Explore the vast range of titles available.

Treatment for non-small-cell lung cancer is evolving from the use of cytotoxic chemotherapy to personalised treatment based on molecular alterations. This past decade has witnessed substantial progress in the treatment of patients with EGFR mutations and ALK rearrangements, and it is now possible to study complex genomic alterations in cancer using next-generation sequencing. Sequencing data from large-scale consortia, such as The Cancer Genome Atlas, as well as several independent groups, have helped identify novel drivers and potentially targetable alterations in lung adenocarcinomas. These data clearly suggest that lung adenocarcinoma is associated with distinct genomic alterations compared with other lung cancer subtypes, and highlight the widespread molecular heterogeneity that underlies the disease. In this Review, we discuss some of the key findings from genomic studies of lung adenocarcinoma.

The genomic and host factors that drive the progression of pre-invasive lesions in non-small cell lung cancer are poorly understood. Studying these factors can advance our knowledge of lung cancer biology, aid in the development of better screening strategies and improve patient outcomes.

Somatic mutations within non-coding regions and even exons may have unidentified regulatory consequences that are often overlooked in analysis workflows. Here we present RegTools ( www.regtools.org ), a computationally efficient, free, and open-source software package designed to integrate somatic variants from genomic data with splice junctions from bulk or single cell transcriptomic data to identify variants that may cause aberrant splicing. We apply RegTools to over 9000 tumor samples with both tumor DNA and RNA sequence data. RegTools discovers 235,778 events where a splice-associated variant significantly increases the splicing of a particular junction, across 158,200 unique variants and 131,212 unique junctions. To characterize these somatic variants and their associated splice isoforms, we annotate them with the Variant Effect Predictor, SpliceAI, and Genotype-Tissue Expression junction counts and compare our results to other tools that integrate genomic and transcriptomic data. While many events are corroborated by the aforementioned tools, the flexibility of RegTools also allows us to identify splice-associated variants in known cancer drivers, such as TP53 , CDKN2A , and B2M , and other genes. Analysing the regulatory consequences of mutations and splice variants at large scale in cancer requires efficient computational tools. Here, the authors develop RegTools, a software package that can identify splice-associated variants from large-scale genomics and transcriptomics data with efficiency and flexibility.

PurposeVorolanib is a multi-target tyrosine kinase inhibitor with anti-angiogenic properties. This study aimed to evaluate the tolerability, safety and efficacy of vorolanib when added to checkpoint inhibitors (CPIs) in patients with advanced solid tumors.MethodsWe conducted a phase 1b study of vorolanib (300 or 400 mg orally once daily) plus pembrolizumab or nivolumab using a standard 3 + 3 design to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). The endpoints included safety, toxicity and objective response rate, according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1).ResultsSixteen patients (9 in pembrolizumab arm, 7 in nivolumab arm) with gastrointestinal or lung cancers were enrolled. All patients had at least 1 treatment-related adverse event (TRAE). The most common TRAEs across all cohorts were lymphopenia (n = 7), leukopenia (n = 5), fatigue (n = 5), and alanine aminotransferase elevation (n = 5); most toxicities were grade (G) 1–2. DLTs were reported in 3 patients at vorolanib 400 mg dose level, with G3 aspartate aminotransferase elevation, G3 rectal hemorrhage, and G3 rash. Of 13 total response-evaluable patients, 2 patients had confirmed partial responses (1 rectal squamous cell cancer and 1 small cell lung cancer). Two patients achieved prolonged stable disease. Vorolanib 300 mg daily was determined to be the RP2D for either pembrolizumab or nivolumab.ConclusionCombination vorolanib 300 mg orally once daily plus CPI appears to be a feasible regimen with manageable toxicity and promising efficacy in select tumor types. NCT03511222. Date of Registration: April 18, 2018.

As the population of individuals with limited English proficiency (LEP) continues to rise in the United States, language barriers have become an increasingly important yet underrecognized driver of disparities in cancer care. This review aims to synthesize current evidence on how LEP affects the cancer care continuum and to offer actionable strategies to promote equity. We conducted a comprehensive review of the literature spanning communication, diagnosis, treatment, outcomes, prevention, research participation, and policy related to LEP populations in oncology. LEP is associated with poorer cancer outcomes, including delayed diagnosis, lower treatment adherence, decreased access to supportive services, and reduced quality of life. These disparities stem from multilevel communication barriers, underuse of professional interpretation, cultural discordance, and limited institutional support for language-concordant care. LEP patients are also underrepresented in cancer research due to language-based exclusion criteria, inadequate translation resources, and provider burden. A multifaceted framework is needed to address LEP-related disparities in oncology. Key strategies include expanding language-concordant care teams, improving interpreter and translation services, designing inclusive research protocols, and embedding language equity into institutional safety culture and policy. Addressing these disparities is a clinical, ethical, and public health imperative requiring systemic investment and leadership.

BackgroundADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T cells (ADP-A2M10) are genetically engineered autologous T cells that express a high-affinity melanoma-associated antigen A10 (MAGE-A10)-specific T-cell receptor (TCR) targeting MAGE-A10+ tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-003 was a phase I dose-escalation trial that aimed to evaluate the safety and antitumor activity of ADP-A2M10 in non-small cell lung cancer (NSCLC) (NCT02592577).MethodsEligible patients were HLA-A*02 positive with advanced NSCLC expressing MAGE-A10. Patients underwent apheresis; T cells were isolated, transduced with a lentiviral vector containing the TCR targeting MAGE-A10, and expanded. Patients underwent lymphodepletion with varying doses/schedules of fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 were administered at 0.08–0.12×109 (dose group 1), 0.5–1.2×109 (dose group 2), and 1.2–15×109 (dose group 3/expansion) transduced cells.ResultsEleven patients (male, n=6; female, n=5) with NSCLC (adenocarcinoma, n=8; squamous cell carcinoma, n=3) were treated. Five, three, and three patients received cells in dose group 1, dose group 2, and dose group 3/expansion, respectively. The most frequently reported grade ≥3 adverse events were lymphopenia (n=11), leukopenia (n=10), neutropenia (n=8), anemia (n=6), thrombocytopenia (n=5), and hyponatremia (n=5). Three patients presented with cytokine release syndrome (grades 1, 2, and 4, respectively). One patient received the highest dose of lymphodepletion (fludarabine 30 mg/m2 on days –5 to –2 and cyclophosphamide 1800 mg/m2 on days −5 to −4) prior to a second infusion of ADP-A2M10 and had a partial response, subsequently complicated by aplastic anemia and death. Responses included: partial response (after second infusion; one patient), stable disease (four patients), clinical or radiographic progressive disease (five patients), and not evaluable (one patient). ADP-A2M10 were detectable in peripheral blood and in tumor tissue. Peak persistence was higher in patients who received higher doses of ADP-A2M10.ConclusionsADP-A2M10 demonstrated an acceptable safety profile and no evidence of toxicity related to off-target binding or alloreactivity. There was persistence of ADP-A2M10 in peripheral blood as well as ADP-A2M10 trafficking into the tumor. Given the discovery that MAGE-A10 and MAGE-A4 expression frequently overlap, this clinical program closed as trials with SPEAR T cells targeting MAGE-A4 are ongoing.

The optimal treatment paradigm for patients with oligometastatic non-small cell lung cancer (NSCLC) remains unclear. Some patients with oligometastatic disease experience prolonged remission after locally consolidative radiation therapy (RT), while others harbor micrometastatic disease (below limits of detection by imaging) and benefit from systemic therapy. To risk-stratify and identify the patients most likely to benefit from locally consolidative RT, we performed a multi-institutional cohort study of 1487 patients with oligometastatic NSCLC undergoing liquid biopsy analysis of circulating tumor DNA (ctDNA). In total, 1880 liquid biopsies were performed and approximately 20% of patients ( n  = 309) had ctDNA measured prior to RT and after their diagnosis of oligometastatic disease. Patients with undetectable ctDNA (pathogenic or likely pathogenic variants in plasma using the Tempus xF assay) before RT had significantly improved progression-free survival (PFS) ( P  = 0.004) and overall survival (OS) ( P  = 0.030). ctDNA maximum variant allele frequency (VAF) pre-RT and ctDNA mutational burden pre-RT were both significantly inversely correlated with PFS (maximum VAF P  = 0.008, mutational burden P  = 0.003) and OS (maximum VAF P  = 0.007, mutational burden P  = 0.045). These findings were corroborated by multivariate Cox proportional hazards models that included eight additional clinical and genomic parameters. Overall, these data suggest that in patients with oligometastatic NSCLC, pre-RT ctDNA can potentially identify the patients most likely to benefit from locally consolidative RT and experience prolonged PFS and OS. Similarly, ctDNA may be useful to identify undiagnosed micrometastatic disease where it may be appropriate to prioritize systemic therapies.

BackgroundADP-A2M10 SPEAR T-cells are genetically engineered autologous T-cells that express a high affinity MAGE-A10-specific T-cell receptor targeting MAGE-A10+tumors in the context of HLA-A*02. This trial is now complete (NCT02592577).MethodsThis first-in-human dose escalation trial utilized a modified 3+3 design to evaluate safety and antitumor activity. Eligible patients (pts) were HLA-A*02+ with advanced non-small cell lung cancer (NSCLC) expressing MAGE-A10. Pts underwent apheresis; T-cells were isolated, transduced with a lentiviral vector containing the TCR targeting MAGE-A10, and expanded. Pts underwent lymphodepletion (LD) with varying doses/schedules of fludarabine (Flu) and cyclophosphamide (Cy) prior to receiving ADP-A2M10. ADP-A2M10 was administered at Dose Level (DL) 1= 0.1×109, DL2 0.5–1.2×109, and DL3/Expansion= 1.2–15×109 transduced cells.ResultsAs of Jan 10, 2020, 11 pts (6 male/5 female) with NSCLC (3 squamous cell, 7 adenocarcinoma, 1 adenosquamous) were treated. Five, 3 and 3 pts received cells at DL1, DL2, and DL3/Expansion, respectively. The most frequently reported adverse events ≥ Grade 3 were lymphopenia (11), leukopenia (9), neutropenia (8), anemia (6), thrombocytopenia (5), and hyponatremia (5). Three pts reported CRS (Grades 1, 2, and 4, respectively). One pt received the highest dose of LD (Flu 30 mg/m2 Day 1 4 and Cy 1800 mg/m2 Day 1–2) prior to a second infusion and had a partial response (PR). This pt subsequently developed aplastic anemia and died. Responses included: 1 pt – PR, 3 pts - stable disease, 2 pts – progressive disease, 1 pt - too early to determine, 4 pts - off-study prior to tumor assessment. SPEAR T-cells were detectable in peripheral blood from pts at each dose level, and in tumor tissue from pts at DL1 and DL3.ConclusionsADP-A2M10 SPEAR T-cells have shown acceptable safety and no evidence of toxicity related to off-target binding or alloreactivity. Given the minimal antitumor activity and the discovery that MAGE-A10 expression frequently overlaps with MAGE-A4 expression, the clinical program has closed. Several trials with SPEAR T-cells targeting MAGE-A4 are ongoing (https://bit.ly/35htsZK).Trial RegistrationNCT02592577Ethics ApprovalThe trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. All the patients provided written informed consent before study entry.

Nearly all patients with small cell lung cancer (SCLC) eventually relapse with chemoresistant disease. The molecular mechanisms driving chemoresistance in SCLC remain un-characterized. Here, we describe whole-exome sequencing of paired SCLC tumor samples procured at diagnosis and relapse from 12 patients, and unpaired relapse samples from 18 additional patients. Multiple somatic copy number alterations, including gains in ABCC1 and deletions in MYCL, MSH2 , and MSH6 , are identifiable in relapsed samples. Relapse samples also exhibit recurrent mutations and loss of heterozygosity in regulators of WNT signaling, including CHD8 and APC . Analysis of RNA-sequencing data shows enrichment for an ASCL1-low expression subtype and WNT activation in relapse samples. Activation of WNT signaling in chemosensitive human SCLC cell lines through APC knockdown induces chemoresistance. Additionally, in vitro-derived chemoresistant cell lines demonstrate increased WNT activity. Overall, our results suggest WNT signaling activation as a mechanism of chemoresistance in relapsed SCLC. Small cell lung cancer (SCLC) patients frequently relapse and become resistant to chemotherapy. Here, the authors analyse the genomic and transcriptomic landscape of primary and relapsed SCLC patients as well as in vitro models, and discover that activation of WNT signalling can drive chemotherapy resistance.

Assessment of depth of response adequately predicted OS and PFS for patients with metastatic non-small cell lung cancer treated with a targeted therapy or immunotherapy, according to study results. CAROLINE E. MCCOACH, MD, AND COLLEAGUES PERSPECTIVE In this analysis, McCoach and colleagues demonstrate that the depth of overall response with ALK tyrosine kinase inhibitors and PD-1 inhibitors in metastatic NSCLC correlates with improvement in PFS and OS, implying a role for depth of overall response as an alternate and earlier readout of drug efficacy in clinical trials. [...]these results clearly indicate increased survival benefit among patients demonstrating greater than 50% depth of overall response, irrespective of the choice of therapy.