Until recently, no first-line targeted treatment options were available for patients with human epidermal growth factor receptor 2 (HER2)–mutant non–small-cell lung cancer (NSCLC). Zongertinib is an oral, irreversible tyrosine kinase inhibitor that selectively inhibits HER2 while sparing wild-type epidermal growth factor receptor (EGFR), thereby minimizing associated toxic effects.
We conducted a phase 1a–1b, multicohort trial to assess zongertinib in patients with advanced or metastatic nonsquamous HER2-mutant NSCLC. Here, we evaluated zongertinib a dose of 120 mg once daily in patients who had not previously received treatment (cohort 2). The primary end point was objective response as assessed by blinded independent central review. Secondary end points included duration of response and progression-free survival. In addition, zongertinib was evaluated in patients with active brain metastases (exploratory cohort 4). Research Summary First-Line Zongertinib in Advanced HER2-Mutant Non–Small-Cell Lung Cancer
In cohort 2, a total of 74 previously untreated patients received zongertinib a dose of 120 mg. As of August 21, 2025, the percentage of patients with a confirmed objective response was 76% (95% confidence interval [CI], 65 to 84); the median duration of response was 15.2 months (95% CI, 9.8 to not evaluable), and the median progression-free survival was 14.4 months (95% CI, 11.1 to not evaluable). Adverse events of any grade occurred in 73 patients (99%), including events of grade 3 or higher in 33 patients (45%). Treatment-related adverse events occurred in 67 patients (91%), including events of grade 3 or higher in 14 patients (19%). In cohort 4, a total of 30 patients with active brain metastases received zongertinib a dose of 120 mg; of these, 47% (95% CI, 30 to 64) had a confirmed intracranial objective response according to Response Assessment in Neuro-Oncology Brain Metastases criteria. In this cohort, treatment-related adverse events of grade 3 or higher occurred in 5 patients (17%).
Zongertinib showed sustained efficacy in previously untreated patients with advanced or metastatic HER2-mutant NSCLC. Treatment-related adverse events were predominantly low-grade. (Funded by Boehringer Ingelheim; Beamion LUNG-1 ClinicalTrials.gov number, NCT04886804.)
45 patients with Non–Small-Cell Lung Cancer (NSCLC) who received the 600-mg dose, 36% had a partial response, the median progression-free survival (PFS) was 8.3 months, estimated 12-month overall survival was 59% 21 patients with metastatic pancreatic ductal adenocarcinoma 24% had a response, the median PFS was 3.0 months and the median overall survival was 10.3 months.
Setidegrasib represents a meaningful advance in targeting KRAS G12D–mutant tumors, demonstrating a 36% response rate with median PFS exceeding 8 months in heavily pretreated NSCLC, and a 24% response rate with ~10 month median overall survival (OS) in third line pancreatic cancer, both notable signals in populations lacking approved targeted therapies.
The CHRYSALIS-2, the cohort C analysis of patients with atypical EGFR mutations showed meaningful and durable activity. Atypical mutations can be difficult to deal with as a clinician, and having concrete data on these (S768I, L861Q and G719ZX) mutations gives assurance that this doublet is active. Overall response rate (ORR) was 52% and median progression-free survival (PFS) was 11.1 months in refractory patients and 19.5 months in the treatment-naive population.
The final overall survival (OS) analysis from the FLAURA2 confirms the well-published findings that Osi + chemo improves survival over Osi monotherapy. OS difference was about 10 months at 47 vs 37 months, with a predictable toxicity tradeoff.
This update demonstrated that encorafenib plus binimetinib was associated with the longest median overall survival (mOS) reported to date among targeted therapies in patients with treatment-naïve BRAF V600E–mutant metastatic NSCLC (mNSCLC). Median OS was 47.6 months in treatment-naïve patients. By the way check the authors there 😊.