OBJECTIVES:To evaluate methodological challenges and regulatory considerations of indirect treatment comparisons (ITCs) with the analysis of French Transparency Committee (TC) decisions and international health technology assessment guidelines. METHODS:We conducted a pragmatic review of ITC guidelines from major health technology assessment bodies and analyzed 138 TC opinions containing 195 ITCs published between 2021 and 2023. We extracted data on ITC methodology, therapeutic areas, acceptability, and limitations expressed by the TC. RESULTS:ITC submissions increased by 44.7% over the study period, but only 13.3% of these comparisons influenced TC decision making. ITCs were more frequently accepted in genetic diseases (34.4%) compared with oncology (10.0%) and autoimmune diseases (11.1%). Methods using individual patient data showed higher acceptance rates (23.1%) than network meta-analyses (4.2%). Main limitations included heterogeneity/bias risk (59%), lack of data (48%), statistical methodology issues (29%), study design concerns (27%), small sample size (25%), and outcome definition variability (20%). When ITCs were the primary source of evidence, the proportion of important clinical benefit was lower (60.9% vs 73.4%) than when randomized controlled trials were available. CONCLUSIONS:Although ITCs are increasingly submitted, particularly in situations in which direct evidence is impractical, their influence on reimbursement decisions remains limited. There is a need for clear and accessible guides so that manufacturers can produce clearer and more robust ITCs that follow regulatory guidelines, from the planning phase to execution.

BackgroundBlocking programmed cell death protein 1 (PD-1) has become a standard cancer immunotherapy, increasingly used in kidney, liver, or heart transplant recipients who develop skin cancer or hepatocellular carcinoma, despite the increased risk of graft failure or rejection. The mechanism of action of PD-1 blockade relies on stimulating CD8+ T cell activity, but its impact on humoral immunity in general and on alloimmunization in particular remains uncertain.ObjectiveThe aim of this study was to investigate the impact on anti-PD-1 treatment on alloimmunization.MethodsThe effect of anti-PD-1 treatment on the generation of anti-HLA (Human Leucocyte Antigen) antibodies was investigated in 72 patients with non-small cell lung cancer vaccinated with an allogeneic plasmacytoid dendritic cell line (PDC*line; six weekly injections), with or without pembrolizumab administered every three weeks. The kinetics and functionality of the anti-HLA generated were analyzed.ResultsThe results show that 51.4% of the patients developed anti-HLA antibodies, primarily dependent on the vaccine dose. In 60% of cases, the antibody response appeared after the sixth injection, peaked after one month, and then gradually declined over two years. Anti-HLA class II antibodies appeared earlier than class I antibodies. Functional assays demonstrated complement-dependent cytotoxicity against allogeneic B lymphocytes and PDC*line cells in the serum of some patients, with no difference related to treatment. PD-1 blockade did not alter the magnitude, kinetics, or cytotoxic potential of the vaccine-induced humoral response. ConclusionThese results indicate that, during allogeneic human vaccination, PD-1 signaling exerts a limited effect on antibody production and effector function, suggesting a more complex regulatory role in humoral immunity than previously thought.

8629 Background: Taletrectinib is a next-generation, CNS-active, selective ROS1 tyrosine kinase inhibitor (TKI) approved by the US FDA for the treatment of patients with locally advanced or metastatic ROS1+ NSCLC based on results from two Phase 2 studies, TRUST-I (NCT04395677) and TRUST-II (NCT04919811). Here we report PROs with taletrectinib from TRUST-II. Methods: Patients with locally advanced or metastatic ROS1+ NSCLC were treated with taletrectinib 600 mg once daily in 21-day cycles. HRQoL and PROs for cancer-specific symptoms were evaluated using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 30-item core module (QLQ-C30) and 13-item lung cancer module (QLQ-LC13). Questionnaires were only distributed to patients from North America and Europe. Data were collected at screening, then subsequently on Day (D)1 of every cycle (C) until C9D1, on D1 of every three cycles until C27D1, and every four cycles thereafter until the end of treatment (within 7 days of last dose). Changes from baseline over time were summarized using descriptive statistics. A change in score of ≥10 points from baseline was considered clinically meaningful. Time to first improvement (TFI) was assessed using Kaplan–Meier methods. Results: At data cutoff (August 31, 2025), the analysis set included 69 patients (23 TKI-naïve and 46 TKI-pretreated). Mean changes from baseline improved or remained stable for most domains across both questionnaires. For global health status/quality of life, the majority of patients showed clinically meaningful improvement or remained stable at multiple timepoints assessed (e.g. 74% of patients at C7). Mean cognitive function score improved or remained stable throughout treatment, with the majority (63–77%) of patients showing improvement or stability and only 9–23% of patients showing worsening at various assessment times. Common disease-related symptoms, including pain and fatigue (QLQ-C30), and dyspnea and coughing (QLQ-LC13), showed consistent clinically meaningful improvement throughout treatment, with a median TFI of 1–3 months across all patients. Coughing was particularly improved in TKI-naïve patients, with a median TFI of < 1 month. Conclusions: Taletrectinib was associated with improved or stable HRQoL in the majority of patients and with rapid relief of disease-related symptoms. In contrast to other ROS1 TKIs, taletrectinib demonstrated preservation of cognitive function over time. Together with the efficacy and safety results, these data further support the use of taletrectinib for patients with ROS1+ NSCLC. Clinical trial information: NCT04919811 .

TPS8130 Background: Taletrectinib is a next-generation, CNS-active, selective ROS1 tyrosine kinase inhibitor (TKI) approved by the US FDA for the treatment of locally advanced or metastatic ROS1+ NSCLC. In stage IB–IIIA NSCLC, which represents about 30% of NSCLC cases, the standard of care is surgical resection with perioperative systemic therapy (neoadjuvant or adjuvant). Results from Phase 3 trials have shown significantly improved outcomes for EGFR and ALK TKIs as adjuvant therapy compared with placebo or chemotherapy in early-stage NSCLC with EGFR mutations or ALK fusions, respectively. However, there remains an unmet need for patients with stage IB–IIIA ROS1+ NSCLC. Given the efficacy and tolerability of taletrectinib in advanced ROS1+ NSCLC, there is a rationale for investigating taletrectinib in patients with earlier-stage NSCLC who have undergone complete tumor resection. Methods: TRUST-IV (NCT07154706) is a randomized, double-blind, multicenter, Phase 3 study evaluating the efficacy and safety of taletrectinib compared with placebo in patients with stage IB, II, or IIIA ROS1+ NSCLC following curative surgery (negative surgical margins). ROS1 fusions may be detected using validated local tissue or liquid assays but must be confirmed by central tissue testing. Patients may have received prior adjuvant platinum-based chemotherapy (≤4 cycles) if clinically indicated, which must be completed ≥7 days prior to randomization. Surgical resection must have occurred 4–16 weeks prior to randomization if no adjuvant chemotherapy was given or 4–30 weeks if adjuvant chemotherapy was given. The estimated enrollment is 180 patients, randomized 2:1 to receive either taletrectinib 400 mg once daily or a matched placebo, stratified by prior adjuvant chemotherapy (yes vs no) and pathological stage (IB vs II vs IIIA). Patients will receive blinded study drug in continuous 28-day cycles until disease recurrence or consent withdrawal, or up to a maximum of 3 years. Contrast computed tomography or magnetic resonance imaging (MRI) of the chest/abdomen/pelvis will be performed at screening, Cycle 4 Day 1 (C4D1), and C7D1, while brain MRI will be performed at screening and C7D1; thereafter, all imaging will be performed every 24 weeks until 5 years and then annually until disease recurrence or end of study. The primary endpoint is disease-free survival (DFS) by investigator assessment. Select secondary endpoints include: DFS rates at 2, 3, 4, and 5 years; DFS by blinded independent central review; overall survival; CNS-DFS; and safety. Exploratory endpoints include patient-reported outcomes for health-related quality-of-life measures and progression-free survival 2. The trial is currently recruiting. Clinical trial information: NCT07154706 .

ABSTRACT Background HER2 (ERBB2) gene mutations are associated with poor prognosis in non‐small cell lung cancer (NSCLC). It is important to identify patients with HER2‐mutant (HER2m) NSCLC, as new targeted treatment options are emerging. However, HER2 testing in clinical practice varies across regions, and real‐world data on HER2m NSCLC are limited. Patients and Methods This retrospective study included patients from the Epidemio‐Strategy and Medical Economics Lung Cancer database (NCT03848052) diagnosed with locally advanced or metastatic (LAM) NSCLC in France (January 1, 2015–December 31, 2020); patients were followed up until April 1, 2022. Data were extracted on April 2, 2022. Primary objectives were to describe the frequency of HER2 testing and test results. Secondary objectives included describing patient characteristics, treatment patterns, and clinical outcomes (stratified by HER2 testing status/results; landmark analyses were conducted to avoid immortal time bias). Results Of 18,069 patients with nonsquamous LAM NSCLC, or squamous LAM NSCLC and no history of smoking, 7530 (41.7%) underwent HER2 testing. Median (interquartile range) time between LAM NSCLC diagnosis and first HER2 test result was 28 days (18–49). Of those tested, 152 (2.0%) had a HER2 mutation (HER2m cohort). In the HER2m cohort, 62.5% (n/N = 85/136) of patients received their first HER2 test result prior to first‐line treatment; platinum‐based chemotherapy was the most frequently received first‐line treatment (52.9%, n/N = 72/136), followed by immunotherapy in the second‐line setting (29.2%, n/N = 26/89). At 6‐month landmark analysis, median (95% confidence interval) overall survival was 18.6 months (14.3–22.5) in the HER2m cohort. Conclusions This real‐world study demonstrates the low frequency of HER2 testing and potential poor prognosis for patients diagnosed with LAM HER2m NSCLC in France between 2015 and 2020. Despite the low prevalence of HER2m NSCLC, these data highlight the importance of routine HER2 testing to enable patients with HER2m NSCLC to receive treatments that can improve clinical outcomes.

Background Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for advanced non-small cell lung cancer (NSCLC), yet primary resistance remains common, with only ~50% of patients responding to first-line chemo-immunotherapy and 20-30% to monotherapy. Existing biomarkers such as PD-L1 expression and Tumor Mutational Burden (TMB) demonstrate limited predictive accuracy, underscoring the need for more comprehensive, integrative approaches. Methods We conducted a prospective, multicenter study involving 439 patients with advanced NSCLC treated with anti-PD-(L)1 ICI across first-line combo with chemotherapy and later-line monotherapy settings. A total of 443 pre-treatment tumor and blood-derived biomarkers-including genomic alterations, immune cell phenotypes, proteic markers, and routine laboratory tests-were profiled. Extensive biostatistics adjusted for PD-L1 expression were conducted. A rigorously benchmarked machine learning (ML) pipeline including 36 feature selection methods embedded into an optimism-correction framework was applied to identify predictors of primary resistance (PrR). Results Single biomarkers showed limited predictive utility, with PD-L1 (AUC 0.62, positive predictive value (PPV) 49.6%), TMB (AUC 0.55, PPV 43.1%), and key gene mutations (e.g., STK11, KEAP1) failing to achieve significance after multiple testing correction. A gradient boosting ML model integrating 18 selected features yielded a corrected AUC of 0.69 and a Positive Predictive Value (PPV) of 60% for PrR, outperforming standard biomarkers. In first-line patients, the model achieved a PPV of 51% and Negative Predictive Value (NPV) of 79% (baseline PrR rate: 29.9%); in subsequent-line patients, PPV reached 64% (PrR rate: 55.1%). Importantly, the signature also stratified Progression-Free Survival (PFS): high-risk patients had a median PFS of 3.9 vs. 14.6 months in low-risk patients (HR 0.307, p < 0.0001). Features from routine blood tests-such as serum chloride, albumin, CRP, and monocyte-to-lymphocyte ratio (MLR)-accounted for half of the final model and demonstrated independent associations with both PrR and PFS (e.g., chloride: OR 0.616, AUC 0.626; HR 0.685, C-index 0.61). SHAP-based individual-level model explainability revealed heterogeneous and nonlinear biomarker contributions, including cases where high CRP, low albumin, or elevated MLR overrode favorable PD-L1 or Treg profiles. A biomarker dashboard including interactive visualizations is available at https://compo.inria.fr/pioneer-website/. Conclusions Multimodal machine learning integration of clinical, genomic, immune, and laboratory data enables improved prediction of ICI resistance in NSCLC beyond current biomarkers. This approach not only captures the multifaceted nature of tumour-host interactions but also highlights the underrecognized predictive value of accessible blood-based markers, offering a path toward individualized immunotherapy decision-making. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work benefited from a government grant handled by the French National Research Agency (ANR) as part of the France 2030 investment plan, under the reference ANR-17-RHUS-0007. This work was supported by a partnership of Aix-Marseille Universite (AMU), Assistance Publique Hopitaux de Marseille (APHM), Centre National de La Recherche Scientifique (CNRS), Institut National de la Sante et de la Recherche Medicale (INSERM), Centre Leon Berard (CLB), Institut Paoli Calmettes (IPC), Gustave Roussy (GR), AstraZeneca (AZ), Veracyte (VERA), Innate Pharma (IPH) & ImCheck Therapeutics (ICT), and initiated by Marseille Immunopole. The authors gratefully acknowledge the support of the APHM, which sponsored the PIONeeR clinical studies. Its role was to control the appropriateness of ethical and legal considerations for all centers and to perform the monitoring of the consents signed and the clinical data recorded and coded as part of the study. The authors are grateful to all the patients and their families, as well as all the investigators, for their participation in the study. This work benefited from support from ITMO Cancer AVIESAN and French Institut National du Cancer (grant #19CM148-00) and from the French National Research Agency (ANR), under the France 2030 program, reference ANR-22-PESN-0017. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was conducted in accordance with the Helsinki declaration, French laws and regulations and the International Conference on Harmonization (ICH) E6 Guideline for Good Clinical Practice. The study was approved by the French ethics committee (Comite de Protection des Personnes Ouest II Angers, no. 2018/08) and the French drug and device regulation agency (Agence Nationale de Securite du Medicament, no. 2018020500208). Informed consent was obtained from each participant before any study procedure. The study is registered at ClinicalTrials.gov ([NCT03493581][1]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03493581&atom=%2Fmedrxiv%2Fearly%2F2026%2F01%2F11%2F2026.01.09.26343779.atom

Integrating multimodal datasets in clinical oncology is frequently hindered by high dimensionality and blockwise missingness, where entire data sources are unavailable for specific patient subsets. Standard survival models often struggle with these gaps, leading to biased results or patient exclusion. We introduce Multimodality Stacking with Blockwise missing values (MSB), a late-fusion framework for survival analysis that independently models modality-specific features before aggregating predictions via a cross-validated stacking meta-learner. MSB was validated on the PIONeeR study (n=443 patients, 378 biomarkers across eight heterogeneous sources) to predict progression-free survival in advanced non-small cell lung cancer patients receiving immunotherapy. MSB yielded higher predictive performance (C-index) than baseline algorithms. Improvements varied by baseline strength: linear models showed a 15.9 MSB provides a statistically validated framework for multimodal survival prediction with blockwise missingness. By enabling systematic biomarker evaluation without requiring complete data, MSB offers a practical tool for predictive modeling in biomedical research, pending external validation. Implementation is available at https://github.com/MohamedBoussena/MSB under Inria license.

Background/Objectives: Recent preclinical studies suggest that acute exercise induces immune modulation, enhances tumor blood perfusion, and is associated with reduced tumor growth. Adding exercise to immunochemotherapy treatment (ICT) has been proposed as a strategy to increase treatment effectiveness. The ERICA trial (NCT04676009) aimed to assess the feasibility of acute aerobic exercise performed immediately before the administration of ICT in patients with metastatic non-small cell lung cancer (mNSCLC) and to explore hypothesis-generating outcomes related to physical fitness and patient-reported outcomes. Methods: Newly diagnosed mNSCLC patients were randomly assigned (2:1) to the exercise or control group. The exercise intervention included supervised acute exercise before each of four ICT cycles plus a 3-month home-based walking program with an activity tracker and step goals. The feasibility of the exercise protocol was assessed through adherence, acceptability, tolerability, and safety. Clinical, physical, and patient-reported outcomes were assessed at baseline and after 3 months. Results: Twenty-six patients (mean age 60.6 years; SD 10.65) participated, with an 87.5% acceptance rate. In the exercise group (n = 17), 80.9% of participants completed the acute exercise sessions, with a median interval of 38 min [IQR, 20-60] between exercise and ICT. No exercise-related adverse effects were reported. After 3 months, 60% of participants in the exercise group were classified as active and maintained their step goals. Self-reported measures suggest that maintaining physical fitness is favorable for reducing fatigue and insomnia, and therefore improving quality of life. Conclusions: Acute exercise performed immediately before each ICT administration in patients with mNSCLC appears feasible and safe.

ROS1 rearrangements define a distinct, targetable subset of non–small cell lung cancer (NSCLC), representing ~2% of non-squamous cases and frequently presenting with metastatic disease and CNS involvement. Multiple ROS1 tyrosine kinase inhibitors (TKIs)—from crizotinib to newer agents such as entrectinib, lorlatinib, repotrectinib, taletrectinib, and the highly selective zidesamtinib—have improved systemic and intracranial outcomes, although resistance remains inevitable and biologically diverse, involving both on-target kinase mutations and off-target mechanisms. This review synthesizes current knowledge on ROS1 biology, diagnostic strategies, therapeutic options, and resistance mechanisms. We outline ROS1 fusion architecture and signaling, highlight partner-specific features, and summarize available diagnostic modalities. In clinical practice, RNA-based next-generation sequencing (NGS), often preceded by immunohistochemistry screening, provides the most sensitive approach for fusion detection and resistance profiling. Given the expanding therapeutic landscape and increasing complexity of treatment sequencing, we adopt a pragmatic, practice-oriented framework. CNS-penetrant next-generation TKIs with activity against common resistance mutations now constitute preferred first-line therapy. Repotrectinib and taletrectinib show strong systemic and intracranial efficacy, including activity against ROS1 G2032R, whereas zidesamtinib offers high selectivity with encouraging early data. Pemetrexed-based chemotherapy remains an effective option, whereas immune checkpoint inhibitors provide limited benefit. At progression, molecular reassessment is essential to guide tailored therapy. Looking ahead, priorities include optimizing sequencing strategies, evaluating perioperative targeted approaches, and incorporating genomic monitoring to anticipate resistance. These advances are reshaping the natural history of ROS1-rearranged NSCLC and supporting a more durable, precision-driven treatment paradigm.

TPS8136 Background: Small Cell Lung Cancer (SCLC) is a neuroendocrine tumor with high proliferation rate, early metastasis and poor prognosis. DLL3 is a validated target for neuroendocrine tumor and is highly expressed in SCLC. ZL-1310 is a novel antibody-drug conjugate (ADC) that employs the TMALIN (Tumor Microenvironment Activable LINker-payload) platform, an anti-DLL3 monoclonal antibody linked to a topoisomerase I inhibitor payload via a protease-cleavable linker. ZL-1310 has demonstrated encouraging systemic efficacy in heavily pre-treated ES-SCLC and showed intracranial activities. Methods: DLLEVATE is a randomized, open-label phase III study to further evaluate the efficacy and safety of ZL-1310 compared to investigator's choice of locally approved and available single agent therapy (ICT). This multi-country Phase III study (NCT07218146) enrolls adults with Extensive Stage (ES)-SCLC patients (pts) who have progressed after platinum-based first-line (1L) therapy or after tarlatamab as second-line (2L) therapy. Those with stable or asymptomatic BM are eligible (including those with no prior brain radiotherapy). The eligible pts are randomized at 1:1 according to presence/absence of brain metastasis, sensitivity to prior chemotherapy and with/without prior tarlatamab. ZL-1310 is given intravenously every 3 weeks until disease progression or unacceptable toxicity. Systemic efficacy is assessed by investigators using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Intracranial efficacy is assessed by blind independent radiologists using Modified Criteria for Radiographic Response Assessment in Neuro-Oncology (mRANO). The study has one interim analysis based on Objective Response Rate (ORR) assessed by Blind Independent Review Committee (BIRC) and the primary analysis based on Overall Survival (OS). Enrollment is underway, and is planned at ~250 sites across several continents. Clinical trial information: NCT07218146 .

BACKGROUND:Recent clinical observations suggested that COVID-19 mRNA vaccines prime innate and adaptive immunity and enhance anti-tumor immune responses, leading to improved survival of patients with cancers. METHODS:We analyzed the cohort of patients with advanced cancers receiving COVID-19mRNA vaccine and treated in a Comprehensive Cancer Centre in 2021. Among these, 281 patients received ICI. The overall survival (OS) of patients receiving at least one mRNA SARS-CoV-2 dose within 100 days before ICI initiation were compared with all other patients. OS was measured from the first date of ICI administration. Cox proportional hazards models with backward selection was used to identify variables significant in univariable analyses. The study was approved with the MR004 methodology on Oct 31st 2025. RESULTS:Among 281 patients, 47 (16.7%) received an mRNA vaccine within 100 days before starting ICI. Baseline characteristics, tumor types and ICI agents were balanced across groups. After a median follow-up of 51 months, OS was significantly improved in patients vaccinated within 100 days prior to ICI (median 51.0 months, 95%CI 33.9-70.0) compared with others (21.0 months, 95%CI 17.7-24.3; p = 0.012). In multivariate analysis, younger age (p = 0.002), female sex (p = 0.003), non-head and neck tumors (p = 0.041), and COVID-19 mRNA vaccination within 100 days before ICI (HR 0.615; 95%CI 0.407-0.928; p = 0.021) remained independently associated with improved OS. CONCLUSIONS:In this cohort including multiple cancer types, administration of COVID-19 mRNA vaccine within 100 days before ICI initiation was independently associated with superior long-term overall survival. These data warrant prospective confirmation.

Osimertinib, a third-generation tyrosine kinase inhibitor (TKI), is a standard first-line (1L) treatment for advanced/metastatic EGFR non-small cell lung cancer (NSCLC). Despite improved overall survival (OS) and progression-free survival (PFS) compared to earlier generation TKIs, resistance and disease progression are common. No standardized second-line (2L) treatment exists for patients who progress after 1L osimertinib. This study assessed real-world (rw) treatment patterns and clinical outcomes in French patients with advanced/metastatic NSCLC who received 2L therapy post-osimertinib progression. This retrospective, observational study used the Epidemio-Strategy and Medical Economics (ESME) LC database (NCT03848052) (January 1, 2015–2023; data extraction September 2023). Patients ≥ 18 years with confirmed advanced/metastatic NSCLC, treated with 1L osimertinib, and documented 2L therapy were included. The study assessed patient characteristics, rw treatment patterns, rwOS, and rwPFS. Among 284 patients (71.1

PURPOSE Datopotamab deruxtecan (Dato-DXd) is a trophoblast cell-surface antigen-2–directed antibody-drug conjugate with a highly potent topoisomerase I inhibitor payload. The TROPION-Lung05 phase II trial (ClinicalTrials.gov identifier: NCT04484142 ) evaluated the safety and clinical activity of Dato-DXd in patients with advanced/metastatic non–small cell lung cancer (NSCLC) with actionable genomic alterations progressing on or after targeted therapy and platinum-based chemotherapy. PATIENTS AND METHODS Patients received Dato-DXd 6 mg/kg once every 3 weeks. The primary end point was objective response rate (ORR) by blinded independent central review. Secondary end points included duration of response (DOR), safety, tolerability, and survival. RESULTS Among 137 patients who received at least 1 dose of Dato-DXd, 71.5% received at least three lines of prior therapies for advanced/metastatic disease. Overall, 56.9% had EGFR mutations and 24.8% had ALK rearrangements. Median treatment duration was 4.4 months (range, 0.7-20.6). The confirmed ORR was 35.8% (95% CI, 27.8 to 44.4) overall, and 43.6% (95% CI, 32.4 to 55.3) and 23.5% (95% CI, 10.7 to 41.2) in those with EGFR mutations and ALK rearrangements, respectively. The median DOR was 7.0 months (95% CI, 4.2 to 9.8), and the overall disease control rate was 78.8% (95% CI, 71.0 to 85.3). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 28.5% of patients. The most common TRAE was stomatitis (preferred term; any grade: 56.2%; grade ≥3: 9.5%). Five (3.6%) patients experienced adjudicated treatment-related interstitial lung disease/pneumonitis, with 1 (0.7%) grade 5 event. CONCLUSION Encouraging and durable antitumor activity was observed with Dato-DXd in this heavily pretreated advanced/metastatic NSCLC population with actionable genomic alterations. The rate of treatment-related grade ≥3 toxicities was comparable with previous observations, and no new safety signals were observed.

Our team recently developed a scoring system called the HOT-score, derived from an unsupervised clustering analysis of 421 HPV-negative head and neck squamous cell carcinomas (HNSCC) from TCGA. The HOT-score is based on a 27-gene signature associated with cytotoxic CD8+ T cell activation, interferon-gamma signaling, and IDO1 expression. These genes were identified through differential expression analysis. The HOT-score is computed as an enrichment score (ES) using Gene Set Variation Analysis (GSVA), providing a bimodal ES distribution ranging from -1 to 1. Tumors are classified either as "hot" phenotypes (ES score > 0) or "cold" phenotypes (ES score < 0). We have previously shown an association between the HOT-score and “hot”/”cold” phenotypes with overall survival (OS) and progression-free survival (PFS) in retrospective cohorts of patients with HNSCC (n=102) and non-small cell lung cancer (NSCLC, n=82) treated with immune checkpoint blockade (ICB). Herein, we evaluated the HOT-score's association with clinical outcomes across a broader range of cancer types in the CRi-Atlas cohort. We analyzed pre-treatment tumor samples from the CRi-Atlas cohort (available at https://cri-iatlas.org/) that included cancers for which ICB therapies are approved. Inclusion criteria required samples to have annotations for progression-free survival, overall survival, or response evaluation by RECIST criteria. Associations with survival outcomes were assessed using Cox proportional hazards modeling, and comparisons of HOT-scores by response categories were performed using the Wilcoxon test. The cohort consisted of 348 bladder carcinomas, 207 kidney clear cell carcinomas, 313 skin cutaneous melanomas, and 45 stomach adenocarcinomas. HOT-scores, analyzed as continuous variables, were significantly lower in patients with progressive disease compared to those with stable disease (P=3.6e-05), partial response (P=3.3e-07), and complete response (P=5.5e-07). HOT-scores were strongly associated with better survival outcomes, including progression-free survival (PFS; n=489, HR 0.67; 95% CI [0.53-0.85]) and overall survival (OS; n=913, HR 0.51; 95% CI [0.41-0.63]). Tumors with "hot" phenotypes exhibited improved survival outcomes compared to those with "cold" phenotypes, with PFS (HR 0.77; 95% CI [0.67-0.97]) and OS (HR 0.54; 95% CI [0.43-0.67]). Notably, in a multivariate analysis accounting for tumor types, both HOT-scores and "hot" phenotypes remained strongly associated with better PFS and OS (P<0.001). The HOT-score is associated with favorable clinical outcomes, including PFS, OS, and RECIST response, across multiple cancer types. Prospective studies are needed to validate its utility for routine clinical implementation. Mehdi Lamkhioued, Foy Jean-Philippe, Aurelie Swalduz, Sandra Ortiz-Cuaran, Andy Karabajakian, Kim-Arthur Baffert, Lucas Michon, Adrien Buisson, Maurice Perol, Sylvie Lantuejoul, Loic Verlingue, Jerome Fayette, Pierre Saintigny. Immunologically active phenotype by gene expression profiling predicts clinical benefit from PD-1/PD-L1 inhibitors in a pancancer cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 735.