Abstract Following peak tobacco incidence in the mid-1980’s there has been a large reduction in lung cancer incidence among men that has not been seen among women. Lung cancer at a young age is now more common among women than men, reversing a decades long pattern. We sought to characterize environmental exposures among young lung cancer patients to understand potential drivers of this change in the epidemiologic profile of young lung cancer patients. We analyzed 187 patients (157 females, 84%) from the Epidemiology of Young Lung Cancer (YLC) study (ClinicalTrials.gov identifier: NCT04640259) using mutation-based grouping by shared biological mechanisms: EGFR Pathway (EGFR+ERBB2), Fusion Positive (ALK+ROS1+RET+NTRK), and Other/Mixed Mutations (including MET exon 14 skipping, TP53, KRAS, BRAF, and additional alterations). Of these, 166 patients (138 females, 83.1%) completed validated food frequency questionnaires. Dietary quality was assessed using the Healthy Eating Index-2015 (HEI-2015) and compared to U.S. reference values from NHANES. Dietary categories with elevated contaminant residue potential were identified using published literature. Statistical comparisons employed one-sample t-tests against reference means and chi-square tests for categorical variables. The EGFR groups and ALK groups had tobacco use history in 32.8% and 13.4% of patients respectively. All groups had similarly high levels of oral contraceptive exposure among women (75-100%). Dietary analysis revealed that EGFR Pathway, Fusion Positive, and Other/Mixed Mutations patients demonstrated HEI-2015 scores (out of 100) of 64.9 ± 10.7, 65.5 ± 9.8, and 63.5 ± 9.5 respectively, compared with the US reference of 58. YLC women demonstrated higher dietary quality scores than men (65.6 ± 9.7 vs. 61.8 ± 11.3), both exceeded U.S. reference values of 60 for females and 56 for males. These YLC patients also consumed more foods from dietary categories associated with elevated contaminant exposure potential, as reflected by higher HEI-2015 component scores (out of 5) for total vegetables (4.2 vs. 3.5), fruits (3.3 vs. 2.5), and whole grains (3.9 vs. 2.6). YLC patients have a diet pattern of higher diet quality, with higher exposure to whole fruits, vegetables and whole grains. While these food groups are presumed to have good health benefits, there is an emerging, under-appreciated literature that produce based whole foods often contain high pesticide/herbicide contaminants. Further investigation of the role of pesticide contaminated fruits/vegetables/whole grains is timely to assess its role, if any, in the changing lung cancer prevalence over the last 4 decades. Citation Format: Sarah D. Gorbatov, Marisa A. Bittoni, Anna H. Wu, Allison Harper, Kotait Virginia, Narjust Florez, Barbara J. Gitlitz, Jorge J. Nieva. Dietary patterns in young lung cancer: mutation-specific environmental associations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5039.

Young-onset lung cancer is enriched for never-smoking and oncogene-driven tumors, yet its inherited genetic basis remains poorly defined. We performed germline whole-genome sequencing in 251 young-onset lung cancer cases (median age 37), which we jointly analyzed with never-smoking cases (n=196; median age 68) and cancer-free controls (n=1,883). We identified enrichments of rare deleterious coding variants across 55 cancer-related gene sets, including EGFR/ERBB2 signaling and genes implicated by prior lung cancer GWAS. Exome-wide analyses of rare coding variants affirmed TP53 as a penetrant lung cancer predisposition gene (odds ratio [OR]=36.1, p=1.02×10 -7 ) and discovered two novel exome-wide significant tumor subtype-dependent associations: IREB2 in cases with fusion-driven tumors (p=1.39×10 -6 ) and SMAD6 in fusion-negative tumors (p=2.05×10 -6 ). Structural variants contributed distinct risk, with enrichment in constrained, lung-expressed genes (OR=5.79, p=5.8×10 -5 ) and very large germline deletions being markedly enriched in cases with fusion-driven tumors. Polygenic risk scores for lung cancer were inversely correlated with rare variant burden, consistent with additive risk from rare and common variants. Collectively, these findings delineate a complex germline architecture underlying susceptibility and molecular subtype in young-onset lung cancer.

IMpower010 (ClinicalTrials.gov identifier: NCT02486718 ) previously showed that atezolizumab improved disease-free survival (DFS) versus best supportive care (BSC) after adjuvant chemotherapy in patients with resected non–small cell lung cancer (NSCLC). We report DFS final analysis, second overall survival (OS) interim analysis, and safety with a ≥5-year follow-up. Patients with completely resected stage IB-IIIA NSCLC were randomly assigned to atezolizumab (1,200 mg once every 3 weeks, 16 cycles) or BSC after platinum-based chemotherapy. At clinical cutoff (January 26, 2024), stratified hazard ratios (HRs; 95% CI) for DFS were 0.85 (95% CI, 0.71 to 1.01; P = .07) in the intention-to-treat (n = 1,005), 0.83 (95% CI, 0.69 to 1.00) in the all-randomized stage II-IIIA (n = 882), and 0.70 (95% CI, 0.55 to 0.91) in stage II-IIIA PD-L1 tumor cell (TC) ≥1% (n = 476) populations. Stratified HRs (95% CI) for OS were 0.97 (95% CI, 0.78 to 1.22), 0.94 (95% CI, 0.75 to 1.19), and 0.77 (95% CI, 0.56 to 1.06), respectively. The unstratified HRs (95% CI) in the stage II-IIIA PD-L1 TC ≥50% population (n = 229) were 0.48 (95% CI, 0.32 to 0.72) for DFS and 0.47 (95% CI, 0.28 to 0.77) for OS, and the unstratified HRs in the stage II-IIIA PD-L1 TC ≥50% without EGFR / ALK alterations (n = 209) population were 0.49 (95% CI, 0.32 to 0.75) and 0.44 (95% CI, 0.26 to 0.74). No new safety signals were reported. IMpower010 is the first study to report survival outcomes with a ≥5-year follow-up and continued to show benefit with atezolizumab versus BSC after adjuvant chemotherapy in patients with resected stage II-IIIA PD-L1–selected NSCLC.

Phase 3 trials of neoadjuvant, perioperative, and adjuvant immune checkpoint inhibitors combined with chemotherapy (ICI-CT) in resectable early-stage NSCLC (eNSCLC) have reported that all three approaches confer an event-free or disease-free survival benefit over CT alone, with acceptable safety profiles. All three strategies are approved standards of care for eNSCLC. This review provides a detailed analysis of these phase 3 ICI-CT trials and addresses the considerations regarding the selection of each approach, including protocol schema and baseline patient and tumor differences, preoperative staging, surgical outcomes, efficacy end points, safety, treatment disposition, and the programmed death-ligand 1 (PD-L1) efficacy biomarker. The differences between regimens and study populations among these ICI-CT trials hamper cross-trial comparisons and highlight the need for head-to-head trials. Patients achieving pathologic complete response with neoadjuvant ICI-CT have better survival outcomes irrespective of subsequent treatment, but the optimal number of preoperative ICI-CT cycles needed to achieve pathologic complete response has not been defined. The choice between a neoadjuvant or perioperative versus adjuvant treatment approach involves a risk-benefit assessment of the potential for preoperative attrition to surgery, postoperative attrition to ICI-CT, and the anticipated toxicity profile. Current limitations of invasive lymph node staging mean that adjuvant ICI remains an important treatment strategy, but preoperative node staging is imperative. Future studies that identify the safety and toxicity contributions of each treatment phase in perioperative trials will confirm whether a pre- or postoperative ICI approach is superior, whether there is added benefit to adjuvant after neoadjuvant ICI-CT, and which patients will benefit the most from each approach.

OBJECTIVE:Patients with relapsed or metastatic head and neck squamous cell carcinoma (HNSCC) after primary local therapy have low response rates with cetuximab, systemic chemotherapy or check point inhibitor therapy. Novel combination therapies with the potential to improve outcomes for patients with HNSCC is an area of high unmet need. METHODS:This is a phase II single-arm clinical trial of locally advanced or metastatic HNSCC patients treated with a combination of soluble EphB4-human serum albumin (sEphB4-HSA) fusion protein and pembrolizumab after platinum-based chemotherapy with up to 2 prior lines of treatment. The primary endpoints were safety and tolerability and the primary efficacy endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). HPV status and EphrinB2 expression were evaluated for outcome. RESULTS:Twenty-five patients were enrolled. Median follow up was 40.4 months (range 9.8 - 40.4). There were 6 responders (ORR 24%). There were 5 responders in the 11 HPV-negative and EphrinB2 positive patients, (ORR 45%) with 2 of these patients achieving a complete response (CR). The median PFS in HPV-negative/EphrinB2 positive patients was 3.2 months (95% CI 1.1, 7.3). Median OS in HPV-negative/EphrinB2 positive patients was 10.9 months (95% CI 2.0, 13.7). Hypertension, transaminitis and fatigue were the most common toxicities. DISCUSSION:The combination of sEphB4-HSA and pembrolizumab has a favorable toxicity profile and favorable activity particularly among HPV-negative EphrinB2 positive patients with HNSCC.

LBA8035 Background: IMpower010 (NCT02486718) met its primary endpoint of significant DFS improvement with atezo vs BSC after adj chemotherapy in resected NSCLC in the PD-L1 TC ≥1% and all-randomized stage II-IIIA populations, leading to worldwide approval of adj atezo for PD-L1 TC ≥1% or PD-L1 TC ≥50% stage II-IIIA NSCLC. At OS IA1, a trend favoring atezo was seen in the PD-L1 TC ≥1% stage II-IIIA population. Here we report findings from the DFS FA and OS IA2. Methods: The IMpower010 study design has been previously described (Felip et al, Lancet 2021). The primary DFS and secondary OS endpoints were tested hierarchically: DFS in the PD-L1 TC ≥1% (SP263) stage II-IIIA, then in the all-randomized stage II-IIIA, and then in the intent-to-treat (ITT; stage IB-IIIA) populations, followed by OS in the ITT population. Secondary endpoints included 3- and 5-y DFS and DFS in the PD-L1 TC ≥50% (SP263) stage II-IIIA population. OS in the ITT population could only be formally tested if the significance boundary for DFS in that population was crossed. Results: At the DFS FA and OS IA2 (clinical cutoff date: Jan 26, 2024), with a minimum follow-up of 60 mo, DFS and OS for the PD-L1 TC ≥1% and TC ≥50% stage II-IIIA populations were consistent with previously observed benefit; the difference in median (m) DFS between arms in the PD-L1 TC ≥1% population was 31.2 mo (Table). In the ITT population, the significance boundary for DFS was not crossed and OS was similar between arms, although data were immature. The safety profile of atezo was consistent with prior analyses. Conclusions: These results provide the first cancer immunotherapy data with ≥5 y of follow-up from a Phase III study in resectable NSCLC. Although the statistical boundary for the ITT population was not crossed, DFS benefit with adj atezo continues to translate into a positive OS trend vs BSC in the PD-L1 TC ≥1% and TC ≥50% stage II-IIIA populations. These results further support the use of adj atezo in PD-L1–selected populations. Clinical trial information: NCT02486718 . [Table: see text]

Abstract Background The Phase III IMpower010 study (NCT02486718) met its primary endpoint at the disease-free survival (DFS) interim analysis (IA; clinical cutoff: Jan 21, 2021), demonstrating significant DFS improvement with atezolizumab (atezo) vs best supportive care (BSC) after adjuvant chemotherapy (chemo) in patients with resected stage II-IIIA NSCLC, including those with PD-L1 TC ≥1%. Based on these findings, atezo was approved as adjuvant therapy after platinum-based chemo in patients with completely resected PD-L1 TC ≥1% stage II-IIIA NSCLC in the US, China and other countries, and in patients with completely resected PD-L1 TC ≥50% stage II-IIIA NSCLC in the EU and other countries. In a previous exploratory analysis at the time of the DFS IA, the IMpower010 Asian subpopulation showed efficacy and safety outcomes that were consistent with those of the global population (Kenmotsu et al. JSMO 2021). Here we report updated data from the IMpower010 Asian subpopulation at the first overall survival (OS) IA. Methods The IMpower010 study design and DFS IA have been previously reported (Felip et al. Lancet 2021). Eligible patients with completely resected stage IB (≥4 cm)-IIIA NSCLC (AJCC/UICC v7) received one to four 21-day cycles of cisplatin-based doublet chemo and were subsequently randomized 1:1 to receive atezo 1200 mg q3w (16 cycles) or BSC. The first pre-specified OS IA was conducted at the clinical cutoff date of Apr 18, 2022. OS in the intention-to-treat (ITT) population will be formally tested if DFS in the ITT population reaches statistical significance at the final DFS analysis. Exploratory OS and updated safety outcomes were evaluated in the Asian subpopulation. Results The Asian ITT population included 233 patients recruited from Japan, mainland China, Taiwan, Korea and Hong Kong. At data cutoff (Apr 18, 2022), the unstratified OS HR was 0.73 (95% CI: 0.28, 1.88) in favor of atezo in the PD-L1 TC ≥1% (SP263) stage II-IIIA population (n=129). The Asian safety-evaluable population included 229 patients (atezo, n=122; BSC, n=107). Any-grade adverse events (AEs) were reported in 95.1% (atezo) and 72.0% (BSC) of safety-evaluable patients; events were Grade 3/4 in 24.6% and 13.1%, respectively. Grade 5 treatment-related AEs occurred in 1 patient in the atezo arm. AEs leading to atezo discontinuation occurred in 21.3% of patients treated with atezo. Conclusions The IMpower010 Asian subpopulation showed an OS trend favoring atezo vs BSC in the PD-L1 TC ≥1% stage II-IIIA population, as was observed in the global population, although OS data were not formally tested in either population at the first OS IA. With longer follow-up, the safety findings for atezo in the IMpower010 Asian subpopulation remained broadly unchanged, were consistent with those of the global IMpower010 population and were in line with the known safety profile of atezo. Medical writing support for this abstract was provided by Kia C. E. Walcott, PhD, of Nucleus Global, an Inizio Company, and funded by F. Hoffmann-La Roche, Ltd. Citation Format: Jie Wang, Yun Fan, Jian Fang, Jianxing He, Yunpeng Liu, Min Tao, Nasser Altorki, Enriqueta Felip, Heather Wakelee, Eric Vallieres, Rossella Belleli, Virginia McNally, Elizabeth Bennett, Barbara J. Gitlitz, Caicun Zhou. IMpower010: Updated overall survival and safety results from Asian patients in a Phase III study of adjuvant atezolizumab vs best supportive care in resected stage IB-IIIA NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT239.

Supplementary Figures S1 - S10. Supplementary Figure S1. Additional information for Patient 1. Supplementary Figure S2. Additional information for Patient 2. Supplementary Figure S3. Additional information for Patient 3. Supplementary Figure S4. Additional clinical information for Patient 4. Supplementary Figure S5. Characterization of EGFR-RAD51 in NR6 cells. Supplementary Figure S6. Relative stability of EGFR-WT, -L858R, and -RAD51. Supplementary Figure S7. Structural model of EGFR-RAD51 filaments. Supplementary Figure S8. On-target inhibition of EGFR-RAD51 by EGFR TKI. Supplementary Figure S9. Cetuximab inhibits ligand-induced activation of downstream signaling pathways in cells expressing EGFR-RAD51. Supplementary Figure S10. cDNA sequence of EGFR-RAD51.

Supplementary Tables S1 - S3. Supplementary Table S1. Summary of EGFR alterations in NSCLC identified by FoundationOne. Supplementary Table S2. Summary of genomic coordinates for the kinase fusions identified in this study. Supplementary Table S3. Results of MTT curve fitting from Prism.

Supplemental Figure 3. Best percentage change from baseline in sum of target lesions is presented for the ALK-positive evaluable patients at 200 mg who had received prior crizotinib and as second-generation ALK TKI. Dashed lines indicate RECIST v1.1 cut-offs for partial response and progressive disease. Of the 16 patients, four had partial responses and four had stable disease. The color scheme represents which second-generation ALK TKI that patient received after crizotinib. Of note, the primary lesion of one of the 16 patients was too small, and thus indeterminate, at the post-baseline assessment, therefore a change in tumor size is not available. This patient had received, in order, prior crizotinib, alectinib, and ceritinib, and developed progression on ensartinib in a non-target brain lesion prior to cycle 3. *Denotes those patients with progressive disease as the best response. >Denotes patients still on study at the time of data cutoff.

The mean concentration of ensartinib in plasma and skin at multiple time points after a single dose of 50 mg/kg is listed in Supplemental Table 2. At 12 hours post-dose, the concentration of ensartinib was 9.0 higher in the skin than in the plasma.

The key pharmacokinetic (PK) parameters (Supplemental Table 3) at the recommended phase 2 dose of 225 mg show that food has minimal impact on absorption of ensartinib.

Supplementary Methods, Supplementary References, Supplementary Table Legends, and Supplementary Figure Legends.