A novel chalcone analog inhibits cancer stemness in CD44+ and CD133+ populations via suppression of ERK signaling.

Stratified impact analysis of intrinsic phenotypes and therapeutic interventions on the clinical prognosis of cross-disease validation: right treatment for right patient in precision radiotherapy.

In the RATIONALE-307 trial, favorable overall survival (OS) outcomes with tislelizumab plus chemotherapy versus chemotherapy alone have been reported, along with improvements in patient-reported outcomes (PROs), including global health status/quality of life (GHS/QoL) and lung cancer-specific symptoms such as cough and dyspnea. Here, we aimed to evaluate the association between patient-reported symptoms and OS among patients with first-line advanced sq-NSCLC. PROs were assessed using the EORTC QLQ-C30 and QLQ-LC13 instruments. A novel three-component joint model (JM) was developed, linking linear mixed and Cox models to evaluate associations between PRO change from baseline scores, recurrent-symptomatic deterioration (RS-D) events, and OS. The association between PROs and OS was summarized via association-effect hazard ratios (HRs) from the JMs. Overall, 328 patients were included: 111 in the tislelizumab plus paclitaxel-carboplatin arm (Tisle + PC), 110 in the tislelizumab plus nab-paclitaxel-carboplatin arm (Tisle + nPC), and 107 in the paclitaxel-carboplatin (PC) alone arm. Compared to PC alone, Tisle + PC and Tisle + nPC arms significantly improved GHS/QoL (mean difference: 6.29 and 10.23, respectively; both p < 0.05). Dyspnea significantly improved in both Tisle arms; chest pain improved in the Tisle + nPC arm only. In the Tisle + PC arm, chest pain and cough were significantly associated with a 36.3% reduced risk of death (both HRs = 0.64; p = 0.02). In this analysis, compared to PC alone, Tisle + PC improved GHS/QoL and dyspnea in both arms, while chest pain improvement was observed only with Tisle + nPC.

ABSTRACTSquamous cell carcinoma of the lung is a difficult-to-treat cancer with high prevalence in the US, and particularly in Kentucky. The goals of this work were to test if the EZH1/2 inhibitor valemetostat improves anti-PD1 responses in squamous cell lung cancer models, and to developex vivomodels to test immunotherapy drug combinations. We found that valemetostat produced augmented anti-tumor responses to anti-PD1 therapy through up-regulation of tumor cell specific Major Histocompatibility Complex Class II (MHC Class II), and a shift towards activated CD8+ T cells. Neutrophils predominated in these tumors regardless of therapy, but examination of bone marrow revealed that valemetostat treated mice and mice that rejected tumors both had more mature neutrophils. Likewise,Ezh2knock-out mice produced neutrophils that were more apoptotic, less migratory, and less able to produce extracellular nets, but had similar ability to kill bacteria asEzh2-WT neutrophils. To test tumor responses to differing neutrophil populations, we engineered three-dimensional air-liquid interface cultures with tumoroids, lung mesenchymal cells, and T cells, with and without bone marrow containing neutrophils and myeloid progenitors from distinct donors. Bone marrow from tumor-naïve or mice with actively growing untreated tumors boosted tumoroid growth, while bone marrow from tumor-rejected or mice with tumors treated with valemetostat was anti-tumor. MHC Class II blockade lowered the ability of bone marrow to boost tumor growth, and reduced the ability of valemetostat with anti-PD1 to reduce tumoroid growth. Patient samples revealed a strong negative correlation between EZH2 and MHC Class II, suggesting that targeting EZH2 activity could lead to marked increase in MHC Class II and improve treatment responses in lung squamous cell carcinomas.

Plain language summary: comparing ivonescimab plus chemotherapy with tislelizumab plus chemotherapy in people with advanced squamous non-small cell lung cancer in the HARMONi-6 study.

Introduction: Optimizing first-line chemoimmunotherapy for advanced squamous non&amp;ndash;small cell lung cancer (sqNSCLC) remains challenging, particularly in balancing efficacy with treatment-related hematologic toxicity. Objective: This study aims to evaluate whether adding polyethylene glycol&amp;ndash;recombinant human granulocyte colony-stimulating factor (PEG&amp;ndash;rhG-CSF) to first-line camrelizumab and platinum-based chemotherapy improves outcomes in patients with advanced sqNSCLC. Methods: In this single-center, randomized controlled trial, 212 patients with treatment&amp;ndash;na&amp;iuml;ve stage IV sqNSCLC were enrolled between 2020 and 2021. Among them, 23 were lost to follow-up, leaving 189 patients included in the study. They were randomly assigned (1:1) to receive either camrelizumab, paclitaxel, and carboplatin (control group, n = 94) or the same regimen plus prophylactic PEG&amp;ndash;rhG-CSF (experimental group, n = 95). The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), overall survival (OS), and safety. Results: Among the evaluable patients, the ORR was significantly higher in the experimental group (58.95% vs. 43.62%; p = 0.0355). The disease control rate was comparable between groups (85.26% vs. 76.60%; p = 0.2431). The experimental group demonstrated significantly longer median PFS (10.5 vs. 8.4 months; hazard ratio [HR] = 0.72, 95% confidence interval [CI] 0.52&amp;ndash;0.99; p = 0.0423) and a strong trend toward improved median OS (not reached vs. 22.3 months; HR = 0.67, 95% CI 0.45&amp;ndash;0.99; p = 0.0432). Survival benefit was consistent across all predefined subgroups. The incidence of neutropenia was significantly lower in the experimental group (p &lt; 0.0001), while fever was more common (p = 0.0256). Other adverse events were similar between groups. Conclusion: The addition of PEG&amp;ndash;rhG-CSF to first-line camrelizumab-based chemoimmunotherapy in advanced sqNSCLC significantly improved tumor response and PFS, showed a promising OS benefit, reduced chemotherapy&amp;ndash;induced neutropenia, and maintained a manageable safety profile. These findings suggest a potential synergistic role for PEG&amp;ndash;rhG&amp;ndash;CSF beyond supportive care in this setting.

Abstract Introduction: Lung adenocarcinoma (LuAd) is thought to arise from the type 2 alveolar epithelial (AT2) cell, the stem cell of the alveolus of the lung. However, we recently found in mice that driving oncogenic KRAS in the non-stem cell of the lung alveolus, the type 1 alveolar epithelial (AT1) cell, drove it to take on an AT2 phenotype and go on to form indolent tumors that modeled lepidic LuAd in humans. Given that it is perhaps the most stable epigenetic change, CpG methylation may be the best method to determine the lineage of human tumors. Using whole genome methylation sequencing, we validated this approach in a genetic mouse model with defined AT1 and AT2 origin tumors and then applied it to human non-small cell lung cancer (NSCLC) resection specimens. Methods: Fluorescence assisted cell sorting was used to purify AT1, AT2, and tumor cells from genetically modified mice and from human NSCLC resection specimens. DNA was converted for methylation sequencing using an enzymatic approach. Libraries were prepared and then sequenced to a target depth of approximately 5X for mouse specimens and 30X for human specimens. Results: AT1-derived tumor cell populations in mice had a significantly higher degree of AT1-specific methylation than AT2-derived tumors. Twelve LuAd, three squamous cell lung cancer (LuSC), four normal AT1 populations, and four normal AT2 populations were collected from specimens from the Stanford University Hospital operating rooms. In the LuAd specimens, EGFR was the most commonly mutated driver with KRAS, KDR, P53, BRAF, BRCA2, MET, RB1, ARID1A, KEAP1, NF1, and STK11 also represented. Driver mutations and abnormal copy number were verified in all LuAd populations, and purity was determined to be up to ∼99%. Comparison of the methylation profile of the tumors to an existing methylation atlas that included profiles of alveolar, bronchial, and upper airway epithelial cells suggested a basal cell origin for LuSc and an alveolar origin for LuAd. One LuSC and three LuAd had such extensive methylation derangement that they lost a methylation signature of any particular tissue origin. We then defined 1808 differentially methylated regions in AT1 versus AT2 cells. Of the remaining 9 LuAd that retained their lung methylation identity, 8 appeared to be of AT1 cell origin and 1 of AT2 cell origin. Higher AT1 methylation score correlated with lower clinical grade, more lepidic and acinar histology, and more ground glass appearance on CT scan. Conclusion: Whole genome methylation sequencing strongly suggests that human LuAd is derived from alveolar epithelial cells, with some tumors being derived from AT1 cells, the non-stem cell of the alveolus. The presence of non-stem cell methylation correlated with favorable clinical indices. Of note, our analysis includes only resectable LuAd, potentially biasing towards indolent tumors more likely to be derived from AT1 cells. Citation Format: Nicholas Juul, Diego Almanza, Maximilian Diehn, Tushar Desai. Whole genome methylation sequencingstrongly suggests a novel, non-stem cell origin for some lung adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB314.

Growing scientific evidence suggested that hepatocyte growth factor (HGF) might play a crucial role in the development of lung cancer, which might be influenced by the epidermal growth factor (EGF)/EGF receptor. However, the specific causality behind the association has not been clarified due to potential bias. Thus, a Mendelian randomization (MR) study was conducted to investigate the effects of gene-determined elevated plasma HGF on the risk of lung cancer and its subtypes, as well as the mediating effects of EGF. Thirteen instrumental variants for plasma HGF were derived from a genome-wide association study (GWAS) with 21,758 European participants, presented in SCALLOP consortium. Datasets of lung cancer and its subtypes (lung adenocarcinoma [LUAD], lung squamous cell cancer [LUSC], and small cell lung cancer [SCLC]) were based on a GWAS conducted by the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium (TRICL-ILCCO) with 29,266 lung cancer cases and 56,450 controls of European descent. We employed the inverse-variance weighted (IVW) MR analysis followed by a series of sensitive analyses to evaluate the associations between genetically determined plasma HGF and the risk of lung cancer and its subtypes. The primary IVW analysis showed that genetically determined HGF was associated with an increased risk of total lung cancer (odds ratio: 1.11, 95% confidence interval [CI]: 1.05–1.17, P = 2.27E−04) and LUAD (odds ratio: 1.18, 95% CI: 1.09–1.27, P = 1.47E−05) but not with LUSC and SCLC, by the sensitivity analyses with different MR methods further confirming these findings. Additionally, mediated analysis demonstrated that EGF mediated the causal associations of HGF with lung cancer and LUAD, with mediating effects of 28.56% and 21.2% on them. Besides, reverse-MR studies further confirmed no reverse causality between lung cancer and plasma HGF. The intercept of MR-Egger regression showed no directional pleiotropy for all associations (P > .05). Upregulated genetically determined plasma HGF levels were associated with an increasing risk of lung cancer, especially for LUAD. Mediated regulation of EGF on these associations indicated a potential pathogenesis pathway in lung cancer, which provides important implications for the prevention and management of lung cancer.

Squamous Non-Small Cell Lung Cancer: Current and Emerging Treatment Options.

PRESERVE-003 is a two-stage phase 3 trial evaluating gotistobart (BNT316/ONC-392), a novel pH-sensitive anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody that selectively depletes regulatory T cells within the tumor microenvironment, in patients with metastatic squamous non-small cell lung cancer (sqNSCLC) without actionable genomic alterations who progressed on programmed cell death protein/programmed death ligand 1 inhibitor/platinum-based chemotherapy-a population with a poor prognosis. Here we report on stage 1, which aimed to confirm the dose and assess the preliminary efficacy (primary outcome: overall survival; secondary outcomes: progression‑free survival, objective response rate and duration of response) and safety of gotistobart compared to docetaxel. Patients with sqNSCLC were randomized (1:1) to gotistobart (6 mg kg-1 with two 10 mg kg-1 loading doses every 3 weeks (N = 45)) or docetaxel (75 mg m-2 every 3 weeks (N = 42)). After a median follow-up of 14.5 months, median overall survival was not reached with gotistobart (95% confidence interval (CI) 9.3 to not evaluable) versus 10.0 months (95% CI 6.2 to 11.9 months) with docetaxel (hazard ratio 0.46, 95% CI 0.25 to 0.84, nominal two-sided P = 0.0102). Safety was manageable, with grade ≥3 treatment-related adverse events in 42% and 49% of patients receiving gotistobart and docetaxel, respectively. Stage 1 results suggest that gotistobart monotherapy can provide clinically meaningful benefit for patients with programmed cell death protein/programmed death ligand 1-resistant and chemotherapy-resistant metastatic sqNSCLC. ClinicalTrials.gov identifier: NCT05671510 .

Squamous nonsmall cell lung cancer (sq-NSCLC) is challenging to treat, with shorter survival when compared with other NSCLC subtypes. Tislelizumab has demonstrated efficacy when combined with chemotherapy for sq-NSCLC. We report 4-year follow-up results from the phase 3 randomized RATIONALE-307 trial evaluating tislelizumab plus chemotherapy as first-line treatment for advanced or metastatic sq-NSCLC. Patients with treatment-naive advanced or metastatic sq-NSCLC were randomized to receive tislelizumab plus paclitaxel/carboplatin (arm A), tislelizumab plus nab-paclitaxel/carboplatin (arm B), or paclitaxel/carboplatin alone (arm C) until disease progression/intolerable toxicity. Crossover was permitted from arm C to tislelizumab monotherapy. The primary end point was progression-free survival (PFS) per independent review. Key secondary end points included overall survival (OS) and safety. At median OS follow-up of 44.8months, tislelizumab plus chemotherapy demonstrated durable survival benefit. Median PFS was 7.7months (95% confidence interval [CI] 6.7-9.9) in arm A, 9.5months (95% CI 7.4-10.1) in arm B, and 5.5months (95% CI 4.2-5.6) in arm C. Median OS was 26.1months (95% CI 19.0-33.8) in arm A, 23.3months (95% CI 18.8-26.4) in arm B, and 19.4months (95% CI 16.0-23.4) in arm C. The 4-year OS rates were 32.2%, 26.0%, and 19.2% for arms A, B, and C, respectively. Crossover occurred in 58.7% of patients from arm C. OS and PFS benefits were observed across most subgroups. Grade ≥ 3 treatment-emergent adverse events occurred in 89.2%, 89.0%, and 84.6% of patients in arms A, B, and C, respectively. No new safety signals emerged. At 4-year follow-up, patients with advanced sq-NSCLC who received tislelizumab plus chemotherapy experienced long-term OS and PFS benefits versus chemotherapy alone, despite high crossover rates. The combination was well-tolerated with no new safety concerns. This regimen may be a promising first-line treatment option for patients with advanced or metastatic sq-NSCLC. ClinicalTrials.gov NCT03594747.

The Clinical Efficacy and Safety of Neoadjuvant Carboplatin, Nab-Paclitaxel and Pembrolizumab Treatment in Patients with Squamous Cell Lung Cancer: A Case Report and Institutional Experience

Anaplastic lymphoma kinase (ALK) is an established therapeutic target in non-small cell lung cancer (NSCLC), predominantly identified in adenocarcinomas. However, ALK rearrangements also occur in de novo squamous and adenosquamous NSCLCs and their clinicogenomic features remain poorly defined. This multi-institutional retrospective analysis included patients with advanced ALK+ NSCLC. Patients with de novo ALK+ squamous and adenosquamous NSCLCs were identified and compared with an ALK+ adenocarcinoma cohort treated with first-line (1L) alectinib. Overall survival (OS), time to progression (TTP), and time to treatment discontinuation (TTD) were analyzed using the Kaplan-Meier methodology. Among 177 patients, 29 had ALK+ squamous (n = 17) and adenosquamous (n = 12) NSCLCs and 148 had ALK+ adenocarcinoma treated with 1L alectinib. Among patients receiving 1L alectinib, OS was significantly shorter for patients with adenosquamous (median, 31.0 months [95% CI, 17.0 to not reached {NR}]) and squamous (27.0 months [95% CI, 5.0 to 35.0]) tumors compared with that for patients with adenocarcinoma (median NR; median follow-up 51.2 months; P < .001). TTP was shorter for squamous (median, 8.0 months [95% CI, 2.0 to 12.0]) versus adenocarcinoma (median, 19.0 months [95% CI, 12.6 to 25.0]) cohorts (P < .001), although the adenosquamous cohort had comparable TTP (median, 20.0 months [95% CI, 9.4 to 30.6]) with the adenocarcinoma cohort (P = .70). TTD was significantly shorter for squamous (median, 9.5 months [95% CI, 1.5 to 13.0]) and adenosquamous (median, 20.0 months [95% CI, 3.0 to 24.0]) versus adenocarcinoma cohorts (52.3 months [95% CI, 40.5 to 57.5]; P < .001). Genomic profiling revealed more frequent TP53 (53% v 25%; P = .026), PDGFRA (16% v 0%; P = .009), KIT (11% v 0%; P = .045), PIK3CA (11% v 0%; P = .045), and MYC (11% v 0%; P = .045) coalterations in the squamous/adenosquamous cohort. ALK+ squamous and adenosquamous NSCLCs are rare, but biologically distinct, with inferior outcomes on 1L ALK TKI, highlighting the need for further research to develop effective treatment strategies.

This study aimed to evaluate the clinical efficacy and safety of nab-paclitaxel in combination with PD-1 inhibitors in elderly patients with advanced squamous cell lung cancer. A retrospective analysis was performed on 40 elderly patients with advanced squamous cell lung cancer treated at the affiliated Zhangjiagang Hospital of Soochow University between March 2020 and July 2024. Patients were assigned to either the chemotherapy group (n = 18), receiving nab-paclitaxel monotherapy, or the combination therapy group (n = 22), receiving nab-paclitaxel plus a PD-1 inhibitor. Treatments were administered every three weeks (per cycle). Short-term efficacy and adverse events were evaluated after every 2–3 cycles, and patients were followed up to assess the incidence of adverse reactions and clinical outcomes, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Compared with the chemotherapy group, patients in the combination therapy group demonstrated improved clinical outcomes, including higher objective response rate(31.8% vs. 22.2%) and disease control rates (86.4% vs. 66.7%), as well as a longer median overall survival time (19 vs. 9 months). In addition, the combination therapy group exhibited significantly higher 6-month (100% vs. 77.8%) and 1-year (72.2% vs. 35.3%) survival rates. The most frequently observed adverse events were leukopenia, anemia, fatigue, nausea and vomiting, myalgia, cough, and interstitial pneumonia, all of which were generally manageable. Nab-paclitaxel combined with PD-1 inhibitors demonstrated superior short-term efficacy and an acceptable safety profile compared with chemotherapy alone in elderly patients with advanced squamous cell lung cancer.

IntroductionImmune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1 antibodies, improve survival in patients with advanced malignancies. However, their combination with chemotherapy may increase the incidence of severe immune-related adverse events (irAEs), including rare but life-threatening dermatologic toxicities.Case reportWe report the case of a 69-year-old male diagnosed with stage IV squamous cell lung cancer who received first-line treatment with carboplatin, paclitaxel, and pembrolizumab. Two days after the third cycle, he developed non-itching macular lesions which progressively extended to over 90% of the body surface area (BSA) and evolved into large bullous lesions with exudation. Antineoplastic treatment was discontinued and the patient was hospitalized.Management and outcomeSystemic corticosteroids, antihistamines, and analgesics were initiated, along with topical wound care with steroids and zinc sulphate. Due to the limited response to treatment, etanercept was administered and the patient was transferred to a specialized burn unit, where corticosteroid therapy and topical wound care were continued until re-epithelialization. Eventually, after 16 days of admission, the patient was discharged with a diagnosis of toxic epidermal necrolysis (TEN) secondary to immunotherapy.DiscussionSJS/TEN are rare, life-threatening cutaneous adverse reactions potentially triggered by ICIs. Management involves prompt identification and discontinuation of the offending drug, initiation of supportive measures, and meticulous skin care. The use of systemic corticosteroids remains controversial. TNF-α inhibitors, such as etanercept, have shown efficacy in different studies, but additional trials are needed to confirm these findings. This case highlights the importance of early recognition and multidisciplinary management of severe ICI-induced dermatologic toxicity.

Bronchial premalignant lesions (PML), precursors of lung squamous cell carcinoma, have distinct molecular subtypes. The proliferative subtype, enriched with bronchial dysplasia, had decreased expression of an antigen-processing/presentation gene coexpression module in progressive/persistent versus regressive PMLs, suggesting a functional impact of these genes on immune evasion. In this study, we performed miRNA sequencing, miRNA in situ hybridization, and spatial proteomics of bronchial biopsies from patients at high risk for lung cancer. An miRNA-gene network analysis identified hsa-miR-149-5p as a potential regulator of the antigen presentation gene module. Staining on adjacent biopsy tissue showed that hsa-miR-149-5p was predominantly expressed in the epithelium and upregulated in progressive/persistent proliferative lesions. Targets of this miRNA, the transcriptional coactivator of MHC-I gene expression, NLRC5, and the genes it regulates, were downregulated in these lesions. Decreased NLRC5 expression reduced both IFNγ-induced MHC-I surface expression and CD8 T-cell cytotoxicity in lung squamous cancer cells. In PMLs, basal cells with high levels of NLRC5 were in close spatial proximity to CD8 T cells, suggesting that these cells exhibit increased functional MHC-I gene expression in vivo. These findings indicate a functional role for hsa-miR-149-5p in PML progression/persistence and suggest this axis as a potential therapeutic target for PML immunomodulation.

117 Safety and Efficacy of Neoadjuvant Chemoimmunotherapy in Squamous Cell Lung Cancer: A Retrospective UK Multicentre Study

128 Mind the ‘Histology Gap’: understanding discrepancy in treatment rates between squamous cell lung cancer and lung adenocarcinoma

INBRX-105, a tetravalent, PD-L1-targeted TNFRSF9 (4-1BB) agonist, demonstrated preclinical antitumor activity. This first-in-human study evaluated INBRX-105 in solid tumors. This open-label, 4-part, phase 1 study evaluated INBRX-105 alone or with pembrolizumab in adults with locally advanced/metastatic, unresectable solid tumors (NCT03809624). INBRX-105 was administered intravenously once every 2 weeks or 4 weeks in parts 1 (single-agent dose escalation; 0.001-3 mg/kg) and 2 (single-agent expansion) or once every 3 weeks in parts 3 (combination dose escalation; INBRX-105 0.03-1.0 mg/kg) and 4 (combination expansion). Part 2 enrolled patients with checkpoint inhibitor-relapsed/refractory (CPI-R/R) tumors. Part 4 enrolled patients with CPI-R/R or CPI-naïve disease. The primary endpoint was safety and tolerability of INBRX-105. Preliminary clinical response was a secondary endpoint. Of 160 patients assessed, 81 received monotherapy (median age, 65 years; female, 50.6%), and 79 combination therapy (median age, 64 years; female, 38%). The INBRX-105 maximum tolerated dose was 0.3 mg/kg once every 3 weeks. Head and neck squamous cell carcinoma (n = 61) and non-small cell lung cancer (n = 25) were the most common tumor types. The most common any-grade INBRX-105-related adverse events (AE) were fatigue (monotherapy, 35.8%; combination, 17.7%), increased aspartate aminotransferase (25.9%; 15.2%), and nausea (19.8%; 17.7%). INBRX-105-related hepatic AEs occurred in 41 patients [monotherapy, n = 25 (grade ≥3, n = 11); combination, n = 16 (grade ≥3, n = 6)]. In all patients, the objective response rate was 8.8% [monotherapy, 3.7%; combination, 13.9% (CPI-naïve, 30%; CPI-R/R, 8.6%)]; the disease control rate was 43.1%. The low response rates and hepatic safety signals observed do not support further clinical development of INBRX-105. Tumor resistance to CPIs often develops, underscoring an unmet need. This first-in-human phase 1 trial evaluated INBRX-105-a tetravalent, PD-L1-targeted 4-1BB agonist-alone or with pembrolizumab. Unfortunately, clinical development of INBRX-105 was ended because of hepatotoxicity and limited efficacy. Novel treatment combinations with nonredundant, complementary immunotherapies are needed.

138 Single-centre review of the use of first line Carboplatin and Paclitaxel for squamous non-small cell lung cancer