Search

Approximately 10% of lung adenocarcinomas (LUADs) have mucinous histology (LUADMuc), which is associated with a light/absent smoking history and a high prevalence of KRAS mutations. We sought to characterize LUADMuc by comparing it with LUAD without mucinous histology (LUADnon-muc) and determine the relative benefit of current treatments. Patients with LUAD from five institutions and The Cancer Genome Atlas Pan-Cancer Atlas classified as LUADMuc or LUADnon-muc were included. Clinicopathologic, genomic, immunophenotypic, transcriptional features, and treatment outcomes were compared between LUADMuc and LUADnon-muc. Of 4082 patients with LUAD, 9.9% had LUADMuc. Compared with LUADnon-muc, patients with LUADMuc had a lighter smoking history (median 15 versus 20 pack-years; P = 0.008), lower programmed death-ligand 1 (PD-L1) tumor proportion score (median 0% versus 5%, P < 0.0001), and lower tumor mutation burden (median 6.8 versus 8.5 mutations/megabase, P < 0.0001). Mutations in KRAS , NKX2-1 [thyroid transcription factor 1 (TTF-1)], STK11 , SMARCA4 , GNAS, and ALK rearrangements were enriched in LUADMuc, while TP53 , EGFR , BRAF , and MET mutations were enriched in LUADnon-muc. At stage IV diagnosis, LUADMuc was more likely to have contralateral lung metastasis (55.2% versus 36.9%, P < 0.0001) and less likely to have brain metastases (23.3% versus 41.9%, P < 0.0001). Compared with LUADnon-muc, LUADMuc cases showed lower intratumor CD8+, PD-1+, CD8+PD-1+, and FOXP3+ cells. Among metastatic cases receiving immune checkpoint inhibitors, compared with LUADnon-muc (n = 1511), LUADMuc (n = 112) had a lower objective response rate (ORR 8.4% versus 25.9%, P < 0.0001), and shorter median progression-free survival (mPFS 2.6 versus 3.9 months, P < 0.0001) and overall survival (mOS 9.9 versus 17.2 months, P < 0.0001). Similarly, patients with LUADMuc had worse outcomes to chemoimmunotherapy. LUADMuc (n = 18) and LUADnon-muc (n = 150) had similar ORR (16.7% versus 34.9%, P = 0.12) and mPFS (4.6 versus 5.6 months, P = 0.17) to treatment with KRASG12C inhibitors, but LUADMuc had shorter mOS (6.8 versus 10.8 months, P = 0.018). LUADMuc represents a distinct LUAD subpopulation with unique clinicopathologic, genomic, immunophenotypic, and transcriptional features, achieving worse outcomes to standard immunotherapy-based treatments. • Approximately 10% of LUADs have a mucinous component (LUADMuc). • Compared with LUADnon-muc, LUADMuc was associated with a lighter smoking history and lower PD-L1 expression. • LUADMuc had a lower tumor mutation burden and more KRAS , STK11 , SMARCA4 , NKX2-1 , and GNAS mutations than LUADnon-muc. • Intratumor CD8+, PD-1+, CD8+PD-1+, and FOXP3+ cell density was lower in LUADMuc compared with LUADnon-muc. • Patients with LUADMuc had poorer outcomes to immunotherapy with or without chemotherapy and KRASG12C inhibitors than LUADnon-muc. [ABSTRACT FROM AUTHOR]

[Display omitted] • Baicalein exhibits inhibitory effects on lung cancer both in vitro and in vivo. • Baicalein significantly inhibits glutamine metabolism in NSCLC cells. • The mTOR inhibition of baicalein were achieved by regulating glutamine metabolism. • Baicalein induces apoptosis by inhibiting the glutamine-mTOR metabolic pathway. • Baicalein exhibits potential as a pro-apoptotic agent in lung cancer therapy. Baicalein, a bioactive component of Scutellaria baicalensis Georgi, has been shown to promote apoptosis in non-small cell lung cancer cells. However, previous studies have not determined if baicalein exerts proapoptotic effects by modulating the metabolic pathways. To investigate if baicalein induces apoptosis in lung cancer cells by modulating the glutamine-mTOR metabolic pathway. The in vivo anti-lung cancer activity of baicalein (50, 100, and 200 mg/kg) was evaluated using a xenograft model. In vitro experiments were used to assess the efficacy of baicalein (for H1299: 12.5, 25, and 50 μM; for A549: 10, 20, and 40 μM) on lung cancer cell proliferation, colony formation, and apoptosis. Metabolomics analysis was performed using liquid chromatography-mass spectrometry. The binding of baicalein to glutamine transporters and glutaminase was examined using molecular docking. The overexpression of glutamine transporters was validated using qRT–PCR and western blot analyses. The levels of ASCT2, LAT1, GLS1, p-mTOR, mTOR, and apoptosis-related proteins were evaluated using western blot analysis. Baicalein inhibited lung cancer xenograft tumor growth in vivo and suppressed proliferation and promoted apoptosis in lung cancer cells in vitro. Additionally, baicalein altered amino acid metabolites, especially glutamine metabolites, in H1299 and A549 cells. Mechanistically, baicalein interacted with glutamine transporters as well as glutaminase and inhibited their activation. The expression of mTOR, an apoptosis-related protein and downstream target of glutamine metabolism, was also inhibited by baicalein treatment. Importantly, we next demonstrated the suppression of mTOR signaling and the induction of apoptosis by baicalein were achieved by regulating glutamine metabolism. Baicalein inhibited the mTOR signaling pathway and induced apoptosis by downregulating glutamine metabolism. The potential of baicalein to induce apoptosis in lung cancer cells by selectively targeting the glutamine-mTOR pathway suggests an encouraging approach for treating lung cancer. [ABSTRACT FROM AUTHOR]

Lung cancer remains a critical public health issue, presenting multifaceted challenges in prevention, diagnosis, and treatment. This article aims to review the current landscape of lung cancer research and management, delineate the persistent challenges, and outline pragmatic solutions. Global experts from academia, regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the National Cancer Institute (NCI), professional societies, the pharmaceutical and biotech industries, and patient advocacy groups were gathered by the New York Lung Cancer Foundation to review the state of the art in lung cancer and to formulate calls to action. Improving lung cancer management and research involves promoting tobacco cessation, identifying individuals at risk who could benefit from early detection programs, and addressing treatment-related toxicities. Efforts should focus on conducting well-designed trials to determine the optimal treatment sequence. Research into innovative biomarkers and therapies is crucial for more personalized treatment. Ensuring access to appropriate care for all patients, whether enrolled in clinical trials or not, must remain a priority. Lung cancer is a major health burden worldwide, and its treatment has become increasingly complex over the past two decades. Improvement in lung cancer management and research requires unified messaging and global collaboration, expanded education, and greater access to screening, biomarker testing, treatment, as well as increased representativeness, participation, and diversity in clinical trials. • Lung cancer research and treatment require strong global collaborations. • Tobacco cessation and screening programs need better implementation, focusing on the at-risk population for screening. • Dedicated funding for treatment and research is needed to guarantee access for underserved communities. • Improved trial design requires early collaboration with academia, industry, organizations, and regulatory authorities. • New technologies and novel biomarkers could help personalize treatment to improve efficacy and lower toxicity. [ABSTRACT FROM AUTHOR]

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) occurs in ∼10%-15% of solid tumors. AMG 193, a CNS-penetrant methylthioadenosine-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor, selectively induces synthetic lethality in MTAP -deleted tumor cells. Here, we report results of the completed monotherapy dose exploration evaluating AMG 193 in patients with MTAP- deleted solid tumors. In this first-in-human, multicenter, open-label, phase I study, patients with advanced CDKN2A -deleted and/or MTAP -deleted solid tumors received AMG 193 orally [once (o.d.) or twice (b.i.d.) daily] continuously in 28-day cycles. Primary objectives were safety and tolerability assessed by dose-limiting toxicities and determination of the maximum tolerated dose; secondary objectives included pharmacokinetics and preliminary antitumor activity measured by RECIST v1.1. As of 23 May 2024, 80 patients in dose exploration received AMG 193 at doses 40-1600 mg o.d. or 600 mg b.i.d. The most common treatment-related adverse events were nausea (48.8%), fatigue (31.3%), and vomiting (30.0%). Dose-limiting toxicities were reported in eight patients at doses ≥240 mg, including nausea, vomiting, fatigue, hypersensitivity reaction, and hypokalemia. The maximum tolerated dose was determined to be 1200 mg o.d. Mean exposure of AMG 193 increased in a dose-proportional manner from 40 mg to 1200 mg. Among the efficacy-assessable patients treated at the active and tolerable doses of 800 mg o.d., 1200 mg o.d., or 600 mg b.i.d. (n = 42), objective response rate was 21.4% (95% confidence interval 10.3% to 36.8%). Responses were observed across eight different tumor types, including squamous/non-squamous non-small-cell lung cancer, pancreatic adenocarcinoma, and biliary tract cancer. At doses ≥480 mg, complete intratumoral PRMT5 inhibition was confirmed in paired MTAP -deleted tumor biopsies, and molecular responses (circulating tumor DNA clearance) were observed. AMG 193 demonstrated a favorable safety profile without clinically significant myelosuppression. Encouraging antitumor activity across a variety of MTAP -deleted solid tumors was observed based on objective response rate and circulating tumor DNA clearance. [ABSTRACT FROM AUTHOR]

Distant metastases in non-small-cell lung cancer (NSCLC) are a poor prognostic factor that negatively impact quality of life. The central nervous system (CNS) is a common site of distant progression in epidermal growth factor receptor-mutated (EGFR m) NSCLC. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor recommended for advanced EGFR m NSCLC and as adjuvant treatment for resected EGFR m NSCLC. In LAURA (NCT03521154), osimertinib demonstrated statistically significant improvement in progression-free survival (PFS) versus placebo in unresectable stage III EGFR m NSCLC without progression during/following chemoradiotherapy (CRT). CNS efficacy and time to death or distant metastases (TTDM) analyses are reported here. Patients without progression during/following definitive platinum-based CRT were randomised 2 : 1 to receive osimertinib (80 mg daily) or placebo until progression [by blinded independent central review (BICR)] or discontinuation. The primary endpoint was PFS by BICR. CNS PFS by neuroradiologist BICR and TTDM by BICR were secondary endpoints. Overall, 216 patients were randomised (143 osimertinib, 73 placebo). Median CNS PFS by neuroradiologist BICR was not reached [95% confidence interval (CI) not calculable (NC)-NC] with osimertinib versus 14.9 months (95% CI 7.4 months-NC) with placebo; hazard ratio (HR) for CNS PFS: 0.17 (95% CI 0.09-0.32). CNS PFS analysis by investigator assessment was consistent with BICR assessment. The cumulative incidence of CNS progression at 12 months was 9% (95% CI 5% to 14%) with osimertinib and 36% (95% CI 24% to 47%) with placebo. There was clinically meaningful improvement in TTDM with osimertinib versus placebo; HR for TTDM: 0.21 (95% CI 0.11-0.38). The cumulative incidence of distant metastases at 12 months was 11% (95% CI 6% to 17%) with osimertinib and 37% (95% CI 26% to 48%) with placebo. Osimertinib demonstrated clinically meaningful improvements in CNS PFS and TTDM versus placebo, supporting osimertinib post-CRT as the standard of care in unresectable stage III EGFR m NSCLC. • CNS metastases are a poor prognostic factor in NSCLC that can negatively impact clinical outcomes and quality of life. • In LAURA, PFS efficacy was similar regardless of pre-CRT positron emission tomography staging. • Osimertinib protected against CNS progression and distant progression versus placebo. • These findings support osimertinib post-CRT as the new standard of care for unresectable stage III EGFR m NSCLC. [ABSTRACT FROM AUTHOR]

Programmed death receptor ligand 1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden (TMB) are key predictive biomarkers for immune checkpoint inhibitor (ICI) efficacy in non-small-cell lung cancer (NSCLC). Data on their variation across multiple samples are limited. Patients with NSCLC and multiple PD-L1 TPS and/or TMB assessments were included. Clinicopathologic and genomic data were analyzed according to PD-L1 and TMB variation. In total, 402 PD-L1 sample pairs and 413 TMB sample pairs were included. Concordance between pairs was moderate for PD-L1 (ρ = 0.53, P < 0.0001) and high for TMB (ρ = 0.80, P < 0.0001). Shorter time between biopsies correlated with higher concordance in PD-L1, but not in TMB. Major increases (ΔTPS ≥ +50%) and decreases (ΔTPS ≤ −50%) in PD-L1 were observed in 9.7% and 8.0% of cases, respectively. PD-L1, but not TMB, decreased with intervening ICI (P = 0.02). Acquired copy number loss of CD274 , PDCD1LG2 , and JAK2 were associated with major decrease in PD-L1 (q < 0.05). Among patients with multiple PD-L1 assessments before ICI, cases where all samples had a PD-L1 ≥1%, compared to cases with at least one sample with PD-L1 <1% and another with PD-L1 ≥1%, achieved improved objective response rate and progression-free survival (PFS). Among patients with at least one PD-L1 <1% and one ≥1% before ICI, cases where the most proximal sample was PD-L1 ≥1% had longer median PFS compared to cases where the most proximal PD-L1 was <1%. Among patients with multiple TMB assessments before ICI, patients with a TMB ≥10 mut/Mb based on the most recent assessment, as compared to those with a TMB <10 mut/Mb, achieved improved PFS and overall survival to ICI; instead, no differences were observed when patients were categorized using the oldest TMB assessment. Despite intrapatient concordance in PD-L1 and TMB, variation in these biomarkers can influence ICI outcomes, warranting consideration for reassessment before ICI initiation when feasible. • Intrapatient paired PD-L1 TPS and TMB assessments have good concordance. • Variations in PD-L1 TPS and TMB with clinical implications may occur. • Intervening ICI therapy is associated with decrease in PD-L1 TPS. • Copy number loss in CD274 , PDCD1LG2 , and JAK2 genes are strongly associated with major decrease in PD-L1 TPS (−50% to −100%). • Variations in PD-L1 TPS and TMB have significant impact on outcomes to a subsequent ICI-based therapy. [ABSTRACT FROM AUTHOR]

• CircMYBL1 suppressed acquired resistance to osimertinib in non-small-cell lung cancer cells. • The results suggest that circMYBL1 could play an important role in facilitating growth and metastasis in susceptible cells. • In-silico analysis and the results show that the target genes of circMYBL1 are involved in tumor growth and metastasis. Circular RNAs (circRNAs) play an important role in the development of acquired resistance to many anticancer drugs. We developed the Non-Small-Cell Lung Cancer (NSCLC) cell lines with acquired resistance to osimertinib, a third-generation of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and evaluated the different expression profiles of circRNAs in osimertinib-sensitive and -resistant NSCLC cell lines using RNA sequencing (RNA-Seq). The expression of selected differentially expressed circRNAs was verified using quantitative real-time PCR (qRT-PCR) in paired osimertinib-sensitive and -resistant NSCLC cell lines, and in plasma samples of osimertinib-sensitive and -resistant NSCLC patients. We found that circMYBL1(has_circ_0136924) was downregulated after acquired resistance to osimertinib, inhibiting circMYBL1 expression facilitated the proliferation, migration, and invasion in osimertinib-sensitive NSCLC cells. CircMYBL1 may be a novel molecular biomarker and therapeutic target for osimertinib-resistant NSCLC. [ABSTRACT FROM AUTHOR]

Robotic thoracic surgery is a minimally invasive technique that allows the surgeon to perform delicate, accurate surgical manoeuvres within the chest cavity without rib spreading. Previous studies have suggested potential benefits of the robotic platform in nodal upstaging due to its versatility, seven degrees of freedom of movement, and superior vision. However, there is currently a paucity of robust clinical data from Australia. This study aimed to assess the perioperative safety and oncological efficacy of anatomical pulmonary resections performed using the robotic platform. Endpoints included mortality and major morbidity outcomes according to Clavien–Dindo classification and rate of pathological nodal upstaging compared with preoperative imaging using positron emission tomography. A single-surgeon retrospective analysis was performed using data collected from two institutions from July 2021 to May 2022, after ethics committee approval. Consecutive patients who underwent anatomical robotic resections were included in the study, with subsequent analysis of patients who had confirmed primary lung cancer. A total of 52 patients underwent robotic anatomical pulmonary resection during the study period. Safety was demonstrated by 0% mortality and a 9.6% major complication rate, which was related to chest tube insertion for prolonged air leak or intensive care unit monitoring during treatment of atrial arrhythmia. After excluding patients who did not have primary lung cancer, 48 patients remained for further analysis; pathological nodal upstaging was observed in nine (18.8%) of these patients. On multivariate analysis, the total number of lymph nodes harvested was found to be a statistically significant predictor of nodal upstaging. Complete microscopic resection (R0) was achieved in 100% of patients. This study represents the most extensive documentation of robotic thoracic procedures in Australia in the existing literature. It demonstrated a satisfactory safety profile with a relatively high rate of nodal upstaging, possibly reflecting the ability of the robotic instruments to perform comprehensive and complete nodal resection at the time of anatomical pulmonary resection. [ABSTRACT FROM AUTHOR]

We aimed to determine if advanced BRAF -mutant NSCLC has a higher thromboembolic events (TEE) rate than the expected. Between 2008 and 2021, 182 patients with BRAF -mutant advanced NSCLC (BRAF V600E, n = 70; BRAF non-V600E, n = 112) were retrospectively identified from 18 centers in Spain. Patients received chemotherapy (n = 147), immunotherapy (n = 69), targeted therapy (n = 42), and immunotherapy + chemotherapy (n = 26). Incidence rate of TEE was 26.4 % (95%CI: 19.9 %–32.9 %). A total of 72 TEE were documented among 48 patients, as 18 patients (37.5 %) developed more than one event. Median time to TEE onset was 2 months, 69 % of TEE occurred in the peridiagnostic period (+/− 90 days from cancer diagnosis), and in 16 pts. (33 %) TEE was the form of lung cancer presentation. Although most TEE were only venous (82 %; PE, n = 33; DVT, n = 16), arterial events were reported in 31 % and occurred earlier, or TEE presented in atypical locations (13.9 %). TEE were related to high hospitalization rate (59 %), recurrence (23 %), and mortality (10.4 %) despite appropriate anticoagulant/antiaggregant treatment. Median OS in patients without-TEE was 19.4 months (95%CI: 4.6–34.1), and significantly shorter in patients with arterial-TEE vs venous-TEE vs both of them: 9.9 months (95%CI: 0–23.5) vs 41.7 months (95%CI: 11.3–72.2 m) vs 2.7 months (95%CI: 2.1–3.3), p = 0.001. Neither clinical or molecular features (BRAF V600E / non-V600E), nor cancer treatment was associated to TEE occurrence. Khorana score underperformed to predict thrombosis at cancer diagnosis, as only 19.2 % of patients were classified as high-risk. Thrombotic events represent a new clinical feature of BRAF -mutant lung cancer. Patients with almost a 30 % incidence of TEE should be offered systematic anticoagulation. • Patients with BRAF -mutant lung cancer exhibit a high incidence of thrombosis. • Most thrombotic events occur during the peridiagnostic period. • A high percentage of patients experience more than one event. • Patients with thrombosis during the peridiagnostic period have worse survival. [ABSTRACT FROM AUTHOR]

Atezolizumab intravenous (IV) is approved for the treatment of various solid tumours. To improve treatment convenience and health care efficiencies, a coformulation of atezolizumab and recombinant human hyaluronidase PH20 was developed for subcutaneous (SC) use. Part 2 of IMscin001 (NCT03735121) was a randomised phase III, open-label, multicentre, noninferiority study comparing the drug exposure of atezolizumab SC with atezolizumab IV. Eligible patients with locally advanced/metastatic non-small-cell lung cancer were randomised 2 : 1 to receive atezolizumab SC (1875 mg; n = 247) or IV (1200 mg; n = 124) every 3 weeks. The co-primary endpoints were cycle 1 observed trough serum concentration (C trough) and model-predicted area under the curve from days 0 to 21 (AUC 0-21 d). The secondary endpoints were steady-state exposure, efficacy, safety, and immunogenicity. Exposure following atezolizumab SC was then compared with historical atezolizumab IV values across approved indications. The study met both of its co-primary endpoints: cycle 1 observed C trough {SC: 89 μg/ml [coefficient of variation (CV): 43%] versus IV: 85 μg/ml (CV: 33%); geometric mean ratio (GMR), 1.05 [90% confidence interval (CI) 0.88-1.24]} and model-predicted AUC 0-21 d [SC: 2907 μg d/ml (CV: 32%) versus IV: 3328 μg d/ml (CV: 20%); GMR, 0.87 (90% CI 0.83-0.92)]. Progression-free survival [hazard ratio 1.08 (95% CI 0.82-1.41)], objective response rate (SC: 12% versus IV: 10%), and incidence of anti-atezolizumab antibodies (SC: 19.5% versus IV: 13.9%) were similar between arms. No new safety concerns were identified. C trough and AUC 0-21 d for atezolizumab SC were consistent with the other approved atezolizumab IV indications. Compared with IV, atezolizumab SC demonstrated noninferior drug exposure at cycle 1. Efficacy, safety, and immunogenicity were similar between arms and consistent with the known profile for atezolizumab IV. Similar drug exposure and clinical outcomes following SC and IV administration support the use of atezolizumab SC as an alternative to atezolizumab IV. • Atezolizumab SC resulted in noninferior exposure versus atezolizumab IV in patients with NSCLC. • Efficacy, safety, and immunogenicity of atezolizumab SC were similar to atezolizumab IV from IMscin001 and historical data. • Exposure following atezolizumab SC was similar to the exposure seen in other approved clinical studies for atezolizumab IV. • The resulting clinical data support the use of atezolizumab SC as an alternative to atezolizumab IV. [ABSTRACT FROM AUTHOR]

• We report prespecified exploratory analyses of an mNSCLC cohort in China (NEPTUNE). 85 chars. • First-line durvalumab + tremelimumab showed a trend of improved OS vs chemotherapy. 85 chars. • This trend was observed in all patients and those with low tumor PD-L1 expression. 84 chars. • 24-month OS and 12-month PFS rates indicated benefit in the survival curve tails. 83 chars. • Durvalumab + tremelimumab was well tolerated with no new safety signals. 74 chars. The phase 3 NEPTUNE study (NCT02542293) evaluated first-line durvalumab plus tremelimumab (DT) versus chemotherapy for metastatic NSCLC. Prespecified exploratory analyses were conducted in an extended cohort enrolled in China. Patients were randomized (1:1) to DT or standard chemotherapy, stratified by PD-L1 tumor cell (TC) expression (≥25 % vs < 25 %), histology, and smoking history. The primary analysis for this cohort was overall survival (OS) in patients with PD-L1 TC < 1 %. Secondary analyses included OS and progression-free survival (PFS) in the ITT population and PD-L1 subgroups, and safety. No alpha was allocated to these cohort analyses (data cut-off, 21-September-2020). 78 and 82 patients were randomized to DT and chemotherapy, respectively; 26 and 29 had PD-L1 TC < 1 % (median follow-up, 31.2 and 29.7 months [censored patients]). Among patients with PD-L1 TC < 1 %, OS favored DT versus chemotherapy (HR 0.60; 95 % CI, 0.32–1.11), with medians of 15.0 months (95 % CI, 10.5–27.4) and 11.7 months (95 % CI, 8.6–20.5), respectively; 24-month rates were 36.0 % (95 % CI, 18.2–54.2) and 17.9 % (95 % CI, 6.5–33.7). In the ITT population, OS was prolonged with DT versus chemotherapy (HR 0.70; 95 % CI, 0.48–1.02); medians were 20.0 and 14.1 months and 24-month rates were 44.2 % and 30.4 %. PFS was similar in the PD-L1 TC < 1 % (HR 1.13; 95 % CI, 0.59–2.14) and ITT (HR 0.95; 95 % CI, 0.66–1.36) populations; 12-month rates were 15.6 % versus 11.3 % and 23.9 % versus 16.6 %. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 31.2 % with DT and 52.6 % with chemotherapy; 3.9 % versus 10.3 % discontinued due to TRAEs. In exploratory analyses, first-line DT showed a trend towards improved OS versus chemotherapy among Chinese patients in the PD-L1 TC < 1 % population and ITT population, with 24-month OS and 12-month PFS rates indicating benefit in survival curve tails. DT was well tolerated with no new safety signals. [ABSTRACT FROM AUTHOR]

Neutrophils in the tumor microenvironment (TME) are heterogeneous populations associated with cancer prognosis and immunotherapy. However, the plasticity and function of heterogeneous neutrophils in the TME of non-small-cell lung cancer (NSCLC) remain unclear. Here, we show that neutrophils produce high levels of interleukin (IL)-8, which induce the differentiation of CD74highSiglecFlow neutrophils and suppress the generation of CD74lowSiglecFhigh neutrophils in the TME of IL-8-humanized NSCLC mice. The CD74highSiglecFlow neutrophils boost anti-tumor T cell responses via antigen cross-presentation. Deleting CD74 in IL-8-humanized neutrophils impairs T cell activation and exacerbates NSCLC progression, whereas a CD74 agonist enhances T cell activation and the efficacy of anti-programmed cell death 1 (PD-1) or osimertinib therapies. Additionally, the CD74highCD63low neutrophils in the TME and peripheral blood of advanced NSCLC patients phenocopy the CD74highSiglecFlow neutrophils in the TME of NSCLC mice and correlate well with the responsiveness to anti-PD-1 plus chemotherapies. These findings demonstrate an IL-8-CD74high neutrophil axis that promotes anti-tumor immunity in NSCLC. [Display omitted] • IL-8 is upregulated in tumor-infiltrated neutrophils and inhibits NSCLC progression • IL-8 promotes the differentiation of CD74high neutrophils in TME of NSCLC • CD74high neutrophils exhibit strong T cell-stimulating activity • CD74high neutrophils are positively correlated with ICB-based therapy outcome in NSCLC Tang et al. identify a CD74high neutrophil subset driven by IL-8 that promotes anti-tumor immunity and serves as a druggable target and a biomarker for durable responsiveness to ICB-based therapies of advanced NSCLC patients. [ABSTRACT FROM AUTHOR]

Here ginsenoside Rg1 was used to synthesise Rg1 carbon nanodots via a one-step hydrothermal method. The surface of the Rg1 carbon nanodots is rich in hydrophilic functional groups with good water solubility and biocompatibility. The Rg1 carbon nanodots exhibited a high inhibitory effect on the proliferation, migration, and proapoptotic ability of non-small cell lung cancer A549 cells. The changes in the levels of ROS, Ca2+, and MMP in A549 cells after the administration of Rg1 carbon nanodots were evaluated and further correlated with relevant proteins in the caspase apoptotic pathway. Proteomic screening revealed that the Rg1 carbon nanodots could regulate A549 cell apoptosis by activating the expression of MAPK pathway-related proteins. In the in vivo experiment, the therapeutic efficacy of the Rg1 carbon nanodots in inhibiting tumour growth was much higher than that of commonly used chemotherapy drugs, with negligible toxicity and side effects. Immunohistochemical staining showed that the expression of caspase- and MAPK pathway-related proteins in mouse tumour tissues was consistent with that at the cellular level. The results suggest that Rg1 carbon nanodots can promote tumour apoptosis and represent a potential therapeutic agent for human non-small-cell lung cancer. • Rg1-CDs exhibit high inhibitory effects on proliferation, migration, and pro apoptotic ability in lung cancer A549 cells. • Both the caspase pathway and MAPK pathway together effectively promote apoptosis of the A549 cells by Rg1-CDs. • Rg1-CDs exhibit significant anti-tumor activity and extremely low biological toxicity. [ABSTRACT FROM AUTHOR]

• The D-T combination is approved for use in noncomparative phase II trials. • D-T combination therapy has significant efficacy in a real-world setting. • The D-T combination has an acceptable toxicity profile. • BRAF V600E alterations must be included in the panel from diagnosis. BRAF V600E mutations occur in 2–5 % of advanced non-small cell lung cancer (NSCLC) patients. The dabrafenib-trametinib (D-T) combination was associated with improved and durable OS in patients in phase II. This study (IFCT-2004 BLaDE study) reported the efficacy of D-T combination in a large retrospective French real-world multicenter cohort of patients with advanced BRAF V600E-mutated NSCLC. Patients with advanced BRAF V600E-mutated NSCLC diagnosed between 01.01.2016 and 31.12.2019 and treated with D-T in combination, regardless of the treatment line, were included. The primary endpoint was the 12-month OS rate (%) in patients receiving D-T as a second-line therapy or beyond. A total of 163 patients were included: 50.3 % were female, 30.2 % were never smokers, 95.1 % had adenocarcinoma, and 78.2 % had a PDL1 ≥ 1 %. The median age was 68.3 years. At D-T initiation, 80.8 % of patients had a PS of 0/1, 78.6 % had stage IV disease, and 20.9 % had brain metastasis. At the cutoff, the median follow-up was 27.4 months. The 12-month OS rate in patients receiving D + T as a second-line therapy or beyond (n = 119) was 67.4 %, with a median progression-free survival (mPFS) of 10.4 months. Among the 44 patients who received D + T as a first-line therapy, the 12-month OS rate was 67.4 %, with an mPFS of 18.2 months. D-T discontinuation for toxicity was reported in 10.3 % of patients. To our knowledge, this is the largest retrospective cohort of BRAF- mutated patients reported. The findings confirmed the significant efficacy of D-T in combination with BRAF V600E-mutated metastatic NSCLC in pretreated and untreated patients. These results under real-world conditions are consistent with those of other registered studies. [ABSTRACT FROM AUTHOR]

Genomic analysis of circulating tumor DNA (ctDNA) is increasingly incorporated into the clinical management of patients with advanced cancer. Beyond tumor profiling, ctDNA analysis also can enable calculation of circulating tumor fraction (TF), which has previously been found to be prognostic. While most prognostic models in metastatic cancer are tumor type specific and require significant patient-level data, quantification of TF in ctDNA has the potential to serve as a pragmatic, tumor-agnostic prognostic tool. This study utilized a cohort of patients in a nationwide de-identified clinico-genomic database with metastatic castration-resistant prostate cancer (mCRPC), metastatic breast cancer (mBC), advanced non-small-cell lung cancer (aNSCLC), or metastatic colorectal cancer (mCRC) undergoing liquid biopsy testing as part of routine care. TF was calculated based on single-nucleotide polymorphism aneuploidy across the genome. Clinical, disease, laboratory, and treatment data were captured from the electronic health record. Overall survival (OS) was evaluated by TF level while controlling for relevant covariables. A total of 1725 patients were included: 198 mCRPC, 402 mBC, 902 aNSCLC, and 223 mCRC. TF ≥10% was highly correlated with OS in univariable analyses for all cancer types: mCRPC [hazard ratio (HR) 3.3, 95% confidence interval (CI) 2.04-5.34, P < 0.001], mBC (HR 2.4, 95% CI 1.71-3.37, P < 0.001), aNSCLC (HR 1.68, 95% CI 1.34-2.1, P < 0.001), and mCRC (HR 2.11, 95% CI 1.39-3.2, P < 0.001). Multivariable assessments of TF had similar point estimates and CIs, suggesting a consistent and independent association with survival. Exploratory analysis showed that TF remained consistently prognostic across a wide range of cutpoints. Plasma ctDNA TF is a pragmatic, independent prognostic biomarker across four advanced cancers with potential to guide clinical conversations around expected treatment outcomes. With further prospective validation, ctDNA TF could be incorporated into care paradigms to enable precision escalation and de-escalation of cancer therapy based on patient-level tumor biology. • Circulating TF is an independent prognostic factor for most common advanced cancer types in real-world settings. • Prospective interventional validation might enable rational escalation or de-escalation strategies. [ABSTRACT FROM AUTHOR]

• ・Evaluating EMT inhibitors for non-small cell lung cancer in a screening. • ・Selected compounds were confirmed by Western blotting and invasion assays. • ・Four compounds were identified, and two compounds inhibited cell invasiveness. Lung cancer with distant metastases is associated with a very poor prognosis, and epithelial-mesenchymal transition (EMT) contributes to cancer metastasis. Therefore, elucidation and inhibition of EMT signaling in lung cancer may be a new therapeutic strategy for improving the prognosis of patients. We constructed a high-throughput screening system for EMT inhibitors. Using this system, we aimed to identify compounds that indeed inhibit EMT. We generated a luciferase reporter cell line using A549 human lung cancer cells and E-cadherin or vimentin as EMT markers. EMT was induced by transforming growth factor β1 (TGF-β1), and candidate EMT inhibitors were screened from a library of 2,350 compounds. The selected compounds were further tested using secondary assays to verify the inhibition of EMT and invasive capacity of cells. Values obtained by the assay were adjusted for the number of viable cells and scored by determining the difference between mean values of the positive and negative control groups. Four compounds were identified as novel candidate drugs. Among those, one (avagacestat) and two compounds (GDC-0879 and levothyroxine) improved the expression of E-cadherin and vimentin, respectively, in epithelial cells. GDC-0879 and levothyroxine also significantly inhibited the invasive capacity of cells. We systematically screened approved, investigational, and druggable compounds with inhibitory effects using a reporter assay, and identified candidate drugs for EMT inhibition. [ABSTRACT FROM AUTHOR]

• Combination chemotherapy with sugemalimab may be cost-effectiveness. • Cost of sugemalimab has a large impact on Markov model results. • Reshaping first-line treatment of lung cancer with sugemalimab in China. Because of its low immunogenicity and associated risk of toxicity, sugemalimab is expected to reshape the first-line treatment landscape for non-small cell lung cancer (NSCLC) in China. However, it remains unclear whether the use of expensive sugemalimab is cost-effective in this population. A Markov model was constructed based on the GEMSTONE-302 study to assess the efficacy of sugemalimab in combination with chemotherapy for first-line treatment of metastatic NSCLC. Efficacy and safety data were entered, with costs and utility values derived from the literature, and incremental cost-effectiveness ratios (ICERs) were estimated, and univariate sensitivity analyses and probabilistic sensitivity analyses were performed. We also considered cost-effectiveness in two different treatment regimen scenarios after disease progression. Compared with the placebo plus platinum-based chemotherapy, patients with metastatic NSCLC treated with sugemalimab plus platinum-based chemotherapy saw an increase of 0.56 life-years (LYs) and 0.41 quality-adjusted life-years (QALYs), and patients with squamous NSCLC resulted in an ICER per QALY of $45,280.02. Patients with nonsquamous metastatic NSCLC resulted in an ICER of $45,294.15 per QALY. Univariate sensitivity analysis showed that disease-free survival utility had the greatest impact on the results. Probabilistic sensitivity analysis (PSA) showed that when the willingness-to-pay (WTP) for QALYs was $27,354/QALY, sugemalimab, in combination with platinum-based chemotherapy, was more cost-effective than the placebo. From a Chinese health care system perspective, first-line treatment of squamous or nonsquamous metastatic NSCLC with sugemalimab plus platinum-based chemotherapy may have cost-effectiveness compared with placebo plus platinum-based chemotherapy at a WTP threshold of $27,354/QALY. [ABSTRACT FROM AUTHOR]

RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion–positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion–positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion–positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion–positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending. • Pralsetinib produced an ORR of 72% in treatment-naive patients with RET fusion–positive NSCLC. • Pralsetinib was generally well tolerated and there were no new safety signals. • The confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting is ongoing [ABSTRACT FROM AUTHOR]

• This is the largest studies for EGFR E709-T710delinsX in lung cancer. • EGFR E709-T710delinsX accounts for 0.44% of EGFR mutant NSCLC patients and 0.17% in NSCLC patients. • Afatinib might exert superior antitumor activity in EGFR E709-T710delinsX mutant patients. Currently, whether patients with rare epidermal growth factor receptor (EGFR) mutations could benefit from EGFR tyrosine kinase inhibitors (TKIs) demands further studies. Limited clinical data are available regarding the molecular characteristics and clinical response in non-small-cell lung cancer (NSCLC) patients harboring EGFR E709-T710delinsX mutations, a rare mutation type in exon 18 of EGFR. In this study, we aimed to explore the molecular distribution and clinical outcome of EGFR E709-T710delinsX mutated Chinese patients. Next-generation sequencing (NGS) tests were performed in 15,078 NSCLC patients. A multicenter retrospective cohort involving 17 advanced lung cancer patients with EGFR E709-T710delinsX was collected to evaluate clinical responses to diverse therapies. In silico protein structure modeling was conducted to predict drug response. 5905 EGFR mutant patients (39.2%, 5905/15078) were identified, with 26 cases (0.44%, 26/5905) harbored EGFR E709-T710delinsD. Afatinib showed a better overall objective response rate (ORR) compared with the first-generation (1G) EGFR TKIs and chemotherapy with significant difference. Superior progression free survival (PFS) was also observed in patients treated with afatinib (afatinib 10.85 m vs 1G EGFR TKIs 4.0 m vs chemotherapy 2.8 m, p = 0.0007). In silico protein structure modeling predicts better binding of afatinib with EGFR E709-T710delinsD compared with other EGFR TKIs. This is the largest studies for EGFR E709-T710delinsX, with 26 cases with EGFR E709-T710delinsX being identified (0.44% in EGFR mutant NSCLC, 0.17% in NSCLC patients). This study also firstly revealed that afatinib might exert superior antitumor activity to the 1G EGFR TKIs and chemotherapy in EGFR E709-T710delinsX mutant patients. [ABSTRACT FROM AUTHOR]

The TP53 mutation is one of the most common gene mutations in non-small cell lung cancer (NSCLC) and plays a significant role in the occurrence, development, and prognosis of both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Recent studies have also suggested the predictive value of TP53 mutations in the response to immunotherapy for NSCLC. It is known that intratumoral microbiota, tumor immune microenvironment (TIME) and histology are associated with the roles of TP53 mutation in NSCLC. However, the intrinsic associations among these three factors and their underlying interaction with TP53 mutation are not well understood. Additionally, the potential of predicting TP53 mutations using deep learning methods has not yet been fully evaluated. In this paper, we comprehensively evaluated the tissue microbiome, host gene expression characteristics, and histopathological slides of 992 NSCLC patients obtained from the cancer genome atlas (TCGA) and validated the findings using multi-omics data of 332 NSCLC patients from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Compared to LUSC, LUAD exhibited more substantial differences between patients with and without TP53 mutation in all three aspects. In LUAD, our results imply underlying links between the tissue microbiome and immune cell components in the TIME, and show that the abundance of immune cells is reflected in histology slides. Furthermore, we propose a novel multimodal deep learning model that focuses on histopathology images, which achieves an area under the curve (AUC) of 0.84 in LUAD. In summary, TP53 mutation of LUAD resulted more significant changes in intratumoral microbiota, TIME and histology than that of LUSC. And histopathology images can be used to predict TP53 mutation in LUAD with reasonable accuracy. [Display omitted] • Revealing the unique multi-omic variations triggered by TP53 mutations in lung cancer subtypes. • A novel multimodal deep learning model was developed to predict TP53 mutation status. • It offers a new perspective on the interactions between the intratumoral microbiome, tumor microenvironment, and pathology. [ABSTRACT FROM AUTHOR]

• Obesity is known to be associated with improved outcomes in patients with NSCLC treated with ICIs. • In this multicenter retrospective cohort, higher mean glucose correlated with worse overall survival in NSCLC patients treated with ICIs. • Further investigation into the individual components of metabolic syndrome is essential to understand their role as predictive biomarkers. Obesity and hypercholesterolemia have been associated with better responses to ICIs in NSCLC, while type 2 diabetes (T2D) has been associated with a worse response. However, the association between glucose levels and outcomes remains unknown. This study investigated the impact of mean baseline glucose levels, T2D, dyslipidemia, and obesity on overall survival (OS) in NSCLC patients undergoing ICI therapy. A multicenter retrospective cohort study was conducted using data from three medical centers, with locally advanced or metastatic NSCLC patients receiving ICI, regardless of treatment line or concurrent therapy. Random venous glucose levels within 4 weeks prior to ICI initiation, BMI, history of dyslipidemia, and T2D, along with OS, were assessed. Patients with BMI < 18.5 were excluded. Among 438 patients, those with the highest quartile of baseline glucose levels had significantly shorter OS compared to those in the lowest quartile (HR, 1.53; 95 % CI, 1.08 – 2.15; p-value = 0.016). This association remind consistent after adjusting for steroid use, diabetes, performance status and glucose-lowering medication use. These effects were consistently observed in subsets of patients treated with ICI monotherapy and with PD-L1 TPS ≥ 1 %. Higher mean baseline glucose levels correlated with shorter survival in patients with NSCLC treated with ICIs. The divergent effects of individual metabolic syndrome components on ICI response in patients with NSCLC underscore the complexity of metabolic influences on treatment outcomes. [ABSTRACT FROM AUTHOR]

[Display omitted] • Question: What is the association of lifestyle factors with lung cancer for genotypes of the cancer-associated gene GHR ? • Approach: Follow-up study of Japanese-ancestry men. • Findings: For major allele homozygotes only, <2 alcohol drinks/week was associated with reduced lung cancer risk. • Other factors: There was no association of GHR genotype with smoking, BMI, physical activity, green tea, or high fat diet. • Meaning: GHR genotype modulates the association of alcohol with lung cancer risk. To test whether genetic variants of the growth hormone receptor gene (GHR) modulate the effect of lifestyle variables on lung cancer (LC) risk. This population-based cohort study involved 6,439 men from the Japan-Hawaii Cancer study drawn from the Kuakini Honolulu Heart Program who were cancer-free at baseline examination (1965–1968; age 45–68 years) and followed-up until December 1999. We determined the association of GHR SNP rs4130113 genotypes GHR - AA (common allele A homozygotes) and GHR - G (minor allele G carriage) with alcohol drinking, BMI, physical activity and cigarette smoking in relation to LC and non-small cell LC (NSCLC). Results were expressed as hazard ratios and 95 % CIs estimated from Cox proportional hazard models. Over mean 26.7 ± 7.4 SD years follow-up, 190 LC cases, including 133 NSCLC cases, were diagnosed. After adjusting for age, education, alcohol intake, BMI, physical activity, cigarette smoking, green tea consumption and dietary saturated fat, main-effect Cox models showed that compared with GHR - AA , GHR - G was associated with protection against LC: HR = 0.75 (95 % CI, 0.56–1.00). Full Cox models showed GHR - G interacted with alcohol intake only (β = 1.171; p = 0.0003; drinks per week: β = 0.279; P = 0.0024). Stratified analyses showed that for GHR-AA , drinkers had reduced LC risk (HR = 0.54; 95 % CI, 0.35–0.85), and that <2 drinks/week had the strongest protection (HR = 0.38; 95 % CI, 0.18–0.83). In contrast, for GHR - G, alcohol drinkers had increased LC risk (HR = 1.70; 95 % CI, 1.07–2.69) which was dose-dependent (P for trend = 0.005). Results for NSCLC were similar. In men with the GHR - AA genotype, alcohol drinking at a low dose poses significantly less risk of LC compared with non-drinkers and higher alcohol consumption., the overall relationship being U-shaped. In contrast, in GHR minor allele carriers, alcohol posed a progressively greater risk of LC as amount consumed increased. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) plus chemotherapy is now a standard treatment for non-small cell lung cancer (NSCLC). Whether ICI plus chemotherapy (ICI-chemo) or ipilimumab plus nivolumab (I-N)-based therapy is superior for patients with NSCLC with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of 1–49 % has not been evaluated. This multicenter retrospective study included NSCLC patients with a TPS score of 1–49 %, who began first-line chemotherapy. Propensity score matching analysis was used to adjust for various confounders and evaluate treatment efficacy. A total of 401 patients were enrolled, of whom 308 received ICI-chemo and 93 received I-N-based therapy. The median OS was 21.0 months in the ICI-chemo group and 20.0 months in the I-N-based therapy group. After propensity score matching, there was no difference in OS or PFS between the ICI-chemo group and the I-N-based therapy group (OS: hazard ratios (HR), 0.83; 95 % confidence interval [CI], 0.54–1.26, PFS: HR, 0.72; 95 % CI, 0.52–1.00). Among PD-L1 TPS 25–49 %, there was a tendency for OS to be favorable for the ICI-chemo group (OS: HR, 0.30; 95 % CI, 0.09–0.85). Treatment discontinuation occurred for 26.2 % of the patients in the ICI-chemo group and 41.9 % in the I-N-based therapy group. Among PD-L1 TPS 1–49 %, there was no significant difference in survival outcomes between the ICI-chemo group and the I-N-based therapy group. Based on the results of a subgroup analysis, ICI-chemo may be superior for treating NSCLC with a TPS of 25–49 %. • The appropriate regimen for NSCLC with a TPS of 1–49 % is unclear. • Among TPS 1–49 %, the survival outcomes appear similar between both groups. • The toxicity discontinuation rate was higher in the I-N-based therapy group. • ICI-chemo may be superior for treating NSCLC with a TPS of 25–49 %. [ABSTRACT FROM AUTHOR]

Lung carcinoma, particularly non-small-cell lung cancer (NSCLC), accounts for a significant portion of cancer-related deaths, with a fatality rate of approximately 19 %. Niclosamide (NIC), originally an anthelmintic drug, has attracted attention for its potential in disrupting cancer cells through various intracellular signaling pathways. However, its effectiveness is hampered by limited solubility, reducing its bioavailability. This study investigates the efficacy of NIC against lung cancer using inhalable hybrid nano-assemblies with chitosan-functionalized Poly (ε-caprolactone) (PCL) as a carrier for pulmonary delivery. The evaluation encompasses various aspects such as aerodynamic and physicochemical properties, drug release kinetics, cellular uptake, biocompatibility, cell migration, autophagic flux, and apoptotic cell death in A549 lung cancer cells. Increasing NIC dosage correlates with enhanced inhibition of cell proliferation, showing a dose-dependent profile (approximately 75 % inhibition efficiency at 20 μg/mL of NIC). Optimization of inhaled dosage and efficacy is conducted in a murine model of NNK-induced tumor-bearing lung cancer. Following inhalation, NIC-CS-PCL-NA demonstrates significant lung deposition, retention, and metabolic stability. Inhalable nano-assemblies promote autophagy flux and induce apoptotic cell death. Preclinical trials reveal substantial tumor regression with minimal adverse effects, underscoring the potential of inhalable NIC-based nano-formulation as a potent therapeutic approach for NSCLC, offering effective tumor targeting and killing capabilities. [Display omitted] • Inhalable CS-PCL nano-assemblies incorporating Niclosamide-therapy for NSCLC • It demonstrates a dose-dependent anti-proliferative impact on cancer cells. • The formulation exhibited increased autophagy and induction of apoptotic cell death. • Animal studies showed notable tumor regression in mice with minimal side effects. • This Niclosamide nano-formulation shows promise for NSCLC treatment. [ABSTRACT FROM AUTHOR]

• Secondary analysis of the prospective randomized PET-Plan trial in LA-NSCLC. • Number of irradiated lymph node stations is a negative prognostic factor. • Total nodal dose correlates with FFLP in those without elective nodal irradiation. • Effects of radiation on tumor-draining lymph nodes require further investigation. The aim of this secondary analysis of the prospective randomized phase 2 PET-Plan trial (ARO-2009-09; NCT00697333) was to evaluate the impact of mediastinal tumor burden and lymphatic spread in patients with locally advanced non-small-cell lung cancer (NSCLC). All patients treated per protocol (n = 172) were included. Patients received isotoxically dose-escalated chemoradiotherapy up to a total dose of 60–74 Gy in 30–37 fractions, aiming as high as possible while adhering to normal tissue constraints. Radiation treatment (RT) planning was based on an 18F-FDG PET/CT targeting all lymph node (LN) stations containing CT positive LNs (i.e. short axis diameter > 10 mm), even if PET-negative (arm A) or targeting only LN stations containing PET-positive nodes (arm B). LN stations were classified into echelon 1 (ipsilateral hilum), 2 (ipsilateral station 4 and 7), and 3 (rest of the mediastinum, contralateral hilum). The endpoints were overall survival (OS), progression-free survival (PFS), and freedom from local progression (FFLP). The median follow-up time (95 % confidence interval [CI]) was 41.1 (33.8 − 50.4) months. Patients with a high absolute number of PET-positive LN stations had worse OS (hazard ratio [HR] = 1.09; 95 % CI 0.99 − 1.18; p = 0.05) and PFS (HR = 1.12; 95 % CI 1.04 − 1.20; p = 0.003), irrespective of treatment arm allocation. The prescribed RT dose to the LNs did not correlate with any of the endpoints when considering all patients. However, in patients in arm B (i.e., PET-based selective nodal irradiation), prescribed RT dose to each LN station correlated significantly with FFLP (HR=0.45; 95 % CI 0.24–0.85; p = 0.01). Furthermore, patients with involvement of echelon 3 LN stations had worse PFS (HR = 2.22; 95 % CI 1.16–4.28; p = 0.02), also irrespective of allocation. Mediastinal tumor burden and lymphatic involvement patterns influence outcome in patients treated with definitive chemoradiotherapy for locally advanced NSCLC. Higher dose to LNs did not improve OS, but did improve FFLP in patients treated with PET-based dose-escalated RT. [ABSTRACT FROM AUTHOR]

• The 1y-PFS was 38% with Mid-P strategy and 47% with ITV strategy. • Median OS was 24.6 (95%CI 15.0–42.4) months in Mid-P and 16.8 (95%CI 9.2–85.2) months in ITV group, respectively. • Loco-regional failure as first event mostly occurred within radiation-field regardless the strategy. • The lung and esophagus radiation toxicities were similar regardless the margin strategy. • The Mid-P strategy cannot be recommended routinely in LA-NSCLCC treated by definitive conformal RT outside clinical trials. Locally advanced non-small cell lung cancer (LA-NSCLC) reported poor 5-year survival rates with frequent local or regional recurrences. Personalized RT may contribute to improve control and clinical outcome. We investigated efficacy and tolerance of "Mid-position" (Mid-P) strategy versus the conventional Internal Target Volume (ITV) strategy in LA-NSCLC patients treated by definitive conformal radiotherapy. This prospective non-comparative randomized monocentric phase II trial included adult patients with non-resected, non-metastatic, non-previously irradiated proven LA-NSCLC treated with definitive normo-fractionated conformal radiotherapy (+/- chemotherapy). Allocated patients (randomisation 2:1) were treated using Mid-P or ITV strategy. A Fleming single-stage design (1-sided α = 0.1, 80 % power, P0 = 30 %, P1 = 50 %) planned enrolment of 36 patients in the Mid-P group. The ITV group ensured the absence of selection bias. The primary outcome was 1-year progression-free- survival (1y-PFS) rate. Among 54 eligible patients included from September 2012 to May 2018, 51 patients were analyzed (Mid-P: N = 34; ITV: 17). The 1y-PFS was 38 % (1-sided 95 %CI 25 %-not reached) with Mid-P strategy, and 47 % (95 %CI [27 %-not reached[) with ITV. Loco-regional failure as first event mainly occurred within radiation-field regardless the strategy. Acute and middle-term radiation toxicities were observed with both strategies. Local control and survival remain poor using the Mid-P strategy in this prospective randomized non-comparative monocentric study investigating Mid-P strategy versus ITV strategy in LA-NSCLC. Since the Mid-P strategy is not integrated into routine software, and perceived as a time-consuming method, Mid-P strategy cannot be recommended in LA-NSCLCC treated by definitive normo-fractionated conformal radiotherapy outside clinical trials. [ABSTRACT FROM AUTHOR]

In the present study, we aimed to investigate the relationship between metabolic parameters of 18F-fluorodeoxyglucose positron emission computed tomography (18F-FDG PET/CT) and the expression of programmed death ligand-1 (PD-L1), as well as the prognostic value of PD-L1, in patients with surgically resected non-small-cell lung cancer (NSCLC). A total of 169 NSCLC patients who received preoperative 18F-FDG PET were retrospectively enrolled in the present study. The correlation between PD-L1 and patient characteristics was evaluated. Based on the expression of PD-L1 and metabolic parameters, patients were classified into low-, medium-, or high-risk groups. The maximum standardized uptake value (SUV max) and total lesion glycolysis (TLG) were significantly higher in NSCLC patients with high PD-L1 expression compared with the low expression group (P < 0.001 for all). Multivariate analysis revealed that pleural invasion (P < 0.001) and SUV max (P < 0.001) were independent predictors of PD-L1 expression. Survival analysis showed that tumor stage (P = 0.004) and pleural invasion (P = 0.007) were independent prognostic indicators of progression-free survival (PFS). Tumor stage (P = 0.001), TLG (P = 0.039), and PD-L1 expression (P = 0.001) were independent prognostic indicators of overall survival (OS). Patients of the high-risk group with high PD-L1 expression and high TLG had a poor prognosis compared with the low-risk group (P < 0.05) and medium-risk group (P < 0.05). In NSCLC patients, the SUV max of 18F-FDG PET/CT was a predictor of PD-L1 expression. The expression of PD-L1 and TLG were independent prognostic factors of OS. The risk stratification standard based on the PD-L1 expression and TLG provided valuable insights into the development of personalized treatment and follow-up. Registration number:ChiCTR2100051554. • SUV max was a predictor of PD-L1 expression in NSCLC patients. • PD-L1 expression and TLG were associated with prognosis. • Risk stratification standard provided valuable insights into the development of personalized treatment. [ABSTRACT FROM AUTHOR]

• The computational simulation model may be useful for predicting therapeutic effectiveness to BRAF compound mutations. • In addition to the generation of genomic information, the construction of a simulation database is important for establishing personalized medicine, helping prevent missing appropriate therapeutic opportunities in patients with druggable driver mutations. The present study clarified the sensitivity of the BRAF tyrosine kinase inhibitor mechanism in patients with BRAF compound mutation and predicted the sensitivity using molecular dynamics simulation. We examined 16 BRAF tumors with p.V600E-positive non-small-cell lung cancer. One patient (6.2%) had a BRAF p.V600E and p.K601_W604 compound mutation with a good clinical response to dabrafenib and trametinib. Molecular dynamics simulation also complemented the effect. The combination of a genetic analysis and computational simulation model may help predict the sensitivity for dabrafenib in cases with a rare BRAF compound mutation. The construction of a genomic and simulation fused database is important for the development of personalized medicine in this field. [ABSTRACT FROM AUTHOR]

• The ICER of durvalumab consolidation therapy in the US was found to be in the range of $59,850 to $145,543 per QALY. • The ICER of durvalumab in European countries was found to be in the range of $62,021 to $76,068 per QALY. • Durvalumab consolidation therapy was found to be cost-effective versus no consolidation therapy in stage III NSCLC patients. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Recently, Durvalumab was approved as a potential immunotherapy for the management of unresectable stage III NSCLC. Economic studies from different parts of the world presented varying findings. Therefore, the objective of this study was to assess the cost-effectiveness of durvalumab consolidation therapy versus no consolidation therapy in patients with unresectable stage III NSCLC. PubMed, Embase, and Cochrane databases were searched till March 2022 to identify all the studies assessing the economic evaluation of durvalumab in patients with unresectable stage III NSCLC who had not progressed after chemoradiotherapy. Eligible studies were screened by two reviewers independently and the quality of included studies was evaluated using the updated version of Consolidated Health Economic Evaluation Reporting Standards (CHEERS 2022) checklists. All costs were converted to 2022 US dollars ($) by adjusting for the gross domestic product (GDP) deflator index and purchasing power parities for GDP. A total of seven studies were found to be eligible for inclusion. The majority of studies were conducted in the US (n = 3), while one study each was conducted in China, Italy, Switzerland, and the UK. The healthcare payers' perspective was most commonly observed among the included studies and the time horizon varied from 5 years to a lifetime. Three studies received funding from Industry. Four included studies used the Markov model, while two employed the semi-Markov model and, one study used decision-analytic model. The ICER of durvalumab consolidation therapy in the US was found to be in the range of $59,850 to $145,543 per Quality-Adjusted Life Years (QALY). Likewise, the ICER of durvalumab in European countries ranged from $62,021 to $76,068 per QALY. The ICER was below the implemented country-specific willingness-to-pay thresholds in all the included studies. Durvalumab consolidation therapy was found to be cost-effective compared to no consolidation therapy after chemoradiotherapy in stage-III NSCLC patients. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of global cancer-related mortality. Although immune checkpoint therapy has achieved remarkable results in lung cancer, EGFR-mutant or ALK-positive non-smallcell lung cancer patients show limited benefit. Besides the low tumor mutational burden, PD-L1 expression and CD8+ tumor-infiltrating T cells, upregulation of CD73/adenosine pathway also contributes to the immune-inert microenvironment of EGFR-mutant NSCLC. However, the detailed mechanism underlying the regulation of CD73 is unclear. TCGA data was used to analyze the CD73 expression in cancer patients. Western blotting, qPCR, and ChIP-PCR were performed in multiple NSCLC cancer cell lines and patient derived organoids were used to explore the regulation of CD73 expression using western blotting. CD73 expression was highly expressed in multiple cancer types. Pharmacological or genetic inhibition of EGFR, MEK, KRAS, or ALK dramatically reduced the CD73 mRNA and protein expression in NSCLC cancer cells and patient-derived organoids with EGFR mutation, KRAS mutation or ALK-rearrangement. C-Jun overexpression-induced CD73 mRNA and protein expression. ChIP assay showed that c-Jun bind to CD73 genomic regions. Higher CD73 expression in NSCLC cancer cells and patient-derived organoids with EGFR mutation, KRAS mutation or ALK-rearrangement. Mechanistically, CD73 is regulated by ERK-Jun pathway, wherein c-Jun regulates CD73 expression via binding to CD73 genomic regions. • High expression of CD73 is found in EGFR-mutant, KRAS-mutant, and ALK positive NSCLC. • CD73 is regulated by ERK-Jun pathway. • C-Jun binds to CD73 genomic regions. [ABSTRACT FROM AUTHOR]

• We compared immune complex antigens between responders and non-responders for nivolumab therapy. • Combination of immune complex antigens may predict the therapeutic effect of nivolumab. • Immune complexome analysis identifies predictive biomarkers in ICI therapy. Immune checkpoint inhibitors (ICIs) have achieved important outcomes in cancer treatment. However, current clinical biomarker tests are not suitable for some patients because they require tumor tissues and have poor predictive value for treatment responses. Therefore, the identification of biomarkers that enable screening tests in all patients is necessary. We performed an immune complexome analysis of non-small cell lung cancer patients treated with nivolumab to comprehensively identify and compare antigens incorporated into immune complexes (IC-antigens) in serum samples from the responders (n = 15) and non-responders (n = 20). Additionally, combinations of IC-antigens characteristic to the responder group were evaluated by logistic regression analysis and receiver operating characteristics curves to examine their predictiveness for ICI treatment responses. The combination of predictive biomarkers detected before treatment was profilin-1, purine nucleoside phosphorylase, alpha-enolase, and nucleoside diphosphate kinase A [p = 0.0043, odds ratio = 2.26, 95% confidence interval (CI) = 1.19–4.28, area under the curve = 0.76]. The combination of predictive biomarkers detected after treatment was peptidyl-prolyl cis–trans isomerase A, ubiquitin-like modifier-activating enzyme 1, complement component C8 beta chain, and apolipoprotein L1 (p = 0.0039, odds ratio = 2.56, 95% CI = 1.25–5.23, area under the curve = 0.77). Combinations of serum IC-antigens may predict the therapeutic effect of nivolumab in non-small cell lung cancer patients. [ABSTRACT FROM AUTHOR]

The tumour microenvironment reshapes the specific gene expression of regulatory T cells (Tregs). A better definition of Treg subpopulations in the non-small-cell lung cancer (NSCLC) milieu is expected to clarify the identity and functional mode of Tregs and lead to the identification of better therapeutic targets. A total of 53 peripheral blood (PB) samples from 36 NSCLC patients and 17 control subjects and 42 matched bronchoalveolar lavage fluid (BALF) samples from 31 NSCLC patients and 11 control subjects were obtained to examine the frequencies of Treg subgroups through flow cytometry. Fifteen PB samples from healthy individuals were collected to explore the differential functions of Treg subsets. The PB samples of 5 patients after chemotherapy were obtained to evaluate the effect of chemotherapy on Treg subsets. Serum CYFRA 21-1 levels in NSCLC patients were determined using an electrochemiluminescence immunoassay. The proportions of CD4+CD25+FoxP3+ Tregs in both PB and BALF were increased in NSCLC patients compared to controls. In BALF, the TIGIT+, Helios+, and TIGIT+Helios+ Treg subset levels were significantly elevated; the levels of the last two subsets were associated with NSCLC development, while the level of TIGIT-Helios- Tregs was decreased. The proportions of overall Tregs and TIGIT+, Helios+, and Helios+TIGIT+ Tregs were positively correlated with the serum CYFRA 21-1 levels in all patients. Functional differences were observed between Helios+TIGIT+ and Helios-TIGIT- Tregs. After chemotherapy, regardless of the reduction in serum CYFRA 21-1 levels, the proportions of Tregs and Treg subsets did not change. Elevated TIGIT+Helios+ and Helios+ Treg levels may play a role in NSCLC tumour progression, and targeting TIGIT and Helios on Tregs may be an effective treatment for NSCLC. • It is the first time to unveil the function of different Treg subsets in BALF of NSCLC patients. • In NSCLC patients, the changes in Treg subsets in BALF are different from those in PB. • Targeting upregulated TIGIT+ and Helios+ Tregs may be an effective treatment for NSCLC. [ABSTRACT FROM AUTHOR]

Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date. In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, S7681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions). Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and 3 but not in group 1. Based on our findings, we propose a novel nNGM classification of atypical EGFR mutations. • The EGFR-TKI efficacy of in uncommon EGFR mutations generally considered TKI sensitive was validated. • Complex EGFR mutations containing exon19del or L858R were EGFR-TKI sensitive, independent of the combination partner. • Very rare single and complex mutations, comprising 40% of atypical mutations, show a high heterogeneity of TKI sensitivity. • TP53 co-mutations may confer a detrimental outcome in TKI-treated patients with very rare EGFR mutations and exon20ins. • We propose a novel nNGM classification for atypical EGFR mutations. [ABSTRACT FROM AUTHOR]

• Ten metabolites were significantly dysregulated in NSCLC. • 13 (S)-HODE and arachidonic acid could be potential biomarkers for NSCLC. • 13 (S)-HODE and arachidonic acid were associated with the Akt pathway in NSCLC by integrating metabolomics and transcriptomics. Non-small-cell lung cancer (NSCLC) is one of the main types of lung cancer. Due to lack of effective biomarkers for early detection of NSCLC, the therapeutic effect is not ideal. This study aims to reveal potential biomarkers for clinical diagnosis. The plasma metabolic profiles of the patients were characterized by liquid chromatography-mass spectrometry (LC-MS). Differential metabolites were screened by p less than 0.05 and VIP greater than 1. Multivariate statistical analysis was used to search for potential biomarkers. Receiver operating characteristic (ROC) curve was used to evaluate the predictors of potential biomarkers. Pathway enrichment analysis was performed on metabolomics data by Ingenuity Pathway Analysis (IPA) and transcriptomics data from GEO were used for validation. A plasma metabolite biomarker panel including 13(S)-hydroxyoctadecadienoic acid (13(S)-HODE) and arachidonic acid was chose. The area under the ROC curve were 0.917, 0.900 and 0.867 for the panel in the different algorithm like Partial Least Squares Discrimination Analysis (PLS-DA), Support Vector Machine (SVM), Random Forest (RF). The candidate biomarkers were associated with the Akt pathway. Genes involved in the biological pathway had significant changes in the expression levels. 13(S)-HODE and arachidonic acid may be potential biomarkers of NSCLC. The Akt pathway was associated with this biomarker panel in NSCLC. Further studies are needed to clarify the mechanisms of disruption in this pathway. [ABSTRACT FROM AUTHOR]

• Only 30% of advanced lung cancer patients are eligible for immunotherapy trials. • Real-world patients on immunotherapy have shorter survival than trial participants. • Rationalising trial entry criteria doubles the proportion of trial-typical patients. • Novel trials need broader entry criteria to improve their generalizability. Based on data from randomized controlled trials (RCTs), immune checkpoint inhibitors (ICI) are standard-of-care in advanced non-small cell lung cancer (aNSCLC). However, trial eligibility criteria are restrictive, and participants and outcomes may not represent the wider population. We aim to assess the generalizability of key phase III RCTs to real-world patients. Among aNSCLC patients enrolled in the Embedding Research (and Evidence) in Cancer Healthcare (EnRICH) program between 26/6/17–18/2/21, we assessed the proportion of patients who fulfilled key trial eligibility criteria: performance status (PS) 0–1, normal laboratory results, no EGFR/ALK mutations, no exclusionary comorbidities (previous cancer, conditions necessitating steroid use, autoimmune diseases, HIV, hepatitis B/C, tuberculosis, interstitial lung disease, organ transplantation). We defined patients who met all assessed criteria as trial-typical and describe ICI uptake and overall survival (OS). Of 454 patients (median age 71 years, 42.1% female), 30% were trial-typical. Less than half received ICI (47.6%), with trial-typical patients more likely to receive ICI (69.1% vs 38.4%, adjusted odds ratio 3.77, 95% CI 2.40–5.91). Median OS was 10.2 and 5.4 months in patients receiving first- and second-line ICI, respectively. Rationalizing trial criteria to include patients with PS ≤ 2 and exclude those with targetable mutations, steroid use, autoimmune diseases, interstitial lung disease, tuberculosis or organ transplantation increased the proportion of trial-typical patients to 57.3%. Landmark phase III RCTs in aNSCLC have limited generalizability. OS of real-world patients receiving ICI is shorter than reported in trials. Novel ICI trials should consider broader eligibility criteria to improve their generalizability. [ABSTRACT FROM AUTHOR]

• For RECIST1.1, response using reduced number of lesions versus up to five targets was assessed. • Assessing the largest two targets achieved high inter-method concordance. • Reduction in the number of lesions assessed did not affect prediction of OS for immunotherapy. • Measuring the largest two targets could be proposed to reduce the RECIST workload. The Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 provides conventional and standardized response assessment for multiple solid tumors. We investigated the smallest number of target lesions that can be measured without compromising response categorization and survival prediction in patients with advanced non-small-cell lung cancer (aNSCLC) undergoing anti-PD-1/PD-L1 monotherapy. 125 aNSCLC patients with at least two measurable lesions undergoing PD-1/PD-L1 inhibitor treatment were retrospectively studied. Tumor measurements allowing up to two lesions per organ and five lesions in total were reviewed. Inter-individual agreement and κ values for inter-method concordance on response status were evaluated based on up to five target lesions versus the largest one through four lesions. C-index was calculated to evaluate the prognostic accuracy of response categorization based on the selected number of target lesions for predicting overall survival (OS). Cox regression analysis was conducted for survival analysis. The highly consistent response assignment (99.2%) could be obtained when measuring the largest two lesions versus up to five lesions. Using the largest two through four lesions produced κ values of 0.986, 1.000 and 1.000 for response assessment, values significantly higher than those obtained when measuring the largest single lesion (κ = 0.850). C-index for overall survival (OS) was similar when assessing the largest one through five lesions, ranging from 0.646 to 0.654. Cox regression analyses showed that radiological response significantly predicted OS, irrespective of the number of target lesions selected. Reducing the number of target lesions does not affect OS prediction in aNSCLC patients treated with anti-PD-1/PD-L1 therapy. Considering the high intra-individual and inter-method concordance, using the largest two lesions in total is proposed to assess response. [ABSTRACT FROM AUTHOR]

In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab. Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1. Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs–the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs–the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy. Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC. • First-in-human phase 1 study in patients with advanced solid tumors who received vibostolimab alone or with pembrolizumab. • Vibostolimab plus pembrolizumab was well tolerated in advanced solid tumors. • Vibostolimab plus pembrolizumab demonstrated antitumor activity in patients with advanced solid tumors. [ABSTRACT FROM AUTHOR]

Tumour burden (TB) is implicated in resistance to programmed cell death-1/PD-L1 inhibitor (immune checkpoint inhibitor [ICI]) therapy. However, whether TB contributes to such resistance in non-small-cell lung cancer (NSCLC) has remained unknown. A total of 260 treatment-naïve patients with advanced NSCLC who started ICI monotherapy (ICI cohort), platinum-doublet therapy (Chemo cohort) or ICI and platinum-doublet therapy (ICI+Chemo cohort) as first-line treatment were consecutively included. TB was estimated on the basis of the sum of the diameters of measurable target lesions as per Response Evaluation Criteria in Solid Tumours. Progression-free survival (PFS) in the ICI cohort was evaluated as per TB as a preplanned primary objective, with the analysis based on propensity score-weighted survival curves and estimation of restricted mean survival time (RMST). The Chemo cohort served as a control to determine whether TB is predictive of ICI treatment outcomes. The ICI+Chemo cohort was exploratory. The relation of TB to tumour immune status was assessed by immune-related gene expression profiling (irGEP) of pretreatment tumour tissue. In the ICI cohort, patients with a low TB showed a significantly longer PFS than did those with a high TB (median, 17.9 vs 4.3 months; weighted hazard ratio, 0.32 [95% confidence interval, 0.19–0.53]). No such difference was apparent in the other cohorts. A significant difference in overall survival was also observed only in the ICI cohort. RMST-based analysis confirmed these results. The irGEP analysis implicated M2-type macrophages, angiogenesis and transforming growth factor–β as well as protumourigenic signalling pathways in ICI resistance conferred by a high TB. A high TB was associated with a poor outcome of ICI therapy for advanced NSCLC as a result of immunosuppressive phenotypes. Development of combination or novel treatment strategies for such disease is thus warranted. • The relation of NSCLC tumour burden to PD-1/PD-L1 inhibitor efficacy was evaluated. • High tumour burden (HTB) was associated with resistance to ICI monotherapy. • HTB was not associated with treatment outcomes for cytotoxic chemotherapy. • HTB was associated with macrophage-related and protumourigenic gene expression. • Patients with HTB may require more aggressive treatment than ICI monotherapy. [ABSTRACT FROM AUTHOR]

Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor. Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator's choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS). Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T. In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm. • Adjuvant platinum-based chemotherapy is accepted as standard of care in stage II and III (NSCLC) patients. • Several studies addressed the question of whether molecular tumor markers may serve as predictive biomarkers. • ITACA was planned to evaluate the predictive utility of ERCC1 and TS mRNA expression levels in completely resected NSCLC. • ITACA results indicate that adjuvant chemotherapy customization based on ERCC1 and TS mRNA levels did not improve efficacy. • In terms of safety, the pharmacogenomic-driven arm was associated with better efficacy/toxicity ratio. [ABSTRACT FROM AUTHOR]

Osimertinib is the standard of care in the initial treatment for advanced epidermal growth factor receptor (EGFR) mutation–positive lung cancer. However, clinical data and reliable prognostic biomarkers are insufficient. We performed a retrospective multicentre cohort study for 538 EGFR mutation–positive patients, who received osimertinib as the initial treatment between August 2018 and December 2019. The main outcome was progression-free survival (PFS). The median observation period was 14.7 months (interquartile range 11.4–20.0). The median PFS was 20.5 months (95% confidence interval [CI] 18.6−not reached). Multivariate analysis showed that sex (male) (hazard ratio [HR] 1.99, 95% CI 1.35–2.93, P = 0.001), malignant effusions (HR 1.51, 95% CI 1.11–2.04, P = 0.008), liver metastasis (HR 1.55, 95% CI 1.03–2.33, P = 0.037), advanced unresectable cases (HR 1.71, 95% CI, 1.04–2.82, P = 0.036), mutation type and programmed cell death-ligand 1 (PD-L1) expression were associated with PFS. The L858R (HR 1.55, 95% CI 1.01–2.38, P = 0.043) and uncommon mutations (HR 3.15, 95% CI 1.70–5.83, P < 0.001) were associated with PFS. PD-L1 expression of 1–49% (HR 1.66, 95% CI 1.05–2.63, P = 0.029), ≥50% (HR 2.24, 95% CI 1.17–4.30, P = 0.015) and unknown (HR 1.53, 95% CI 1.05–2.22, P = 0.026) was associated with PFS. The main reasons for treatment discontinuation among 219 patients were disease progression (44.3%), pneumonitis (25.5%) and other adverse events (16.0%). During initial treatment with osimertinib, PD-L1 expression is significantly related to PFS. Adverse events are a noteworthy reason for discontinuation. • Osimertinib is standard treatment for advanced EGFR mutation-positive lung cancer. • Clinical data and reliable prognostic biomarkers remain insufficient. • Tumour PD-L1 expression level is associated with progression-free survival. • Adverse events are a common reason for treatment discontinuation. [ABSTRACT FROM AUTHOR]

Disease progression is often considered a binary state reflecting presence or absence of response. Meaningful heterogeneity between metastatic sites of a given patient may exist, however, and may impact therapeutic outcomes. To characterize the heterogeneity of progression with immunotherapy, we evaluated lesion-level dynamics of pembrolizumab-treated patients across three tumor types. Individual metastatic lesion dynamics were analyzed retrospectively in patients with advanced melanoma, non-small-cell lung cancer (NSCLC), and gastric or gastroesophageal junction (G/GEJ) cancer who received pembrolizumab in KEYNOTE-001 or KEYNOTE-059. Primary progression was defined as radiologic progression as per RECIST v1.1 occurring at the first on-treatment study scan (∼9-12 weeks, +2-week window) and secondary progression as progression occurring beyond the first scan (∼14 weeks and beyond). The change in sum of target lesions and of individual lesions was examined, as were patterns and timing of progression. 9239 individual lesions from 1194 patients were analyzed. Among patients with primary progression [39% (200/511) of patients with melanoma, 41% (179/432) with NSCLC, 61% (154/251) with G/GEJ cancer], most patients (51%-63%) had a mixture of growing, stable, and shrinking lesions. Despite overall primary progression, a minority of patients (19%-25%) had tumor growth at every metastatic site and 17%-32% had ≥1 shrinking lesion. Among patients with secondary progression [22% (113/511) of patients with melanoma, 27% (117/432) with NSCLC, 18% (44/251) with G/GEJ cancer], few patients had rebound growth (>20% increase in diameter from nadir) in all lesions whereas the majority (74%-84%) had sustained regression in ≥1 lesion. Lesion-level heterogeneity at the time of disease progression was common in pembrolizumab-treated patients, with many patients demonstrating ongoing disease control in a subset of tumor sites. These results may inform clinical decision-making, trial design, and tumor sampling in the future. • A patient-level approach to assess radiologic progression obscures lesion-level changes, which are commonly heterogeneous. • Size changes in target and non-target lesions were studied in pembrolizumab-treated patients in KEYNOTE-001 and KEYNOTE-059. • Most patients with primary progression in these studies had a mixture of growing, stable, and shrinking lesions. • Few patients with secondary progression had rebound growth in all lesions, and most had sustained regression in ≥1 lesion. • Lesion-level progression heterogeneity was common in pembrolizumab-treated patients with melanoma, NSCLC, or G/GEJ cancer. [ABSTRACT FROM AUTHOR]

Prior antibiotic therapy (pATB) is known to impair efficacy of single-agent immune checkpoint inhibitors (ICIs), potentially through the induction of gut dysbiosis. Whether ATB also affects outcomes to chemo-immunotherapy combinations is still unknown. In this international multicentre study, we evaluated the association between pATB, concurrent ATB (cATB) and overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in patients with non-small-cell lung cancer (NSCLC) treated with first-line chemo-immunotherapy at eight referral institutions. Among 302 patients with stage IV NSCLC, 216 (71.5%) and 61 (20.2%) patients were former and current smokers, respectively. Programmed death-ligand 1 tumour expression in assessable patients (274, 90.7%) was ≥50% in 76 (25.2%), 1%-49% in 84 (27.9%) and <1% in 113 (37.5%). Multivariable analysis showed pATB-exposed patients to have similar OS {hazard ratio (HR) = 1.42 [95% confidence interval (CI): 0.91-2.22]; P = 0.1207} and PFS [HR = 1.12 (95% CI: 0.76-1.63); P = 0.5552], compared to unexposed patients, regardless of performance status. Similarly, no difference with respect to ORR was found across pATB exposure groups (42.6% versus 57.4%, P = 0.1794). No differential effect was found depending on pATB exposure duration (≥7 versus <7 days) and route of administration (intravenous versus oral). Similarly, cATB was not associated with OS [HR = 1.29 (95% CI: 0.91-1.84); P = 0.149] and PFS [HR = 1.20 (95% CI: 0.89-1.63); P = 0.222] when evaluated as time-varying covariate in multivariable analysis. In contrast to what has been reported in patients receiving single-agent ICIs, pATB does not impair clinical outcomes to first-line chemo-immunotherapy of patients with NSCLC. pATB status should integrate currently available clinico-pathologic factors for guiding first-line treatment decisions, whilst there should be no concern in offering cATB during chemo-immunotherapy when needed. [ABSTRACT FROM AUTHOR]

• For stage IB NSCLC patients without LVI and VPI, they might not be a candidate of additional systemic therapy. • Reliable prognostic factors are needed to identify patients in the different risk groups in stage IB NSCLC patients without LVI and VPI. • These tools in this study could be useful in assisting patient counseling and guiding treatment decision making. This study aims to formulate a risk classification system predicting the cancer-specific survival (CSS) for postoperative stage IB NSCLC patients without lymphovascular (LVI) and visceral pleural (VPI) invasion to guide treatment decision making and assist patient counseling. A total of 4,238 patients were included in this study. Patients were randomly divided into training and validation cohorts (7:3). The risk factors were identified by Cox regression. Concordance index (C-index), calibration curves, and Decision Curve Analyses (DCAs) were used to evaluate the performance of nomogram. We applied X-tile to calculate the optimal cut-off points and develop a risk classification system. The Kaplan-Meier method was conducted to evaluate CSS in different risk groups, and the significance was evaluated by log-rank test. Among the 4,238 patients, 1,014(23.9%) suffered cancer-specific death. In the training cohort, univariable and multivariable Cox regression analyses revealed that age, gender, pathological subtype, grade, tumor size, the number of removed lymph nodes and surgical type were significantly associated with CSS. According to these results, the nomogram was formulated. The C-index of the prediction model was 0.755 in the training cohort (95%CI: 0.733–0.777) and 0.726 (95%CI: 0.695–0.757) in the validation cohort. The calibration curves in training and validation cohort exhibited good agreement between the predictions and actual observations. The Decision Curve Analyses (DCAs) showed net benefit can be achieved for nomogram. A risk classification system was further constructed that could perfectly classify patients into three risk groups. In this study, we constructed a nomogram to support individualized evaluation of CSS and a risk classification system to identify patients in the different risk groups in stage IB NSCLC patients without LVI and VPI. These tools could be useful in guiding treatment decision making and assisting patient counseling. [ABSTRACT FROM AUTHOR]

• A retrospective study on older patients with non-small-cell lung cancer was conducted. • Clinical impact of pembrolizumab plus chemotherapy was studied in these patients. • Pembrolizumab combined with platinum and pemetrexed leads to poor clinical outcomes. • Poor performance status and low albumin level were prognostic factors. Combination therapy of immune checkpoint inhibitors and chemotherapy is considered to be one of the standard treatment options for patients with advanced non-small-cell lung cancer (NSCLC). However, the clinical significance of immune checkpoint inhibitors combined with chemotherapy in elderly patients with NSCLC has not yet been fully understood. Therefore, this study aimed to evaluate how aging affects the therapeutic impact of chemotherapy combine with immune checkpoint inhibitors in elderly patients. We retrospectively analyzed 203 patients with advanced NSCLC who were treated with the combination therapy of pembrolizumab and chemotherapy between January 2019 and December 2019 at 12 institutions in Japan. We analyzed the clinical impacts of age on the following two groups: those who received pembrolizumab with platinum and pemetrexed (pemetrexed regimen) and those who received pembrolizumab with carboplatin and nab-paclitaxel/paclitaxel (paclitaxel regimen). Progression-free and overall survival were assessed via the Kaplan-Meier method. Multivariate analysis demonstrated that progression-free and overall survival were significantly shorter in elderly patients (aged ≥75 years) with NSCLC than in non-elderly patients (aged <75 years) with NSCLC in the pemetrexed regimen group. In contrast, there were no significant differences in progression-free and overall survival between elderly patients and non-elderly patients with NSCLC in the paclitaxel regimen group. In elderly patients with NSCLC, a programmed death-ligand 1 tumor proportion score of ≥50% was significantly associated with progression-free survival, and performance status of ≥2 was significantly associated with overall survival. Low albumin level (<3.5 g/dL) was significantly associated with both progression-free and overall survival. The results of this retrospective study show that the pemetrexed regimen, but not the paclitaxel regimen, was related to poor clinical outcomes in elderly patients with NSCLC. [ABSTRACT FROM AUTHOR]

• Patients with relapsed NSQ-NSCLC were included in this phase III trial. • We compared docetaxel plus intercalated erlotinib to docetaxel monotherapy. • Docetaxel plus intercalated erlotinib showed detrimental results. • Combination of docetaxel and intercalated erlotinib should not be explored further. Earlier preclinical and phase II research showed enhanced effect of docetaxel plus intercalated erlotinib. The NVALT-18 phase III study was designed to compare docetaxel with docetaxel plus intercalated erlotinib in relapsed metastasized non-squamous (NSQ) non-small cell lung cancer (NSCLC). Patients with relapsed Epidermal Growth Factor Receptor (EGFR) wild type (WT) NSQ-NSCLC were randomized 1:1 to docetaxel 75 mg/m2 intravenously on day 1 every 21 days (control), or docetaxel 75 mg/m2 intravenously on day 1 plus erlotinib 150 mg/day orally on day 2–16 every 21 days (experimental arm). Progression free survival (PFS) was the primary endpoint, secondary objectives were duration of response, overall survival (OS) and toxicity. Between October 2016 and April 2018 a total of 45 patients were randomized and received treatment in the control (N = 23) or experimental arm (N = 22), the study was stopped due to slow accrual. Median PFS was 4.0 months (95% CI: 1.5–7.1) versus 1.9 months (95% CI 1.4–3.5), p = 0.01 respectively; adjusted hazard ratio (HR) 2.51 (95% CI: 1.16–5.43). Corresponding median OS was 10.6 months (95% CI: 7.0–8.6) versus 4.7 months (95% CI: 3.2–8.6), p = 0.004, with an adjusted HR of 3.67 (95% CI: 1.46–9.27). Toxicity was higher with combination therapy, with toxicity ≥ CTCAE grade 3 in N = 6 (26%) in the control arm and N = 17 (77%) in the experimental arm (p < 0.001), mainly consisting of gastrointestinal symptoms and leukopenia. Our study shows detrimental effects of docetaxel plus intercalated erlotinib, and strongly discourages further exploration of this combination in clinical practice. [ABSTRACT FROM AUTHOR]

A multi-component paclitaxel (PTX) −loaded β -elemene nanoemulsion by transferrin modification (Tf-PE-MEs) was developed to enhance non-small-cell lung cancer (NSCLC) treatment. After transferrin modification, the particle size of Tf-PE-MEs was (14.87 ± 1.84) nm, and the zeta potential was (−10.19 ± 0.870) mV, respectively. In vitro experiments showed that Tf-PE-MEs induced massive apoptosis in A549 cells, indicating that it had significant cytotoxicity to A549 cells. Through transferrin modification, Tf-PE-MEs accumulated at the tumor site efficiently with overexpressed transferrin receptor (TfR) on the surface of A549 cells. This will allow increasing PTX and β -elemene concentration in the target cells, enhancing the therapeutic effect. Compared to PTX alone, Tf-PE-MEs displayed good anti-tumor efficacy and diminished systemic toxicity in vivo studies. With favourable therapeutic potential, this study provides a new strategy for the combined anticancer treatment of non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

Stratification strategies for chemotherapy plus PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) are critically demanded. We performed high-throughput panel-based deep next-generation sequencing and low-pass whole genome sequencing on prospectively collected circulating tumor DNA (ctDNA) specimens from 460 patients in the phase 3 CHOICE-01 study at different time points. We identified predictive markers for chemotherapy plus PD-1 inhibitor, including ctDNA status and genomic features such as blood-based tumor mutational burden, intratumor heterogeneity, and chromosomal instability. Furthermore, we established an integrated ctDNA-based stratification strategy, blood-based genomic immune subtypes (bGIS) scheme, to distinguish patients who benefit from the addition of PD-1 inhibitor to first-line chemotherapy. Moreover, we demonstrated potential applications for the dynamic monitoring of ctDNA. Overall, we proposed a potential therapeutic algorithm based on the ctDNA-based stratification strategy, shedding light on the individualized management of immune-chemotherapies for patients with advanced NSCLC. [Display omitted] • Prospectively collected ctDNA samples from phase 3 RCT on immunochemotherapy for NSCLC • Pretreatment ctDNA negativity generally predicts favorable survival prognosis • bTMB-high, bITH-low, and bCIN-low patients benefit from chemotherapy plus anti-PD-1 • A ctDNA-based genomic-integrated stratification for individualized immunochemotherapy Stratification strategies for chemotherapy plus anti-PD-1 treatment in advanced NSCLC are critically demanded. Xu et al. develop an integrated ctDNA-based stratification strategy based on a phase 3 RCT to distinguish patients benefiting from the addition of PD-1 inhibitor and propose a potential individualized therapeutic mode for patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

• The occurrence of leptomeningeal metastasis can be monitored by fluorescence imaging. • Down-regulation of CEACAM6 can inhibit the migration and invasion of tumor cells. • Non-small-cell lung cancer can be inhibited by efficient delivery of siRNA. Non-small-cell lung cancer (NSCLC), with the most challenging problem of leptomeningeal metastasis (LM), is the most prevalent malignancy worldwide. Our previous research found that carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) serve as a potential biomarker in NSCLC-LM. Which is also a therapeutic target for NSCLC and related to cell migration, invasion, and metastasis. Herein, we first constructed a diagnostic and treatment-integrated Au NPs/DNAzyme/siRNA nanoplatform to detect the CEACAM6 RNA in cerebrospinal fluid and living cells, and inhibit tumor growth by gene therapy. The nanoprobe would be triggered by CEACAM6 RNA and the fluorescence signal would be amplified by DNAzyme cyclic reaction for in-situ imaging. The sensitivity and specificity of Au nanoprobe for the detection of CSF samples were 83.33% and 91.67%, respectively. The delivery of siRNA by Au NPs can enhance its uptake and accumulation by tumor cells, leading to a down-regulation of the CEACAM6 protein and ultimately inhibiting the invasion and migration of tumor cells. Furthermore, this nanoprobe have been effectively implemented for in-situ fluorescence imaging and tumor growth inhibition in mice models. It is undoubted that such a combination nanoplatform would be a promising diagnosis and treatment-integrated strategy for potential biomarker detection and cancer therapy. [ABSTRACT FROM AUTHOR]

We previously reported that combined therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and AXL inhibitor ONO-7475 is effective in preventing the survival of drug-tolerant cells in high-AXL-expressing EGFR-mutated non-small cell lung cancer (NSCLC) cells. Nevertheless, certain residual cells are anticipated to eventually develop acquired resistance to this combination therapy. In this study, we attempted to establish a multidrug combination therapy from the first-line setting to overcome resistance to this combination therapy in high-AXL-expressing EGFR-mutated NSCLC. siRNA screening assay showed that fibroblast growth factor receptor 1 (FGFR1) knockdown induced pronounced inhibition of cell viability in the presence of the osimertinib–ONO-7475 combination, which activates FGFR1 by upregulating FGF2 via the c-Myc pathway. Cell-based assays showed that triple therapy with osimertinib, ONO-7475, and the FGFR inhibitor BGJ398 significantly increased apoptosis by increasing expression of proapoptotic factor Bim and reduced cell viability compared with that observed for the osimertinib–ONO-7475 therapy. Xenograft models showed that triple therapy considerably suppressed tumor regrowth. A novel therapeutic strategy of additional initial FGFR1 inhibition may be highly effective in suppressing the emergence of osimertinib- and ONO-7475-resistant cells. • Osimertinib and ONO-7475 combination is under development for EGFR-mutated NSCLC. • FGF2–FGFR1 axis contributes to adaptive resistance to this combination. • Osimertinib, ONO-7475, and BGJ398 triple therapy suppresses drug-tolerant cells. • It is safe and prevents tumor regrowth in tumor cell-derived xenograft models. [ABSTRACT FROM AUTHOR]