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Small cell lung cancer (SCLC) is an exceptionally lethal malignancy for which more effective therapies are urgently needed. Several lines of evidence, from SCLC primary human tumours, patient-derived xenografts, cancer cell lines and genetically engineered mouse models, appear to be converging on a new model of SCLC subtypes defined by differential expression of four key transcription regulators: achaete-scute homologue 1 (ASCL1; also known as ASH1), neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1) and POU class 2 homeobox 3 (POU2F3). In this Perspectives article, we review and synthesize these recent lines of evidence and propose a working nomenclature for SCLC subtypes defined by relative expression of these four factors. Defining the unique therapeutic vulnerabilities of these subtypes of SCLC should help to focus and accelerate therapeutic research, leading to rationally targeted approaches that may ultimately improve clinical outcomes for patients with this disease.This Opinion, written by many leading experts in small cell lung cancer (SCLC) research, proposes a new model of SCLC subtypes defined by differential expression of four key transcription regulators. Such classification should help to focus and accelerate therapeutic research.

The selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours. Patients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m2 (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov, NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting). Between May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72–85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [<1%] of 260 patients), increased aspartate aminotransferase (two [<1%]), and nausea (two [<1%]). No treatment-related deaths occurred. These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active. Safety data indicate that long-term administration of larotrectinib is feasible. Bayer and Loxo Oncology.

Background Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. RO6870810 is a novel, small-molecule BET inhibitor. Methods We conducted a Phase 1 study of RO6870810 administered subcutaneously for 21 or 14 days of 28- or 21-day cycles, respectively, in patients with the nuclear protein of the testis carcinoma (NC), other solid tumours, or diffuse large B-cell lymphoma (DLBCL) with MYC deregulation. Results Fatigue (42%), decreased appetite (35%) and injection-site erythema (35%) were the most common treatment-related adverse events. Pharmacokinetic parameters demonstrated linearity over the dose range tested and support once-daily dosing. Pharmacodynamic assessments demonstrated sustained decreases in CD11b levels in peripheral blood mononuclear cells. Objective response rates were 25% (2/8), 2% (1/47) and 11% (2/19) for patients with NC, other solid tumours and DLBCL, respectively. Responding tumours had evidence of deregulated MYC expression. Conclusions This trial establishes the safety, favourable pharmacokinetics, evidence of target engagement and preliminary single-agent activity of RO6870810. Responses in patients with NC, other solid tumours and DLBCL provide proof-of-principle for BET inhibition in MYC -driven cancers. The results support further exploration of RO6870810 as monotherapy and in combinations. Clinical trials registration NCT01987362.

Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7–22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2–4·8), and median duration of response was not reached (95% CI 8·31–not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7–10·9). 20 (17%) of 117 patients reported grade 3–4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. Bristol-Myers Squibb.

Purpose: To evaluate the safety, recommended phase II dose (RP2D) and efficacy of pexidartinib, a colony stimulating factor receptor 1 (CSF-1R) inhibitor, in combination with weekly paclitaxel in patients with advanced solid tumors. Patients and Methods: In part 1 of this phase Ib study, 24 patients with advanced solid tumors received escalating doses of pexidartinib with weekly paclitaxel (80 mg/m2). Pexidartinib was administered at 600 mg/day in cohort 1. For subsequent cohorts, the dose was increased by ⩽50% using a standard 3+3 design. In part 2, 30 patients with metastatic solid tumors were enrolled to examine safety, tolerability and efficacy of the RP2D. Pharmacokinetics and biomarkers were also assessed. Results: A total of 51 patients reported ≥1 adverse event(s) (AEs) that were at least possibly related to either study drug. Grade 3–4 AEs, including anemia (26%), neutropenia (22%), lymphopenia (19%), fatigue (15%), and hypertension (11%), were recorded in 38 patients (70%). In part 1, no maximum tolerated dose was achieved and 1600 mg/day was determined to be the RP2D. Of 38 patients evaluable for efficacy, 1 (3%) had complete response, 5 (13%) partial response, 13 (34%) stable disease, and 17 (45%) progressive disease. No drug–drug interactions were found. Plasma CSF-1 levels increased 1.6- to 53-fold, and CD14dim/CD16+ monocyte levels decreased by 57–100%. Conclusions: The combination of pexidartinib and paclitaxel was generally well tolerated. RP2D for pexidartinib was 1600 mg/day. Pexidartinib blocked CSF-1R signaling, indicating potential for mitigating macrophage tumor infiltration.

Small cell lung cancer (SCLC) is characterised by high relapse rates. Tumour-initiating cells (TICs) are responsible for drug resistance and recurrence of cancer. Rovalpituzumab tesirine (Rova-T), a potent humanised antibody–drug conjugate, selectively targets delta-like protein 3, which is highly expressed in SCLC TICs. The experimental drug CBL0137 (CBL) inhibits the histone chaperone FACT (facilitates chromatin transcription), which is required for the expression of transcription factors that are essential for TIC maintenance. Rova-T and CBL each target SCLC TICs as single agents. However, acquired or intrinsic resistance to single agents is a major problem in cancer. Therefore, we investigated the potential effect of combining Rova-T and CBL in SCLC to eradicate TICs more effectively. Our preclinical studies report a novel and highly translatable therapeutic strategy of dual targeting TICs using Rova-T in combination with CBL to potentially increase survival of SCLC patients.

SummaryBackground Tumor-associated macrophages (TAMs) promote tumor growth, metastasis, and therapeutic resistance via colony-stimulating factor-1 (CSF-1), acting through CSF-1 receptor (CSF-1R) signaling. This phase 1 study determined the safety, tolerability, pharmacokinetics-pharmacodynamics, immunogenicity, and efficacy of the anti–CSF-1R antibody LY3022855 in solid tumors. Methods Patients with advanced solid tumors refractory to standard therapy were enrolled and treated in 2 dosing cohorts: weight-based (part A) and non–weight-based (part B). Part A patients were assigned to intravenous (IV) dose-escalation cohorts: 2.5 mg/kg once per week (QW), 0.3 mg/kg QW, 0.6 mg/kg QW, 1.25 mg/kg once every 2 weeks (Q2W) and 1.25 mg/kg QW doses of LY3022855. Non–weight-based doses in part B were 100 mg and 150 mg IV QW. Results Fifty-two patients (mean age 58.6 ± 10.4 years) were treated with ≥1 dose of LY3022855 (range: 4–6). Five dose-limiting toxicities (left ventricular dysfunction, anemia, pancreatitis, rhabdomyolysis, and acute kidney injury) occurred in 4 patients. The non–weight-based 100 mg QW dose was established as the RP2D. The most common treatment-emergent adverse events were increase in liver function variables, fatigue, nausea, vomiting, diarrhea, anorexia, pyrexia, increased lipase, amylase, and lactate dehydrogenase. Clearance decreased with increasing dose and weight-based dosing had minimal effect on pharmacokinetics. Serum CSF-1, and IL-34 levels increased at higher doses and more frequent dosing, whereas TAMs and CD14dimCD16bright levels decreased. Three patients achieved stable disease. No responses were seen. Conclusions LY3022855 was well tolerated and showed dose-dependent pharmacokinetics-pharmacodynamics and limited clinical activity in a heterogenous solid tumor population. ClinicalTrials.gov IDNCT01346358 (Registration Date: May 3, 2011).

BackgroundActivating fusions of the NTRK1, NTRK2 and NTRK3 genes are drivers of carcinogenesis and proliferation across a broad range of tumour types in both adult and paediatric patients. Recently, the FDA granted tumour-agnostic approvals of TRK inhibitors, larotrectinib and entrectinib, based on significant and durable responses in multiple primary tumour types. Unfortunately, testing rates in clinical practice remain quite low. Adding plasma next-generation sequencing of circulating tumour DNA (ctDNA) to tissue-based testing increases the detection rate of oncogenic drivers and demonstrates high concordance with tissue genotyping. However, the clinical potential of ctDNA analysis to identify NTRK fusion-positive tumours has been largely unexplored.MethodsWe retrospectively reviewed a ctDNA database in advanced stage solid tumours for NTRK1 fusions.ResultsNTRK1 fusion events, with nine unique fusion partners, were identified in 37 patients. Of the cases for which clinical data were available, 44% had tissue testing for NTRK1 fusions; the NTRK1 fusion detected by ctDNA was confirmed in tissue in 88% of cases. Here, we report for the first time that minimally-invasive plasma NGS can detect NTRK fusions with a high positive predictive value.ConclusionPlasma ctDNA represents a rapid, non-invasive screening method for this rare genomic target that may improve identification of patients who can benefit from TRK-targeted therapy and potentially identify subsequent on- and off-target resistance mechanisms.

Liquid biopsy is a valuable precision oncology tool that is increasingly used as a non-invasive approach to identify biomarkers, detect resistance mutations, monitor disease burden, and identify early recurrence. The Tempus xF liquid biopsy assay is a 105-gene, hybrid-capture, next-generation sequencing (NGS) assay that detects single-nucleotide variants, insertions/deletions, copy number variants, and chromosomal rearrangements. Here, we present extensive validation studies of the xF assay using reference standards, cell lines, and patient samples that establish high sensitivity, specificity, and accuracy in variant detection. The Tempus xF assay is highly concordant with orthogonal methods, including ddPCR, tumor tissue-based NGS assays, and another commercial plasma-based NGS assay. Using matched samples, we developed a dynamic filtering method to account for germline mutations and clonal hematopoiesis, while significantly decreasing the number of false-positive variants reported. Additionally, we calculated accurate circulating tumor fraction estimates (ctFEs) using the Off-Target Tumor Estimation Routine (OTTER) algorithm for targeted-panel sequencing. In a cohort of 1,000 randomly selected cancer patients who underwent xF testing, we found that ctFEs correlated with disease burden and clinical outcomes. These results highlight the potential of serial testing to monitor treatment efficacy and disease course, providing strong support for incorporating liquid biopsy in the management of patients with advanced disease.

This study developed a novel methodology to correlate genome-scale microRNA (miRNA) expression profiles in a lung squamous cell carcinoma (LUSC) cohort (n = 57) with Surveillance, Epidemiology, and End Results (SEER)-Medicare LUSC patients (n = 33,897) as a function of composite tumor progression indicators of T, N, and M cancer stage and tumor grade. The selected prognostic and chemopredictive miRNAs were extensively validated with miRNA expression profiles of non-small-cell lung cancer (NSCLC) patient samples collected from US hospitals (n = 156) and public consortia including NCI-60, The Cancer Genome Atlas (TCGA; n = 1016), and Cancer Cell Line Encyclopedia (CCLE; n = 117). Hsa-miR-142-3p was associated with good prognosis and chemosensitivity in all the studied datasets. Hsa-miRNA-142-3p target genes (NUP205, RAN, CSE1L, SNRPD1, RPS11, SF3B1, COPA, ARCN1, and SNRNP200) had a significant impact on proliferation in 100% of the tested NSCLC cell lines in CRISPR-Cas9 (n = 78) and RNA interference (RNAi) screening (n = 92). Hsa-miR-142-3p-mediated pathways and functional networks in NSCLC short-term survivors were elucidated. Overall, the approach integrating SEER-Medicare data with comprehensive external validation can identify miRNAs with consistent expression patterns in tumor progression, with potential implications for prognosis and prediction of chemoresponse in large NSCLC patient populations.