NCCN Adds Zongertinib to Clinical Practice Guidelines in NSCLC

The National Comprehensive Cancer Network (NCCN) has updated their Clinical Practice Guidelines in Oncology for the treatment of patients with non–small cell lung cancer (NSCLC) to include zongertinib tablets (Hernexeos) as a preferred subsequent therapy option for the treatment of patients with advanced or metastatic HER2-mutant disease who have received prior systemic therapy.1,2

The latest version of the guidelines, which were updated on August 15, 2025, list zongertinib as preferred following progression on first-line systemic therapy.2 The guidelines also note that zongertinib can be given following progression on second-line therapy in zongertinib-naive patients.

“[Zongertinib] is a meaningful advancement as the first orally administered treatment targeted for HER2-mutant NSCLC,” Vicky Brown, senior vice president and head of Immunology, Oncology, and Eye Health at Boehringer Ingelheim, stated in a news release.1 “The update to the NCCN guidelines gives oncologists further confidence in prescribing it to these patients with unmet need. While rare, HER2 mutations in NSCLC are associated with a poor prognosis. All patients with advanced NSCLC should understand their HER2 status and whether they may benefit from treatment with [zongertinib].”

Notably, zongertinib was granted accelerated approval by the FDA for the treatment of adult patients with unresectable or metastatic nonsquamous NSCLC whose tumors harbor HER2 TKD activating mutations as detected by an FDA-approved test and who have been treated with prior systemic therapy.3 This regulatory decision was backed by data from the phase 1 Beamion LUNG-1 trial (NCT04886804), which evaluated zongertinib monotherapy in patients with advanced HER2-altered NSCLC.

Among evaluable patients who had previously been treated with platinum-based chemotherapy and were naive to HER2-targeted TKIs or antibody-drug conjugates (ADCs; n = 71), the objective response rate (ORR) was 75% (95% CI, 63%-83%), and the 6-month duration of response (DOR) rate was 58%. Among patients who had previously received platinum-based chemotherapy and a HER2-targeted ADC (n = 34), the ORR was 44% (95% CI, 29%-61%), and the 6-month DOR rate was 27%.

The Beamion LUNG-1 trial enrolled adult patients with histologically or cytologically confirmed, unresectable, or metastatic nonhematologic HER2-mutant malignancies.4 Eligible patients were required to have at least 1 measurable lesion, as defined by RECIST 1.1 criteria, as well as an ECOG performance status of 0 or 1. During the dose-escalation portion of the trial, patients were administered escalating doses of zongertinib to establish the maximum tolerated dose. This was followed by the dose-expansion portion, which further evaluated the recommended dose for antitumor efficacy and tolerability specifically in patients with HER2-mutant nonsquamous NSCLC who had received prior systemic therapy.

The primary end points of the study were the incidence of dose-limiting toxicities in the dose-escalation portion and ORR in the dose-expansion portion. Secondary end points included DOR, progression-free survival, disease control rate, overall survival, safety outcomes, and pharmacokinetic profiling.

Regarding safety, adverse effects (AEs) leading to dose reductions occurred in 7% of patients, and AEs leading to treatment discontinuations occurred in 2.9% of patients.5 Most treatment-related AEs were grade 1 or 2 in severity. The most common any-grade AEs were diarrhea (52%) and rash (32%).

Building on the Beamion LUNG-1 findings, zongertinib is currently being evaluated in the ongoing phase 3 Beamion LUNG-2 trial (NCT06151574).6 This randomized study is comparing zongertinib vs standard-of-care therapy in patients with HER2-mutant, unresectable or metastatic nonsquamous NSCLC to further assess the efficacy and long-term safety of the agent in this population.

References

1. NCCN Clinical Practice Guidelines recommend Boehringer’s Hernexeos for HER2 (ERBB2)-mutant advanced NSCLC as preferred subsequent therapy. News release. Boehringer Ingelheim. August 15, 2025. Accessed August 19, 2025. https://www.boehringer-ingelheim.com/us/media/press-releases/nccn-clinical-practice-guidelines-recommend-boehringers-therapy
2. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 8.2025. Accessed August 19, 2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
3. FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations. FDA. August 8, 2025. Accessed August 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-non-squamous-nsclc-her2-tkd-activating-mutations
4. Beamion LUNG-1: a study to test different doses of zongertinib in people with different types of advanced cancer (solid tumours with changes in the HER2 gene). ClinicalTrials.gov. Updated July 28, 2025. Accessed August 5, 2025. https://clinicaltrials.gov/study/NCT04886804
5. Hernexeos. Prescribing information. Boehringer Ingelheim; August 2025. Accessed August 19, 2025. https://patient.boehringer-ingelheim.com/us/products/hernexeos/bipdf/hernexeos-dtc-prescribing-information
6. Beamion LUNG-2: a study to test whether zongertinib (BI 1810631) helps people with advanced non-small cell lung cancer with HER2 mutations compared with standard treatment. ClinicalTrials.gov. Updated August 6, 2025. Accessed August 19, 2025. https://clinicaltrials.gov/study/NCT06151574?term=NCT06151574&rank=1