Zongertinib, Sevabertinib Reshape Treatment Landscape for Patients With HER2-Mutated NSCLC

Patients with HER2-mutated non–small cell lung cancer (NSCLC) historically had little beyond chemotherapy. Now, 2 FDA-approved oral TKIs are rewriting expectations for response, duration, and tolerability in both the first-line and previously treated settings, according to faculty who participated in an OncLive® Scientific Interchange and Workshop held during the 2026 ASCO Annual Meeting.¹

“HER2 mutations are actually quite rare, [occurring in] 2% to 4% [of patients with NSCLC], but they’re not rare to thoracic medical oncologists,” Joshua K. Sabari, MD, who moderated the workshop, said. “[There] was a very poor prognosis in this patient population historically, with a high rate of brain metastases.In my fellowship, which was not that long ago, these patients were treated with chemotherapy in the frontline setting. [I have] been thinking about how much we’ve improved [treatment] for this patient population.”

Sabari is the director of High Reliability Organization Initiatives at the Perlmutter Cancer Center and an assistant professor in the Department of Medicine at NYU Grossman School of Medicine, both in New York, New York.

In the workshop, additional faculty members participated in a discussion centered on the treatment landscape of HER2-mutated NSCLC, including approved and emerging agents in the first-line setting, updates in the management of the disease in the second line and beyond, and treatment selection considerations with currently available agents.

How could data with sevabertinib and zongertinib reshape the frontline setting?

In recent years, the HER2-targeted TKIs zongertinib (Hernexeos) and sevabertinib (Hyrnuo) have emerged as effective treatment options for patients with HER2-mutated NSCLC. In February 2026, the FDA granted accelerated approval to zongertinib for an expanded indication in adult patients with unresectable or metastatic nonsquamous NSCLC harboring HER2 (ERBB2) tyrosine kinase domain (TKD) activating mutations, as detected by an FDA-authorized test.² The regulatory decision was supported by data from the phase 1a/1b Beamion LUNG-1 trial (NCT04886804).

Findings from Beamion LUNG-1 that were presented during the 2026 European Lung Cancer Congress and subsequently published in the New England Journal of Medicine revealed that treatment-naive patients with HER2-mutated NSCLC who received zongertinib (cohort 2; n = 74) experienced a confirmed objective response rate (ORR) of 76% (95% CI, 65%-84%), with a complete response (CR) rate of 11%.³ The disease control rate (DCR) was 96% and the median time to objective response was 1.4 months (95% CI, 1.1-6.9).

The median progression-free survival (PFS) in cohort 2 was 14.4 months (95% CI, 11.1-not evaluable [NE]). The median duration of response (DOR) was 15.2 months (95% CI, 9.8-NE).

Zongertinib also displayed notable activity among patients with treatment-naive or pretreated disease with active brain metastases at baseline (cohort 4; n = 30). This population experienced a confirmed intracranial ORR of 47%, including a CR rate of 7%. The DCR was 87%. The median DOR and PFS values were 6.9 months (95% CI, 2.9-NE) and 8.2 months (95% CI, 4.1-11.3), respectively.

Within cohort 4, patients who underwent no prior brain radiotherapy who had confirmed measurable intracranial disease (n = 17) had an ORR of 59% and a CR rate of 6%. The DCR was 94% and the median DOR was 6.2 months (95% CI, 2.7-NE). The median PFS was NE (95% CI, NE-NE).

“The numbers are a bit small, but if you look at the waterfall plot, we are seeing central nervous system response in this patient population [with a] DOR and PFS shorter than what we see in patients in the chest or extracranially in this population,” Sabari commented.

Although sevabertinib has not earned FDA approval in first-line HER2-mutated NSCLC to date, the agent has been showing promise in the space in the phase 1/2 SOHO-01 trial (NCT05099172). Data from cohort F of SOHO-01 supported the FDA’s May 2026 decision to grant priority review designation to sevabertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC harboring HER2 TKD activating mutations.⁴

Updated data from cohort F of SOHO-01 presented during ASCO 2026 showed that treatment-naive patients who received sevabertinib (n = 73) experienced an ORR of 75.3% (95% CI, 63.9%-84.7%) and a DCR of 89.0% (95% CI, 80%-95%).⁵ The median DOR was 12.2 months (95% CI, 8.8-NE) and the median PFS was 13.5 months (95% CI, 10.0-NE). The median follow-up was 15.0 months at the November 17, 2025, data cutoff.

“In terms of efficacy, if we look at response rates, zongertinib is numerically higher, not by much,” Fawzi F. Abu Rous, MD, a medical oncologist at Henry Ford Health in Detroit, Michigan, commented. “What really gives zongertinib its distinction is that it's a very clean drug. In my experience, you give it and you forget about it. The diarrhea is minimal and the rash is minimal. With sevabertinib, you have to manage [adverse effects (AEs)], which is fine, but patients have to deal with rash and diarrhea. One thing we have learned more and more about it after we learned about the resistance mechanisms is that sevabertinib covers EGFR, which is where the AEs come from. But that might be a way to avoid some of the resistance mechanisms, which I would imagine would be through the EGFR pathway.”

What are the latest updates in HER2-mutated pretreated NSCLC?

The faculty members shifted the focus of their discussion to the management of patients with previously treated HER2-mutated NSCLC. In this setting, both zongertinib and sevabertinib have earned FDA approval.^6,7 In August 2025, the FDA approved zongertinib for the treatment of patients with unresectable or metastatic nonsquamous NSCLC with HER2 TKD activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy.⁶ In November 2025, the FDA approved sevabertinib for the same indication.⁷

Findings from cohort 1 of Beamion LUNG-1 (n = 75), which enrolled previously treated patients with TKD mutations, revealed that the ORR per RECIST 1.1 criteria was 71% (95% CI, 60%-80%), with a CR rate of 7%.⁸ The DCR was 96% (95% CI, 89%-99%) and the median DOR was 14.1 months (95% CI, 6.9-NE). At a median follow-up of 11.3 months (95% CI, 10.2-12.3), the median PFS was 12.4 months (95% CI, 8.2-NE).

Additionally, patients with previously treated disease harboring non–TKD mutations (cohort 3; n = 20) experienced an ORR of 30% (95% CI, 15%-52%) with a DCR of 65% (95% CI, 43%-82%). Patients who received a prior HER2-directed antibody-drug conjugate with TKD-mutated disease (cohort 5; n = 31) experienced an ORR of 48% (95% CI, 32%-65%), including a CR rate of 3%. The DCR was 97% (95% CI, 84%-99%).

“I've also seen [some] failure or progression,” Sabari said. “I think some of these mutations may not be activating mutations. [This is] important to understand. There are also extracellular domain mutations. It [will be] helpful to better study this. We need more data in the non–TKD mutant population.”

In cohort D of SOHO-01, which enrolled pretreated patients (n = 81), sevabertinib produced an ORR of 66.7% (95% CI, 55.3%-76.8%), with a DCR of 81.5% (95% CI, 71%-89%).⁵ The median DOR was 9.5 months (95% CI, 6.3-13.5) and the median PFS was 8.3 months (95% CI, 6.9-12.3). At the November 17, 2025, data cutoff, the median follow-up was 19.5 months.

“At the end of the day in metastatic lung cancer, the first goal of care is still quality of life,” Jianjun Zhang, MD, PhD, a professor in the departments of Thoracic/Head and Neck Medical Oncology and Genomic Medicine, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, commented. “So the toxicity will be an important part of [selecting a treatment], but of course people would like to live longer. Also, patients have different preferences, and some people just don't want to come to the hospital. For them, you're going to go with oral medications.”

“I have a lot of patients that drive far too. [With] the intravenous [IV] therapies, I'm thinking very closely about [that]. If there is a pill option, most of my patients prefer that. Even if sometimes the data are not as great, they’d rather take the pill and not have to come see you quite as much as they would have to with the IV therapies,” Christine Auberle, MD, an assistant professor of medicine in the John T. Milliken Department of Medicine, Division of Oncology, at Washington University Medicine in St. Louis, Missouri, concluded.

References

1. HER2-mutant NSCLC: translating emerging evidence into clinical practice. An OncLive Scientific Interchange and Workshop. OncLive. May 29, 2026. Accessed June 15, 2026.
2. FDA grants accelerated approval to zongertinib for unresectable or metastatic non-squamous non-small cell lung cancer. FDA. February 26, 2026. Accessed June 15, 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. FDA grants sevabertinib priority review as a first-line treatment for patients with HER2-mutant non-small cell lung cancer. News release. Bayer. May 18, 2026. Accessed June 16, 2026. https://www.bayer.com/media/en-us/fda-grants-sevabertinib-priority-review-as-a-first-line-treatment-for-patients-with-her2-mutant-non-small-cell-lung-cancer/
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. FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations. FDA. August 8, 2025. Accessed June 16, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-non-squamous-nsclc-her2-tkd-activating-mutations
7. FDA grants accelerated approval to sevabertinib for non-squamous non-small cell lung cancer. FDA. November 19, 2025. Accessed June 17, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sevabertinib-non-squamous-non-small-cell-lung-cancer
8. Heymach JV, Ruiter G, Ahn MJ, et al. Zongertinib in previously treated HER2-mutant non-small-cell lung cancer. N Engl J Med. 2025;392(23):2321-2333. doi:10.1056/NEJMoa2503704