinib in patients with advanced HER2-mutant non-small cell lung cancer (NSCLC). J Clin Oncol. 2026;44(suppl 16):8622. doi:10.1200/JCO.2026.44.16_suppl.8622
5. FDA grants accelerated approval to sevabertinib for locally advanced or metastatic non-squamous non-small cell lung cancer. FDA. September 9, 2026. Accessed September 30, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sevabertinib-locally-advanced-or-metastatic-non-squamous-non-small
6. Heymach JV, Ruiter G, Ahn MJ, et al. Zongertinib in patients with pretreated HER2-mutant advanced NSCLC: Beamion LUNG-1. Cancer Res. 2025;85(8)2. doi:10.1158/1538-7445.AM2025-CT050
7. Le X, Kim TM, Loong HH, et al. Sevabertinib in advanced HER2-mutant non-small cell lung cancer. N Engl J Med. 2025;393(18):1819-1832. doi:10.1056/NEJMoa2511065
8. Jänne PA, Goto Y, Kubo T, et al. Final analysis results and patient-reported outcomes from DESTINY-Lung02-a dose-blinded, randomized, phase 2 study of trastuzumab deruxtecan in patients with HER2-mutant metastatic NSCLC. J Thorac Oncol. 2025;20(12):1814-1828. doi:10.1016/j.jtho.2025.07.129