PURPOSE Although several agents targeting epidermal growth factor receptor ( EGFR) exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to the inhibition of wild-type (WT) EGFR are common with these agents and affect overall tolerability. Zipalertinib (CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) with a novel pyrrolopyrimidine scaffold leading to enhanced selectivity for EGFR ex20ins-mutant versus WT EGFR with potent inhibition of cell growth in EGFR ex20ins-positive cell lines. METHODS This phase 1/2a study of zipalertinib enrolled patients with recurrent or metastatic EGFR ex20ins-mutant non–small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. RESULTS Seventy-three patients were treated with zipalertinib at dose levels including 30, 45, 65, 100, and 150 mg orally twice a day. Patients were predominantly female (56%), had a median age of 64 years, and were heavily pretreated (median previous systemic therapies 2, range 1-9). Thirty six percent of patients had received previous non-ex20ins EGFR TKIs and 3/73 (4.1%) patients received previous EGFR ex20ins TKIs. The most frequently reported treatment-related adverse events of any grade included rash (80%), paronychia (32%), diarrhea (30%), and fatigue (21%). No cases of grade 3 or higher drug-related rash or diarrhea were observed at 100 mg twice a day or below. Objective responses occurred across all zipalertinib dose levels tested, with confirmed partial response (PR) observed in 28/73 (38.4%) response-evaluable patients. Confirmed PRs were seen in 16/39 (41%) response-evaluable patients at the dose of 100 mg twice a day. CONCLUSION Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash.

INTRODUCTION:HER2 is mutated in 2-4% of non-small cell lung cancers (NSCLC) and is associated with poor prognosis. Tyrosine kinase inhibitors (TKIs) targeting HER2 have historically been hampered by insufficient efficacy against exon 20 insertion mutations and lack of specificity, resulting in off-target adverse events. Zongertinib is an oral, irreversible HER2-selective TKI that spares wild-type EGFR, thereby minimizing associated toxicities. Zongertinib was recently approved in the United States (accelerated), China (conditional), and Japan for patients with previously treated advanced HER2-mutant NSCLC. AREAS COVERED:This article outlines the discovery and clinical development of zongertinib that led to these approvals. We discuss the first-in-human Beamion LUNG-1 trial (NCT04886804), in which zongertinib demonstrated encouraging and durable activity, with a manageable safety profile, in patients with HER2-mutant advanced NSCLC. Finally, we summarize ongoing clinical trials of zongertinib, including its assessment as first-line treatment for advanced HER2-mutant NSCLC. EXPERT OPINION:Zongertinib is the first oral TKI approved for HER2-mutant NSCLC and will provide patients with a convenient, tolerable and effective treatment option in an area of significant unmet need. Next steps include its potential transition to a first-line setting, identification of additional indications, and development of novel combination regimens.

The increasing use of the immune checkpoint inhibitor nivolumab places a significant financial burden on healthcare systems, contributes to environmental concerns, and strains hospital capacities. The nivolumab average exposure and exposure variation of a fixed subcutaneous (SC) dosing regimen (1200 mg every 4 weeks) is significantly higher compared with 3-mg/kg every 2 weeks intravenous dosing. We aimed to develop alternative dosing regimens for SC nivolumab to reduce drug expenses and lower the treatment burden for patients while ensuring effective exposure. Population pharmacokinetic simulation was conducted using a population pharmacokinetic model developed by the license holder to explore alternative SC regimens. In this process, patients were divided into three weight groups: less than 60 kg, 60–90 kg, and more than 90 kg. Furthermore, two experimental progressive alternative dosing regimens were developed, one based on a minimum effective concentration-driven approach. The second progressive alternative regimen was based on using the 1200-mg SC formulation as an intravenous infusion. We developed an alternative bodyweight-based regimen consisting of SC 1200 mg every 7 weeks (<60 kg), 1200 mg every 6 weeks (60–90 kg), and 1200 mg every 5 weeks (>90 kg). This new alternative dosing regimen would save an average of €24,345 (35

Non-small cell lung cancer (NSCLC) that overexpresses human epidermal growth factor receptor 2 (HER2) is associated with poor prognosis, and no HER2-targeting therapies for HER2-overexpressing NSCLC are currently approved in the first-line setting. Pembrolizumab plus pemetrexed and platinum-based chemotherapy is a recommended first-line treatment option for nonsquamous NSCLC with no actionable genomic alterations. However, improved outcomes with pembrolizumab-based therapies correlate with higher programmed death-ligand 1 (PD-L1) levels, underscoring the need for more targeted treatment options for patients with lower PD-L1 tumor proportion scores (TPS; <50%). DESTINY-Lung06 is a multicenter, open-label, randomized, phase III trial evaluating the efficacy and safety of trastuzumab deruxtecan (T-DXd) in combination with pembrolizumab in the first-line setting in patients with HER2-overexpressing (≥25% moderate/strong membrane staining), PD-L1 TPS <50% NSCLC. Planned enrollment will be approximately 686 patients randomly assigned to either T-DXd 5.4 mg/kg with pembrolizumab 200 mg intravenously every 3 weeks (Q3W) or pembrolizumab 200 mg plus pemetrexed 500 mg/m2 with platinum-based chemotherapy (cisplatin 75 mg/m2 or carboplatin under the concentration-time curve 5 mg min/mL) intravenously Q3W. Progression-free survival by blinded independent central review and overall survival are the primary and key secondary endpoints of the study, respectively.Clinical trial registration: www.ClinicalTrials.gov identifier is NCT06899126; EudraCT identifier is 2024-515658-26-00.

Background KEYNOTE-024 (KN024) positioned first-line pembrolizumab monotherapy as the standard for metastatic non-small cell lung cancer (NSCLC) with PD-L1 ≥50%, but eligibility criteria may limit generalizability to routine care. We aimed to evaluate real-world eligibility rates and compare patient characteristics, effectiveness, and costs between trial-eligible and ineligible patients, and against the KN024 trial population. Methods We conducted a retrospective cohort study in two Dutch hospitals (2017–2025). Adults with metastatic NSCLC receiving first-line pembrolizumab monotherapy were classified by KN024 eligibility (major ineligibility factors: ECOG ≥2, active brain metastases, PD-L1 <50%, autoimmune disease). Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan–Meier and adjusted Cox models. Sixty-month cumulative mean costs (CMC), stratified by pembrolizumab and other hospital expenditures, were calculated using inverse probability of censoring weighting. Results 324 patients were included in the study, of whom less than half were KN024-eligible (47%). Among trial-eligible patients, median OS was shorter than in KN024 (22.3 vs 26.3 months). Ineligible patients showed a pattern towards shorter OS (16.7 vs. 22.3 months) despite similar PFS (9.0 vs. 10.2 months) compared to eligible patients, while healthcare expenditures at 60 months were comparable. Conclusions The findings reflect a significant difference between characteristics of trial populations and patients in clinical practice. While on-treatment disease control and healthcare costs are similar regardless of eligibility, ineligible patients experience shorter OS, likely due to reduced post-progression survival. The combination of comparable costs with divergent survival outcomes between subgroups warrants dedicated cost-effectiveness analyses incorporating an appropriate comparator and quality-of-life data.

8612 Background: Tepotinib is a highly selective MET inhibitor with clinical activity in patients with MET ex14 skipping NSCLC. We previously reported long-term efficacy and safety outcomes of tepotinib from VISION in patients with ≥3-years follow-up (data cut-off: May 20, 2024; Mazieres et al. ELCC 2025 [Poster 81P]). Here, we provide a subset analysis of patients from VISION who achieved long-term responses to tepotinib to identify clinical characteristics associated with durable benefit. Methods: Patients with advanced MET ex14 skipping NSCLC detected by liquid (L+) and/or tissue (T+) biopsy received tepotinib 500 mg (450 mg active moiety) once daily. The primary endpoint was objective response by independent review using RECIST v1.1. Secondary endpoints included duration of response and safety. Exploratory analyses of baseline and on-treatment liquid biopsy biomarkers were carried out for potential prognostic, predictive, or pharmacodynamic relevance. For this subset analysis, patients with a long-term response were defined as those with a duration of response (DOR) to tepotinib of >36 months. Results: Of 313 patients enrolled, 26 patients had a DOR >36 months (range: 36.6–78.9). In these patients, median age was 67.7 years (range: 52–84), 53.8% were male, 50.0% were White and 34.6% were Asian, 92.3% had adenocarcinoma, 53.8% had a history of smoking, and 53.8% were L+ and 65.4% were T+. Median duration of treatment was 50.7 months (range: 15.9–83.1). Seventeen patients received tepotinib as first-line and nine as second-or-later line therapy. Twenty-four patients achieved >50% decrease, while six patients achieved >80% decrease in the sum of longest diameters from baseline. Eighteen patients’ cancer had not progressed at the data cut-off of May 20, 2024, and 14 patients were still receiving treatment. In 12 patients who discontinued treatment, reasons for discontinuation were: adverse events (5 patients [peripheral edema in 2 patients]), disease progression per investigator (3 patients), non-compliance (1 patient), consent withdrawal (1 patient), and other reasons (2 patients). Among patients with long-term responses who stopped treatment early due to adverse events (prior to disease progression), continued responses were observed for up to 52 months after tepotinib discontinuation without any further subsequent anticancer treatment. Of nine patients who received treatment prior to tepotinib, four patients received immunotherapy alone, and eight patients received chemotherapy without immunotherapy. Baseline and on-treatment biomarker data will be presented. Conclusions: Patients who achieved long-term responses to tepotinib in VISION had similar clinical characteristics and safety outcomes to the overall population of patients from VISION (Mazieres et al. ELCC 2025 [Poster 81P]); ongoing biomarker analyses may help to further characterize these patients. Clinical trial information: NCT02864992 .

Supplementary Table S1. Antibodies used for flow cytometry staining. Supplementary Table S2. Clinical and immunological Characteristics of lost-to-follow up patients versus patients Supplementary Table S3. Patient data of patients whose blood was received for at least two time points. Patient characteristics, clinical response and immune populations after treatment. Supplementary Figure S1. Absolute numbers of immune cells per liter peripheral blood of NSCLC patients treated with chemotherapy. Supplementary Figure S2. Proportions of major T cell subsets in NSCLC patients treated with chemotherapy. Supplementary Figure S3. Monocyte subsets in peripheral blood of NSCLC patients treated with chemotherapy. Supplementary Figure S4. Co-inhibitory receptor expression on proliferating CD8 TEMRA cells in peripheral blood of chemotherapy-treated NSCLC patients. Supplementary Figure S5. Ki67+ CD8/ tumor burden ratio in NSCLC patients in relation to clinical outcome. Supplementary Figure S6. PD1 and CTLA4 expression on Tregs.

The decision regarding resectability in stage III non-small-cell lung cancer (NSCLC) is complex. To improve consistency in eligibility criteria in clinical trials, the European Organisation for Research and Treatment of Cancer (EORTC) initiated a Delphi study to establish a standardised definition of technical resectability for stage III NSCLC. 36 experts from the EORTC, European Respiratory Society, International Association for the Study of Lung Cancer, European Society for Radiotherapy and Oncology, European Thoracic Oncology Platform and International Breast Cancer Study Group, European Society of Thoracic Surgeons, and European Society of Pathology formulated 34 consensus statements on the definition of resectability. Consensus was defined as 75% agreement. After three Delphi rounds there was unanimous consensus that the decision on resectability should be made by experienced thoracic surgeons within the context of a multidisciplinary team. Initial assessments should include PET-CT, brain MRI, and invasive mediastinal staging. Stage IIIA was generally classified as resectable. Tumours with N2 involvement might be resectable depending on the nature of lymph node involvement (ie, single or multi-station, bulky or non-bulky, and invasive or non-invasive). Stage IIIB might be considered resectable, depending on lymph node characteristics: N2single mostly resectable; N2multi mostly unresectable; N2bulky mostly unresectable; and N2invasive or N3 unresectable. Stage IIIC was classified as unresectable. The proposed definitions aim to standardise inclusion criteria for clinical trials facilitating a more consistent evaluation of multimodal treatments for stage III NSCLC. Further data collection, especially on the nature of N2 disease, is needed to refine the definition.

OBJECTIVES:Identifying the primary tumor in cancer of unknown primary (CUP) remains a major clinical challenge. While WGS-based tissue-of-origin (TOO) prediction has improved diagnostic precision, its use is constrained by cost and availability. We investigated whether a low-complexity surrogate, combining SMARCA4 mutations and smoking history, can identify a lung cancer origin in CUP (CUP-Lung). METHODS:We retrospectively identified 305 provisional CUP cases from two Dutch CUP referral centers (2022-2025). Integration of whole-genome sequencing (WGS)-based TOO prediction with clinicopathological data identified 58 patients (18.9%) with CUP-Lung. Associations between SMARCA4 mutations, smoking history, and CUP-Lung were assessed using comparative and regression analyses. RESULTS:SMARCA4 mutations were present in 36.2% of CUP-Lung cases, significantly higher than in the overall CUP cohort (10.7%) and TCGA lung cancer datasets (6-8%). CUP-Lung cases had higher tumor mutational burden (median 21.5 vs. 12.6 mut/Mb, p < 0.001) and enriched smoking-related mutational signatures (p < 0.001). Smoking history was reported in 87.9% of cases. Smoking history (OR 4.9, 95% CI 2.2-10.9, p < 0.001) and SMARCA4 mutation (OR 10.3, 95% CI 4.5-23.8, p < 0.001) independently predicted CUP-Lung, together conferring a 76.0% probability of lung origin. No statistical differences were found between cases with and without detectable pulmonary involvement. CONCLUSION:Combined smoking history and SMARCA4 mutations support lung cancer classification even in the absence of detectable pulmonary involvement enabling organ-directed treatment when WGS is unavailable.

TPS8679 Background: The anti–PD-1 pembrolizumab (pembro) + chemotherapy (chemo) is a standard of care first-line therapy for metastatic NSCLC with no EGFR or ALK alterations. Despite these advances, here remains an unmet need for patients with tumors that have certain mutations, including those in the KRAS gene. KRAS mutations are associated with poor OS in NSCLC. Calderasib (MK-1084), a next-generation, selective KRAS G12C-GDP covalent inhibitor, has previously demonstrated preliminary antitumor activity in combination with pembro ± chemo in KRAS G12C–mutant metastatic NSCLC in the phase 1 KANDLELIT-001 study. The anti-EGFR cetuximab has shown promising efficacy in combination therapies in NSCLC with KRAS G12C mutations. The phase 2 KEYMAKER-U01J study (NCT07252739) is evaluating the addition of investigational agents to pembro in advanced or metastatic nonsquamous NSCLC with KRAS G12C mutations; the treatment arms presented here include pembro + calderasib ± cetuximab. Methods: This phase 2, randomized, open-label study is enrolling participants (pts) aged ≥18 years with previously untreated histologically or cytologically confirmed stage IIIB, IIIC, or IV (M1a, M1b, or M1c) nonsquamous NSCLC (AJCC v9), with a KRAS G12C mutation that is ineligible for curative resection or chemoradiation. Pts must also have measurable disease per RECIST v1.1, an ECOG PS of 0 or 1, and provide a tumor sample for biomarker analysis. Following a safety lead-in of ~10 pts in arm 3, 1:1:1 randomization of ~120 pts will occur. In arm 1 (control arm), pts will receive up to 18 cycles of pembro 400 mg Q6W intravenously (IV) plus carboplatin AUC 5 mg/mL/min up to 2 cycles and pemetrexed 500 mg/m 2 Q3W until discontinuation criteria are met. Pts in arm 2 (reference arm) will receive up to 18 cycles of pembro 400 mg IV Q6W plus calderasib orally until discontinuation criteria are met. Pts in arm 3 will receive up to 18 cycles of pembro 400 mg IV Q6W plus calderasib with cetuximab 500 mg/m 2 IV Q2W until discontinuation criteria are met. Discontinuation criteria include unacceptable AEs, PD, occurrence/progression of another malignancy, or pt/physician withdrawal. Randomization will be stratified by PD-L1 tumor proportion score (< 50% vs ≥50%). Dual primary endpoints are safety (dose-limiting toxicities, AEs, and AEs leading to study discontinuations) and objective response (CR or PR) per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints are duration of response and PFS per RECIST v1.1 by BICR, OS, and pharmacokinetic characterization. On-study tumor imaging will occur Q6W until week 24, Q9W until week 51, then Q12W, or more frequently if clinically indicated. AEs will be graded per NCI CTCAE v5.0. Enrollment began in December 2025, with 80–105 sites scheduled to enroll globally. Clinical trial information: NCT07252739 .

PURPOSE:Rilvegostomig, an anti-PD-1/TIGIT bispecific antibody, was evaluated in this first-in-human, multicenter, phase I/II, open-label study (NCT04995523) in checkpoint inhibitor (CPI)-experienced patients with programmed death ligand-1 (PD-L1)-positive advanced or metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS:In Part A, patients (n = 51) received intravenous rilvegostomig at escalating doses of 70, 210, 750, and 1500 mg, once every 3 weeks (Q3W). Dose expansion in Part B (n = 32) was initiated once the recommended phase II dose (RP2D) was declared in Part A. Safety, tolerability, pharmacodynamics, pharmacokinetics and preliminary antitumor activity were evaluated. RESULTS:In Part A no dose-limiting toxicities were observed, the maximum tolerated dose was not reached and the rilvegostomig RP2D for dose expansion in Part B was 750 mg Q3W. At data cut-off (April 21, 2025), 90.4% of patients had treatment-emergent adverse events (TEAEs) of any grade, 18.1% of patients had investigator-assessed immune-mediated AEs, and 54.2% had treatment-related AEs (TRAEs), including 8.4% with grade 3 TRAEs, with few treatment-related discontinuations (2.4%). At the RP2D, objective response rate was 5.6%, 6-month disease control rate was 31.5%, median progression-free survival (PFS) was 3.8 months, and 12-month PFS was 11.9%. CONCLUSIONS:The evidence of clinical efficacy in a pretreated population, favorable tolerability and low rate of treatment discontinuation observed in Parts A and B support further evaluation of rilvegostomig in Parts C-E of the study, which assess safety and efficacy in CPI-naïve patients with nonsquamous and/or squamous NSCLC with PD-L1 tumor proportion score ≥1% or ≥50%.

BACKGROUND: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. METHODS: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 at 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). RESULTS:In cohort 2, a total of 74 previously untreated patients received zongertinib at 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 at 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%). CONCLUSIONS: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.).