Broadening HER2-Mutated NSCLC Data Support First-Line Zongertinib Followed by T-DXd

With 2 TKIs, zongertinib (Hernexeos) and sevabertinib (Hyrnuo), and the antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) all in play in the HER2-mutated non–small cell lung cancer (NSCLC) treatment paradigm, the central question is no longer which drug works best, but how to order them so later treatment decisions can deliver optimal outcomes.¹

Data from the phase 3 DESTINY-Lung04 trial, presented at the 2026 IASLC World Conference on Lung Cancer, framed a discussion by lung cancer experts during a recent OncLive^® Scientific Interchange and Workshop.

“It does raise more concerns here because you don’t know if this OS is a toxic effect, but it’s a large enough effect that you can’t ignore it,” John V. Heymach, MD, PhD, of MD Anderson Cancer Center in Houston, said.

Sandip P. Patel, MD, FASCO, of the University of California San Diego Moores Cancer Center, moderated the panel.

How should HER2 alterations be tested for and classified in NSCLC?

The panelists routinely combine tissue and liquid biopsy next-generation sequencing with HER2 immunohistochemistry (IHC) and noted that some centers add RNA sequencing. David Planchard, MD, PhD, of Institut Gustave Roussy in Villejuif, France, said his team runs IHC for HER2, MET, and MTAP at baseline and uses fluorescence in situ hybridization only in doubtful cases. Jamie E. Chaft, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, said that disease with HER2 TKD mutations is typically managed with a TKI, while non-TKD–mutated disease management depends on the specific variant. Heymach uses zongertinib for non-TKD–mutated disease despite the drug’s label, whereas Planchard called T-DXd a reasonable treatment option, although he noted that there are limited data to support this approach.

What did DESTINY-Lung04 show in the first-line HER2-mutated NSCLC setting?

The trial randomly assigned 454 patients with HER2 exon 19 or 20 mutations to receive T-DXd (n = 227) or pembrolizumab (Keytruda) plus platinum chemotherapy (n = 227).² The median PFS values by blinded independent central review were 14.3 months (95% CI, 12.4-16.5) vs 8.3 (95% CI, 7.0-9.9) months, respectively (HR, 0.63; 95% CI, 0.50-0.79; P < .0001). The objective response rates (ORRs) were 70.0% (95% CI, 63.6%-75.9%) vs 44.5% (95% CI, 37.9%-51.2%), and the median durations of response were 13.4 months (95% CI, 10.4-17.2) vs 9.7 months (95% CI, 7.0-11.1), respectively. The respective median OS values were 29.3 months (95% CI, 26.2-33.4) vs 33.1 months (95% CI, 27.7-40.7; HR, 1.15; 95% CI, 0.88-1.52) with data at 46.9% maturity, with no formal hypothesis testing.

Why did the PFS benefit seen with T-DXd in DESTINY-Lung04 not carry through to OS?

Adjudicated drug-related interstitial lung disease (ILD) occurred in 20.8% of patients receiving T-DXd vs 2.3% of those receiving chemoimmunotherapy, including 4 grade 5 events (1.8%). Conversely, in DESTINY-Lung02, the rate of adjudicated drug-related ILD with T-DXd was 14.9% at 5.4 mg/kg.³ Chaft attributed most of the gap between the PFS and OS outcomes in DESTINY-Lung04 to the trial’s crossover design, emphasizing that most of the ILD events were not fatal. Heymach stressed the downstream consequences of developing ILD, saying, “once [a patient has] had ILD, it’s hard to give all sorts of other therapies, [and patients] can’t go on any clinical studies.”

The panelists also faulted the trial’s eligibility criteria. which required brain metastases to be treated first; this may have enriched for a population with more indolent disease and therefore strengthened the control arm. Planchard compared this pattern with efficacy trends seen in ALK-positive disease, in which large PFS gains did not translate to OS benefits of the same magnitude because patients later received other targeted therapy.

How should first-line therapy be chosen and brain metastases managed in HER2-mutated NSCLC?

For a patient with a HER2 exon 20 YVMA insertion, the panel’s consensus was to use zongertinib, then T-DXd. In treatment-naive patients, zongertinib produced an ORR of 76% in cohort 2 of the Beamion LUNG-1 trial, and sevabertinib generated an ORR of 75% (95% CI, 64%-85%) in cohort F of the SOHO-01 trial, with grade 3 diarrhea reported in 5% of patients.^4,5 Heymach said that sevabertinib’s gastrointestinal burden and limited central nervous system penetration lead him to favor zongertinib, particularly in patients with brain metastases.

For patients with asymptomatic brain metastases, the faculty explained that they would start systemic therapy and reserve stereotactic radiosurgery for rescue treatment. Ernest Nadal, MD, PhD, of the Catalan Institute of Oncology in Barcelona, Spain, advised frequent MRI surveillance, and Heymach stated that he is increasingly reluctant to irradiate because of the risk of radiation necrosis.

Which variants and resistance mechanisms alter the HER2-mutated NSCLC treatment sequence?

Heymach called the HER2 C805S mutation “a sevabertinib-responsive mutation,” and also noted that the HER2 L755P is resistant to most TKIs, making T-DXd the more effective treatment option for patients with this disease subtype. Nadal also reported that durable responses have been seen with afatinib (Gilotrif) in patients with transmembrane mutations. Notably, in SOHO-01, 30% of evaluable patients had an identifiable resistance alteration at progression, most commonly in HER2 T862A (16%); HER2 C805S mutations were not detected.⁶

What unmet needs remain for HER2-mutated NSCLC management?

The panelists called for community education on variant-specific differences between HER2 mutation types. Patel explained that he has seen ERBB2 exon 20–mutated disease mistaken for EGFR-mutated disease and treated with amivantamab (Rybrevant). The experts also urged first-line trials to permit crossover and enroll patients with untreated brain metastases. Nadal noted that several NSCLC drugs remain unreimbursed in much of Europe. Real-world ILD monitoring practices also remain a concern.

References

1. Redefining the standard of care in advanced HER2-altered non–small cell lung cancer: navigating frontline advances and evolving sequencing strategies. An OncLive Scientific Interchange and Workshop. OncLive. September 14, 2026. Accessed October 29, 2026
2. Rotow J, Okamoto I, Goto K, et al. First-line trastuzumab deruxtecan (T-DXd) in patients with metastatic HER2-mutant NSCLC: DESTINY-Lung04 primary results. Presented at: International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract PL03.08.
3. 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
4. Heymach JV, Yamamoto N, Girard N, et al. Zongertinib in treatment-naive patients with HER2-mutant NSCLC, including those with active brain metastases: Beamion LUNG-1. Presented at: 2026 European Lung Cancer Congress; March 25-28, 2026; Copenhagen, Denmark. Abstract 6MO.
5. 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
6. Le X, Kim TM, Loong H, et al. Molecular landscape of acquired resistance to sevabertinib in HER2-mutant NSCLC: exploratory biomarker analysis of SOHO-01. Presented at: 2026 World Conference on Lung Cancer; September 2026. Abstract MO12.04.