Background Small-cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis and limited therapeutic progress over recent decades. Although PD-L1 inhibitors have modestly improved survival, responses are not durable. There are no predictive biomarkers that would allow for a personalized treatment strategy. Targeting DNA damage repair deficiencies represents a promising treatment strategy in various solid tumors. Poly(ADP-ribose) polymerase (PARP) inhibitors such as olaparib have demonstrated efficacy in homologous recombination deficiency (HRD)-positive tumors, and preclinical data suggest synergistic activity with immune checkpoint blockade. Methods GUIDANCE is a biomarker-driven, multicenter, single-arm, open-label phase II trial evaluating maintenance therapy with durvalumab and olaparib in patients with advanced or metastatic SCLC without progression after first-line therapy with platinum, etoposide and durvalumab. Patients are prospectively selected for HRD based on homologous recombination repair gene alterations and/or a genomic instability score. Following central pre-screening, 29 patients will be enrolled. Patients receive durvalumab (1500 mg every 4 weeks) and olaparib (300 mg twice daily) until progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) by RECIST 1.1. Secondary endpoints are overall survival, safety and tolerability. Exploratory analyses include circulating tumor DNA (ctDNA) monitoring of individual TP53 mutations, assessment of SLFN11 expression, and characterization of immune cell composition via multiplex immunohistochemistry. Discussion This trial investigates a chemotherapy-free, genomically stratified maintenance strategy targeting both DNA damage repair deficiency and immune evasion in SCLC. By integrating HRD-based patient selection with concurrent PARP and immune checkpoint inhibition, GUIDANCE aims to establish a more individualized therapeutic approach and to generate a signal for further evaluation in biomarker-defined patient populations. Trial registration number EuraCT 2024-512373-27-00.

Supplementary Figure S2: Kaplan-Meier statistics on median real-world overall survival (rwOS) in different subgroups

Supplementary Figure S3: In support of Fig. 5: PD-L1 expression in the different therapy subgroups

BACKGROUND:Small-cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis and limited therapeutic progress over recent decades. Although PD-L1 inhibitors have modestly improved survival, responses are not durable. There are no predictive biomarkers that would allow for a personalized treatment strategy. Targeting DNA damage repair deficiencies represents a promising treatment strategy in various solid tumors. Poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib have demonstrated efficacy in homologous recombination deficiency (HRD)-positive tumors, and preclinical data suggest synergistic activity with immune checkpoint blockade. METHODS:GUIDANCE is a biomarker-driven, multicenter, single-arm, open-label phase II trial evaluating maintenance therapy with durvalumab and olaparib in patients with advanced or metastatic SCLC without progression after first-line therapy with platinum, etoposide and durvalumab. Patients are prospectively selected for HRD based on homologous recombination repair gene alterations and/or a genomic instability score. Following central prescreening, 29 patients will be enrolled. Patients receive durvalumab (1500 mg every 4 weeks) and olaparib (300 mg twice daily) until progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) by RECIST 1.1. Secondary endpoints are overall survival, safety and tolerability. Exploratory analyses include circulating tumor DNA (ctDNA) monitoring of individual TP53 mutations, assessment of SLFN11 expression, and characterization of immune cell composition via multiplex immunohistochemistry. DISCUSSION:This trial investigates a chemotherapy-free, genomically stratified maintenance strategy targeting both DNA damage repair deficiency and immune evasion in SCLC. By integrating HRD-based patient selection with concurrent PARP and immune checkpoint inhibition, GUIDANCE aims to establish a more individualized therapeutic approach and to generate a signal for further evaluation in biomarker-defined patient populations. Trial registration number EuraCT 2024-512373-27-00.

Supplementary Figure S1: Localization of genetic co-alterations (Created with cBioPortal [Scheffler M][https://www.cbioportal.org])

Small cell transformation (SCT) represents a rare mechanism of acquired resistance to EGFR inhibitors in EGFR-mutant NSCLC and is associated with poor prognosis. HER2 amplification constitutes another less frequent resistance mechanism, acting as a bypass of EGFR signaling. The coexistence of SCT and HER2 amplification has not been previously described and is exceedingly rare. We report a patient with EGFR-mutant NSCLC who developed concurrent SCT and HER2 amplification during treatment with osimertinib. Following rapid disease progression on chemoimmunotherapy, the patient achieved clinically meaningful and radiographic response (Response Evaluation Criteria in Solid Tumors version 1.1) to trastuzumab deruxtecan.

Purpose: KRAS G12V is among the most frequent KRAS mutations in non-small cell lung cancer (NSCLC), yet its clinical and molecular features remain poorly understood. Experimental Design: In this retrospective study, we analyzed 636 patients with KRAS G12V-mutated NSCLC diagnosed between 2018 and 2023. Clinical, pathological, and molecular characteristics, including co-mutations, smoking history, PD-L1 expression, CD8+ T-cell infiltration, and treatment outcomes, were assessed. Results: The majority of patients (94.2%) were current or former smokers, with a median tobacco exposure of 40 pack-years. Co-mutations were frequent, most commonly in TP53 (40.2%), STK11 (30.2%), and KEAP1 (29.3%). Heavy smokers exhibited significantly higher PD-L1 expression and more frequent TP53, KEAP1, and NTRK1–3mutations than light smokers. CD8+ T-cell infiltration showed a non-significant trend toward higher values in G12V compared to non-G12V KRAS subtypes. Among 151 patients with advanced disease, those treated with immune checkpoint blockade (ICB) alone or in combination with chemotherapy had significantly higher response rates and improved real-world progression-free (rwPFS) and overall survival (rwOS) compared to chemotherapy alone. In patients with PD-L1 TPS ≥50%, ICB-based treatment achieved a median rwOS of 30 months. Conclusions: KRAS G12V-mutated NSCLC is characterized by a strong association with tobacco use, high co-mutation rates in clinically relevant genes, and a favorable response to PD-L1-based immunotherapy. The observed mutation landscape supports the potential for dual checkpoint blockade in a significant subset.

Background: Targeted therapies have transformed advanced non-small-cell lung cancer (aNSCLC), but whether structured clinical networks deliver survival gains at population level remains unclear. In 2010, the Cologne Network Genomic Medicine (NGM) Lung Cancer implemented comprehensive sequencing, expert interpretation, and personalised treatment recommendations into routine care. We evaluated its long-term effect on overall survival (OS). Methods: In a regional matched historical cohort study, patients with aNSCLC diagnosed Jan 2014–March 2019 and receiving first-line (1L) systemic therapy were followed to Dec 2023. NGM participants were linked to German statutory health insurance (AOK) claims and matched by age, sex, and treatment year to patients treated outside the network. OS was compared by Kaplan–Meier and Cox regression. Findings: Among 666 NGM and 3,330 matched non-NGM patients, NGM participation conferred a significant survival benefit (median OS 1.02 vs 0.65 years; HR 0.74, 95% CI 0.68–0.81; p<0.001), with one-year and five-year OS of 50.6%/11.4% vs 35.9%/7.1%. NGM patients more often received 1L tyrosine kinase inhibitors (TKI; 5.9% vs 3.5%; p=0.004) and immune checkpoint inhibitor-based therapy (9.9% vs 6.4%; p=0.001). Among TKI-treated patients, median OS more than doubled (2.35 vs 1.07 years; p=0.008). Interpretation: Transferring precision oncology from a single specialised centre into an entire region delivered a substantial population-level survival benefit persisting over years, with higher use of targeted and immune therapies. As the earliest and longest-observed implementation, the Cologne NGM provided a blueprint for implementing precision oncology in routine care.

INTRODUCTION:KRAS Q61 mutations represent a heterogeneous molecular subgroup and account for 1-7% of allKRAS mutations in non-small cell lung cancer (NSCLC). The prognostic value of this cohort and its response to different treatment regimens remain unclear. METHODS:Between 2011 and 2023, diagnostic samples from patients with NSCLC were analyzed by next-generation sequencing (NGS). Molecular data were correlated with clinical records and time-to-event analyses were performed using the Kaplan-Meier estimate. RESULTS:Of the 8862 analyzed probes, we identified 487 patients (5.5%) with KRAS Q61 mutations and further analyzed 365 patients. Most presented with Q61H (74.0%) and Q61L (20.8%) mutations which demonstrated distinct patterns in smoking history (7% versus 3.3% never-smokers) and co-mutational landscape. The most frequent co-mutations in Q61H were STK11 (45.8%), TP53 (32.1%) and KEAP1 (31.3%), whereas Q61L was mutually exclusive to STK11 and had a lower incidence of co-occuring KEAP1 mutations (11.5%). Median overall survival for the entire cohort was 12.3 months with a favorable survival of 22.1 and 65.4 months for patients receiving combined chemoimmunotherapy and immunotherapy as first-line treatment, respectively. Real-world progression-free survival was significantly prolonged in patients receiving immunotherapy, either as monotherapy or combined therapy, versus chemotherapy in the first-line setting (p<0.01). CONCLUSION:KRAS Q61H and Q61L were the predominant mutational subtypes and demonstrated distinct molecular and clinical characteristics, with differences in co-mutational landscape and survival differences. Immunotherapy-based regimens were associated with more favorable outcomes compared to chemotherapy, particularly in patients with high PD-L1 expression, underscoring the importance of subtype-specific molecular characterization in clinical decision-making.

e20647 Background: KRAS mutations occur in approximately 30% of non-small cell lung cancers (NSCLC) and frequently involve the hotspot codon G12. While common variants such as G12C, G12V and G12D have been extensively studied, data on rare G12A, G12S, G12R and G12F substitutions remain limited. This real-world analysis characterizes the molecular and clinical features of a large cohort of NSCLC patients harboring rare KRAS codon 12 mutations. Methods: We looked for stage IV NSCLC at initial diagnosis harboring rare KRAS codon 12 mutations (G12A, G12S, G12R and G12F) from the national Network Genomic Medicine (nNGM) database diagnosed between 2018 and 2024. Clinical, pathological and molecular characteristics were analyzed, including co-mutations, smoking-history, PD-L1 expression, treatment patterns and outcomes. Results: A total of 527 individuals were included. KRAS G12A mutations were identified by next-generation sequencing (NGS) in 316 cases (60%), followed by G12S (15%), G12R (13%) and G12F (12%). The median age of the cohort was 66 years (range: 38–89), with no major differences in sex distribution (47% female, 53% male). Most patients were former or current smokers (overall: 477 (91%), G12A/S/R/F: 91/94/82/93%) and adenocarcinoma was the predominant histology (overall: 480 (91%), G12A/S/R/F: 90/89/93/99%). Median PD-L1 tumor proportion score (TPS) in the overall cohort was 5% (range: 0–100), with differences between subtypes (G12A/S/R/F: 5/30/1/10%). The most frequent co-mutations in the overall cohort were TP53 , STK11 , KEAP1 and SMARCA4 , showing subtype-specific patterns ( TP53 : 43/43/36/43%, STK11 : 21/23/36/29%, KEAP1 : 21/16/26/18%, SMARCA4 : 9/29/0/14% for G12 A/S/R/F respectively). At initial diagnosis the most common metastatic sites were bone (38%) and lung (38%) metastasis, with notable differences between subtypes (bone: 44/36/11/40%, lung: 40/36/45/21% for G12 A/S/R/F). Treatment data were available for 285 patients, of whom 36 (13%) received chemotherapy, 199 (70%) chemo-immunotherapy, and 50 (18%) immune checkpoint inhibitor monotherapy. Median overall survival (mOS) did not significantly differ between subtypes, however a trend toward shorter survival was observed in G12R-mutated tumors (mOS: 6.7 months (95% CI, 4.1–15.9)), whereas longer survival was seen in G12A-mutated tumors (mOS: 11.7 (95% CI, 9.2–16.6). Conclusions: NSCLC harboring rare KRAS codon 12 mutations (G12A, G12S, G12R and G12F) are characterized by a high prevalence of tobacco exposure, frequent co-mutations in clinically relevant genes, and a heterogeneous molecular landscape across the four analyzed subtypes. Despite comparable median overall survival, the observed subtype-specific patterns underscore the biological diversity of rare KRAS codon 12 mutations and suggest that these subgroups be considered in future clinical trials.

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.).

Targeted treatment of non-small cell lung cancer (NSCLC) with driver aberrations has drastically improved the outcome of a subset of patients. However, for successful adaptation in the clinical routine, many stakeholders are involved, like comprehensive cancer centers, molecular pathology, peripheral hospitals, and oncology practices. Here, we present a single center experience in personalized treatment of lung cancer in Germany. Patients with advanced NSCLC and the need for systemic treatment after identification of a targetable driver mutation have been included in this analysis. Detection of the mutations was performed within a diagnostical network. Treatment was chosen depending on the respective driver mutation. We identified 58 patients (26 male, 32 female) with treatment relevant driver mutations: 33 patients (56.9 %) had an EGFR mutation, nine patients (15.5 %) presented with ALK translocation, five patients (8.6 %) were detected to have BRAF mutations, four had ROS1 translocations (6.9 %) and 8 patients had MET mutations (13.8 % each). In one patient, concomitant BRAF and MET amplifications were detected. 52 patients received targeted therapy. The median overall survival was 35.5 months (95 % CI, 18.0-52.9 months). 32 patients (64 %) received subsequent treatment after initiation of targeted therapy first-line. Our single-center experience demonstrates that advances in the field of targeted NSCLC therapy are quickly incorporated into clinical routine in Germany. Noteworthy, no new safety information was found.

Integrated model for patient stratification and clinical outcome prediction with KRAS G12Ci monotherapy in KRASG12C-mutant NSCLC.

Baseline Patient Characteristics – Cohort B

Survival outcomes according to KEAP1 and STK11 co-mutation status: A) Cohort A; B) Cohort B; C) further subclassifying KEAP1MUT tumors according to STK11 mutation status; D) PFS and OS according to STK11 co-mutation status in KSCWT tumors in the overall study cohort.

8619 Background: EGFR inhibitors (EGFRi) are highly effective in EGFRmut NSCLC, but resistance inevitably emerges. Among the mechanisms of acquired resistance, RAS/MEK pathway activation has been identified in both cell models and patients. Preclinical and clinical data support efficacy of dual MEK and EGFR inhibition in this setting. In the EATON trial we investigated the combination of the MEK inhibitor (MEKi) trametinib (TMT) and the third-generation (3gen) EGFRi nazartinib (NAZ) in patients with EGFRmut NSCLC. Methods: EATON (NCT03516214, AIO-TRK-0216) is an academic multicenter, phase I, dose-escalation trial conducted in Spain and Germany. Primary endpoint: maximal tolerated dose (MTD)/recommended phase 2 dose (RP2D); secondary endpoints: pharmacokinetics (PK), safety, preliminary efficacy. Key eligibility criteria: Advanced/metastatic EGFRmut NSCLC, EGFR p.T790M-positive/-negative, no MET amplification, any treatment line. Dose escalation was based on a modified 3+3 up-and-down design in up to 18 patients [Storer, 1989]. TMT and NAZ were dosed once daily (qd) at pre-defined dose levels (DL) of 0.5 mg/100 mg (DL -1), 1.0 mg/100 mg (DL 1), 1.5 mg/100 mg (DL 2), 1.5 mg/150 mg (DL 3), 2 mg/150 mg (DL 4). The dose-limiting toxicities (DLT) period comprised the first 28 treatment days. Results: In total, 19 patients were dosed (mean age, 62 years (range, 44-81); 14 female (73.7%)). Prior EGFRi and 3gen EGFRi use were noted in 17 (89.5%) and 14 (73.7%), respectively. Patients were treated at DL -1 (N=4), DL 1 (N=13), and DL 2 (N=3), with 18 (94.7%) eligible for dose-escalation decisions. DLTs were observed in 4 (22.2%) patients (Grade 3 creatinine phosphokinase elevation, N=3; Grade 3 hypertension, N=1). The MTD was determined to be TMT 1.0 mg qd and NAZ 100 mg qd. After repeated dosing (C1D15) at the MTD, geo-mean C max of NAZ was 336 ng/ml (N=14, CV% 44.8) and of TMT 19.5 ng/ml (N=7, CV% 22.6). Geo-mean AUC tau of NAZ was 3950 ng/ml*h (N=14, CV% 48.7) and of TMT 301 ng/ml*h (N=7, CV% 27.3). Treatment-related adverse events (TRAEs) of any grade were observed in all patients (N=19; 100%) and of Grade ≥3 in nine (47.4%). Discontinuation rates were 26.3% (N=5) and 21.1% (N=4), for TMT and NAZ. Sixteen (84.2%) patients were evaluable for RECIST 1.1 response assessment and 19 (100%) for time-to-event outcomes. One patient had a partial response (ORR, 6.3%; 95% CI, 1.6-30.2) and six had stable disease (37.5%). Median progression-free survival was 2 months (95% CI, 1.7-2.2). Molecular determinants of response and resistance were investigated by 3’ RNA and DNA sequencing. Conclusions: At the MTD, treatment was safe and moderately tolerable. Preliminary efficacy in this unselected and heavily pre-treated population was limited. A comprehensive biomarker-driven approach may help identify patients more likely to derive clinical benefit. Clinical trial information: NCT03516214 .

Durable combination therapy benefit