INTRODUCTION:Optimal first-line immunotherapy duration in metastatic NSCLC with controlled disease remains unclear. We evaluated 6-month nivolumab-ipilimumab (Nivo-Ipi) in patients with disease control (DC). METHODS:This randomized, open-label, noninferiority trial enrolled treatment-naive patients with metastatic NSCLC (aged 18-75 y, Eastern Cooperative Oncology Group performance status 0-1, no actionable genomic alterations). After 6-month induction treatment with Nivo (3 mg/kg biweekly) plus Ipi (1 mg/kg every 6 wk), patients with DC were randomized to continue treatment or stop and resume at disease progression. The primary outcome was progression-free survival (PFS). RESULTS:Among 265 patients enrolled, 71 were randomized to the continuation control arm (n = 36) or to the experimental arm (n = 35), with trial premature interruption because of the lack of European filing for the immunotherapy combination. Median PFS follow-up was 47.8 months (95% confidence interval [CI]: 43.1-51.0). In the per-protocol population, median PFS was 18.7 months (95% CI: 7.1-37.1) in the continuation arm versus not reached (NR) (95% CI: 16.1-NR) in the experimental arm. Median OS was 55.5 months (95% CI: 32.4-NR) in the continuation arm versus NR in the experimental group. The 18-month OS was 80.6% (95% CI: 63.5-90.2) and 93.8% (95% CI: 77.3-98.4), respectively. Grade 3 to 5 treatment-related adverse event rates were higher in the continuation arm (54.3% versus 23.5%). Median time until definitive quality-of-life deterioration was 15.5 months (95% CI: 10.0-NR) for the continuation arm but NR in the experimental arm (hazard ratio = 0.36, 95% CI: 0.14-0.92, p = 0.03). CONCLUSIONS:Stopping Nivo-Ipi combination at 6 months in DC patients demonstrated no survival harm at 4 years, reduced severe immune-related adverse events, and delayed quality-of-life deterioration.

Introduction In studies evaluating the efficacy of anti-programmed cell death (ligand)1 (anti-PD-(L)1) in patients with non-small-cell lung cancer (NSCLC), smokers tend to have better clinical outcomes than non-smokers. However, whether co-existing emphysema is associated with differences in clinical outcomes, regardless of smoking status remains unclear. Methods In a single-arm, prospective, multicenter, phase II trial, patients aged 18-75 years with metastatic NSCLC, PD-L1≥25% and a performance status (PS) of 2-3 received durvalumab until progression or toxicity. Pre-planned analyses classified emphysema visually as follows: <10% (no/mild emphysema), 10 to 25% (moderate emphysema) and >25% (severe emphysema). We also quantified emphysema (%LAV-950HU), along with bronchial (wall thickness) and small pulmonary vessels (cross-sectional area<5 mm²). Results Fifty patients were enrolled with 49 analyzable CT scans, of whom 43 (87.8%) had emphysema. Twenty-eight patients (57%) had an emphysema extent >10%, with a median %LAV-950 HU of 0.97 [IQR: 0.25-3.12]. In univariate analyses, compared to mild emphysema, patients with moderate emphysema had a significantly poorer overall survival (OS (HR 2.73, 95%CI [1.25-5.98]), whereas severe emphysema had not. Objective response rate and progression free survival were similar in all groups. In multivariate analyses, OS remained lower in patients with moderate emphysema (HR: 2.53, 95%CI [1.12-5.71]), after adjustment for smoking, age and PS. There was no difference according to bronchial and vascular involvement. Conclusion In a single-arm cohort of PS2-3 patients with advanced NSCLC treated with 1st-line durvalumab, the presence of moderate emphysema was associated with worse overall survival.

Introduction:Extensive-stage SCLC (ES-SCLC) is a highly aggressive type of lung cancer with a high risk of early progression and limited survival. Standard of care for first-line treatment is platinum-etoposide chemotherapy plus anti-PD-L1 immune checkpoint inhibitors. Methods:Intergroupe Francophone de Cancérologie Thoracique-1905 CLINATEZO is a nationwide, non-interventional, retrospective study of consecutive patients with ES-SCLC who received atezolizumab plus platinum-based chemotherapy as part of the French Early Access Program that ran from May 2019 to March 2020. In this analysis, predictors of long-term response (defined by a real-world progression-free survival [rwPFS] > 12 mo) and long-term survival (defined by an overall survival [OS] > 24 mo) were assessed. Results:A total of 517 patients were enrolled from 65 centers. After a median follow-up of 53.8 months, median, 12-month, and 48-month rwPFS rates were 5.2 (95% confidence interval [CI]: 5.0-5.4) months, 14.6% (95% CI: 11.6-17.9), and 6.8% (95% CI: 4.7-9.4), respectively. Median, 24-month, and 48-month OS rates were 11.3 (95% CI: 10.1-12.4) months, 21.1% (95% CI: 17.7-24.8), and 11.4% (95% CI: 8.8-14.4), respectively.Long-term response was observed in 12.6% patients. Median OS was 9.7 months in patients with rwPFS less than or equal to 12 months and 53.7 months in patients with rwPFS more than 12 months. Baseline characteristics associated with rwPFS more than 12 months were being a former smoker (versus current smoker, p = 0.003) and having an Eastern Cooperative Oncology Group performance status of 0 to 1 (versus 2, p = 0.048).Long-term survival was observed in 20.5% patients. Median OS was 8.8 months in patients with OS less than or equal to 24 months and 52.9 months in patients with OS more than 24 months. Predictors of long-term survival were younger age (p = 0.030), limited stage at initial diagnosis of SCLC (p = 0.022), and previous line of platinum-based chemotherapy (p = 0.01). Conclusions:CLINATEZO demonstrates the reproducibility of the key survival outcomes of landmark trials, in a real-life setting, for patients with ES-SCLC. Only low smoking history and performance status were associated with long-term response in our cohort.

Antibody-drug conjugates (ADCs) are rapidly transforming the treatment landscape of advanced non-small cell lung cancer (NSCLC), yet validated predictive biomarkers to guide their use remain lacking. ICARUS-LUNG01 is a prospective, phase II study designed to integrate clinical outcomes with longitudinal translational analyses. In this multicenter trial, 100 pretreated patients with advanced NSCLC received the TROP2-directed ADC datopotamab deruxtecan (Dato-DXd). The study reported an objective response rate (ORR) of 26.0%, with a median progression-free survival (PFS) of 3.6 months, and a greater benefit observed in non-squamous tumors. Baseline and on-treatment tumor analyses suggested that resistance to Dato-DXd could be associated with a lack of TROP2 cytoplasmic staining and the early activation of DNA repair pathways. Conversely, the activation of immune-related pathways was associated with treatment response. Validation of these findings in phase III studies will be essential to define biomarkers, ultimately enabling more precise identification of patients most likely to benefit from Dato-DXd.

Basic and translational research in lung cancer is a rapidly evolving field with a transformational impact on early detection, diagnosis, therapeutic development, and personalization of care. Recent advances have greatly increased our understanding of the molecular genomics, proteomics, pathogenesis, and cellular biology of this deadly malignancy. The International Association for the Study of Lung Cancer (IASLC) recently formed a Basic and Translational Science (BaTS) Committee to further enhance the scientific leadership of IASLC in thoracic cancer research. This review by members of the committee highlights the breadth of current research in NSCLC, with a focus on molecular risk factors and processes in tumorigenesis, heterogeneity, phenotypic plasticity, metabolic reprogramming, immunobiology, the immune microenvironment, and microbiome. This review also identifies future research areas that may lead to further improvement in survival outcomes and curative therapies especially for patients with advanced NSCLC.

Sleep quality contributes to the improvement of quality of life in cancer patients. However, sleep disturbances, of variable and heterogeneous etiologies, are common and frequently overlooked in lung cancer patients. The present study undertakes a rapid review of available peer-reviewed literature on sleep quality in lung cancer patients, specifically non-small-cell lung cancer patients. MEDLINE, Embase, and CENTRAL online databases were used to identify 513 published articles from which 26 publications were selected through abstract and title screening, full-text review, and quality assessment. Most publications (96.15

TPS8130 Background: In patients with rare cancers, there is an unmet medical need for investigating innovative therapeutics. Indeed, these diseases are rarely assessed in clinical trials. Thymic epithelial tumors (TET) are rare heterogeneous thoracic malignancies. B3 TET and thymic carcinomas are more aggressive and prone to metastatic spreading. The standard 1 st line treatment relies on platinum-based chemotherapy. Consensual 2 nd line treatment has not been identified yet. Several studies showed limited efficacy of PD-1 blockade in B3 TET and thymic carcinomas. Concurrent blockage of TIGIT and PD-1 immune checkpoint B3 TET may improve outcomes according to translational studies. Methods: IMMUNORARE 5 (NCT06790706) is a platform of 5 single arm phase II trials testing the safety and efficacy of Domvanalimab (anti-TIGIT) and Zimberelimab (anti PD-1) in 5 independent cohorts of rare cancers. The trial, sponsored by Lyon University Hospital, is conducted in 15 French centers, in partnership with the corresponding French national reference centers. The B3 TET and thymic carcinomas cohort, led in collaboration with the RYTHMIC Network (www.rythmic.org), will enroll 26 patients after failure of at least one line of platinum-based chemotherapy, with evaluable lesions at baseline according to RECIST criteria. Patients previously treated with immunotherapy are not eligible. Patients will receive Domvanalimab and Zimberelimab intra-venous, every three weeks, until disease progression or unacceptable toxicity. The primary endpoint is the progression-free survival rate at 6 months. The secondary endpoints are overall response rate and duration of the response, progression-free survival, overall survival and tolerability. The trial is designed with a two-stage Simon design, with early termination for futility (5% one-sided alpha level, 80% power). The treatment would be considered interesting if the percentage of patients free from disease progression at 6-months is statistically higher than 40%; 65% is expected. Translational research projects will be developed aiming at deciphering cellular and molecular mechanisms involved in response to treatment. Moreover, data from the prospective database of the RYTHMIC network will be investigated to build a synthetic historical arm representative of the efficacy of the standard treatments in a similar population of patients. Clinical trial information: NCT06790706 .

Introduction: Eastern Cooperative Oncology Group performance status 2 to 3 is associated with poor survival and chemotherapy-related adverse events (AEs). The impact of poor PS on the safety and efficacy of immune checkpoint inhibitors has not been elucidated. This study aimed to assess first-line durvalumab in patients with PS 2 to 3 with advanced NSCLC and high programmed cell death-ligand 1 (PD-L1) expression. Methods: In this single-arm, prospective, multicenter, phase II trial, patients with PS 2 to 3 aged 18 to 75 years with metastatic NSCLC and PD-L1 tumor proportion score more than or equal to 25% received durvalumab until progression or toxicity. Primary end point was safety, that is incidence of grade more than or equal to 3 TRAEs during the first 8 weeks. Secondary end points included blinded independent central review overall response rate, progression-free survival, duration of response, overall survival (OS), and PS improvement at 8 weeks and health-related quality of life. Results: A total of 50 patients were enrolled. Median follow-up was 26.2 (19.9–35.2) months. Prevalence of grade more than or equal to 3 TRAEs during the first 8 weeks was 10.0% (five of 50, 95% confidence interval [CI] 1.7–18.3), and no grade 5 occurred. Overall response rate at 8 weeks was 26% (95% CI 13.8–38.2). Median duration of response, progression-free survival, and OS were 11.8 months (95% CI, 7.2-not reached), 2.3 months (95% CI 1.7–5.6), and 7.1 months (95% CI 3.9–14.5), respectively. The 12-month OS rate was 40% (95% CI 26.5–53.1). Median OS in patients with PS 2 and PS 3 was 11.4 (95% CI 4.4–32.8) and 3.0 (95% CI 0.2–5.6) months, respectively. Of 27 patients, 12 (44.4%) still receiving durvalumab at 8 weeks had improved PS (p = 0.0096). Mean global QLQ-C30 score significantly increased at 8 weeks. Conclusions: In patients with a PS of 2 to 3 with advanced NSCLC and high PD-L1 expression, first-line durvalumab was safe with 40% 1-year OS.

INTRODUCTION:Amivantamab, an EGFR-MET bispecific antibody, is approved for multiple indications in EGFR-mutated advanced NSCLC as monotherapy or combined with other agents. Intravenous amivantamab is associated with a 67% infusion-related reaction (IRR) rate. METHODS:The phase 2 SKIPPirr study (NCT05663866) enrolled participants with EGFR-mutated (exon 19 deletion or exon 21 L858R) advanced NSCLC after progression on osimertinib and platinum-based chemotherapy who received intravenous amivantamab plus oral lazertinib (amivantamab-lazertinib), a third-generation tyrosine kinase inhibitor. Aiming to mitigate IRRs, four independent prophylactic approaches were evaluated using Simon's two-stage design with an expansion stage if a cohort passed both stages: oral dexamethasone 4 mg twice daily given on cycle (C) 1 day (D) -1 (two doses); oral dexamethasone 8 mg twice daily given on C1D-2, C1D-1, and the morning of C1D1 (five doses); oral montelukast 10 mg once daily given on C1D-4, C1D-3, C1D-2, C1D-1, and C1D1 (five doses); subcutaneous methotrexate 25 mg (one dose) given anytime between C1D-7 and C1D-3. The primary end point was C1D1 IRR incidence. RESULTS:As of June 24, 2024, 68 participants were treated across all cohorts. The dexamethasone 8 mg cohort passed stages 1 and 2 proceeding to the expansion stage, with 24 additional participants treated. At C1D1, nine of 40 participants (22.5%) experienced IRRs, resulting in an approximately threefold decrease versus historical data (67.4%). By the end of C3, 10 of 41 participants (24.4%) in the dexamethasone 8 mg cohort experienced IRRs (grades 1-2, except one grade 3 on C2D1). Amivantamab-lazertinib's safety and efficacy were consistent with previous reports. CONCLUSIONS:Prophylaxis with 8 mg oral dexamethasone meaningfully reduced IRRs and can be readily implemented in clinical practice.

The ever-increasing use of immune checkpoint inhibitors (ICIs) has significantly improved cancer management, but at the cost of frequent immunologic side effects. Among them, neurologic immune-related adverse events (nirAEs) are less common but pose a challenge to clinicians due to their severity, heterogeneous nature and nonspecific clinical presentation, making diagnosis complex. The prognosis of these nirAEs, especially those related to the central nervous system (CNS), correlates with their rapid recognition and therapeutic management. Indeed, the therapeutic options are sometimes unfamiliar and may be further complicated by the lack of recommendations in the event of failure of a well-managed first-line treatment. Finally, the attribution of ICIs to certain CNS disorders is controversial and may lead to an incorrect decision to discontinue or contraindicate treatment, resulting in an irremediable loss of opportunity for the patient. Therefore, the aim of this review is to present known/suspected CNS nirAEs induced by ICI, their diagnostic approach and management through therapeutic advice for optimal treatment and rechallenge opportunities.

PURPOSE:The randomized, open-label, global phase III TROPION-Lung01 study compared the efficacy and safety of datopotamab deruxtecan (Dato-DXd) versus docetaxel in patients with pretreated advanced/metastatic non-small cell lung cancer (NSCLC). METHODS:Patients received Dato-DXd 6 mg/kg or docetaxel 75 mg/m2 once every 3 weeks. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Objective response rate, duration of response, and safety were secondary end points. RESULTS:In total, 299 and 305 patients were randomly assigned to receive Dato-DXd or docetaxel, respectively. The median PFS was 4.4 months (95% CI, 4.2 to 5.6) with Dato-DXd and 3.7 months (95% CI, 2.9 to 4.2) with docetaxel (hazard ratio [HR], 0.75 [95% CI, 0.62 to 0.91]; P = .004). The median OS was 12.9 months (95% CI, 11.0 to 13.9) and 11.8 months (95% CI, 10.1 to 12.8), respectively (HR, 0.94 [95% CI, 0.78 to 1.14]; P = .530). In the prespecified nonsquamous histology subgroup, the median PFS was 5.5 versus 3.6 months (HR, 0.63 [95% CI, 0.51 to 0.79]) and the median OS was 14.6 versus 12.3 months (HR, 0.84 [95% CI, 0.68 to 1.05]). In the squamous histology subgroup, the median PFS was 2.8 versus 3.9 months (HR, 1.41 [95% CI, 0.95 to 2.08]) and the median OS was 7.6 versus 9.4 months (HR, 1.32 [95% CI, 0.91 to 1.92]). Grade ≥3 treatment-related adverse events occurred in 25.6% and 42.1% of patients, and any-grade adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8.8% and 4.1% of patients, in the Dato-DXd and docetaxel groups, respectively. CONCLUSION:Dato-DXd significantly improved PFS versus docetaxel in patients with advanced/metastatic NSCLC, driven by patients with nonsquamous histology. OS showed a numerical benefit but did not reach statistical significance. No unexpected safety signals were observed.

8501 Background: Few treatments with limited benefit are currently available after failure of targeted therapies, immunotherapy and platinum-based chemotherapy in patients (pts) with advanced NSCLC. Dato-DXd is an antibody-drug conjugate (ADC) composed of a TROP-2-directed monoclonal antibody linked to a topoisomerase I inhibitor via a peptide cleavable linker. In the phase 3 TROPION-Lung01 study, Dato-DXd demonstrated a statistically significant improvement of PFS over docetaxel in previously treated pts with advanced NSCLC. Here we report the results of ICARUS-Lung01 (NCT04940325), a multi-center, single-arm, phase 2 study evaluating activity, safety, and biomarkers of response/resistance to Dato-DXd in pretreated pts with advanced NSCLC. Methods: Intravenous Dato-DXd 6 mg/kg was given every 21 days to pts with advanced NSCLC, ECOG 0/1, who progressed on 1-3 lines of therapy (including actionable genomic alteration (AGA)-specific therapy if indicated). All pts underwent fresh tumor tissue biopsies at baseline, on-treatment (week 3 or 6) and end of treatment. Primary endpoint: investigator-assessed confirmed objective response rate (ORR). A set of translational analyses was performed to determine biomarkers associated with response/resistance, including TROP2 tumor membrane expression, TROP2-dynamics and spatial distribution (by AI-digital pathology), genomics, transcriptomic, spatial proteomics (by imaging mass cytometry) and CTCs. Results: A total of 100 pts received ≥1 dose: median age 60 years (26-83); 62% males, 89% smokers, 82% non-squamous (NSQ) histology, 23% AGA, median number of prior therapy lines 2 (1-5). At data cut-off (Dec 04, 2023), 92% discontinued therapy, 92 % had disease event, 67% died. Median treatment duration was 2.8 months (mos) (95%CI, 2.1-4.8), median follow-up 19.4 mos (95%CI, 18.2-20.4). Efficacy and safety results are shown in the table. Conclusions: In this heavily pretreated population, Dato-DXd showed similar efficacy and safety results to those reported in TROPION-Lung01. Patients with NSQ appeared to derive the greatest benefit. Translational analyses to determine biomarkers associated with response and/or resistance will be presented. Clinical trial information: NCT04940325 . [Table: see text]