The evolution of non-small cell lung cancer metastases in TRACERx.

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.

Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer.

BACKGROUND: Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 and CD3, showed promising antitumor activity in a phase 1 trial in patients with previously treated small-cell lung cancer. METHODS: In this phase 2 trial, we evaluated the antitumor activity and safety of tarlatamab, administered intravenously every 2 weeks at a dose of 10 mg or 100 mg, in patients with previously treated small-cell lung cancer. The primary end point was objective response (complete or partial response), as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Overall, 220 patients received tarlatamab; patients had previously received a median of two lines of treatment. Among patients evaluated for antitumor activity and survival, the median follow-up was 10.6 months in the 10-mg group and 10.3 months in the 100-mg group. An objective response occurred in 40% (97.5% confidence interval [CI], 29 to 52) of the patients in the 10-mg group and in 32% (97.5% CI, 21 to 44) of those in the 100-mg group. Among patients with an objective response, the duration of response was at least 6 months in 59% (40 of 68 patients). Objective responses at the time of data cutoff were ongoing in 22 of 40 patients (55%) in the 10-mg group and in 16 of 28 patients (57%) in the 100-mg group. The median progression-free survival was 4.9 months (95% CI, 2.9 to 6.7) in the 10-mg group and 3.9 months (95% CI, 2.6 to 4.4) in the 100-mg group; the estimates of overall survival at 9 months were 68% and 66% of patients, respectively. The most common adverse events were cytokine-release syndrome (in 51% of the patients in the 10-mg group and in 61% of those in the 100-mg group), decreased appetite (in 29% and 44%, respectively), and pyrexia (in 35% and 33%). Cytokine-release syndrome occurred primarily during treatment cycle 1, and events in most of the patients were grade 1 or 2 in severity. Grade 3 cytokine-release syndrome occurred less frequently in the 10-mg group (in 1% of the patients) than in the 100-mg group (in 6%). A low percentage of patients (3%) discontinued tarlatamab because of treatment-related adverse events. CONCLUSIONS: Tarlatamab, administered as a 10-mg dose every 2 weeks, showed antitumor activity with durable objective responses and promising survival outcomes in patients with previously treated small-cell lung cancer. No new safety signals were identified. (Funded by Amgen; DeLLphi-301 ClinicalTrials.gov number, NCT05060016.).

A TIAM1-TRIM28 complex mediates epigenetic silencing of protocadherins to promote migration of lung cancer cells.

Lung cancer is the leading cause of cancer deaths. Its high mortality is associated with high metastatic potential. Here, we show that the RAC1-selective guanine nucleotide exchange factor T cell invasion and metastasis-inducing protein 1 (TIAM1) promotes cell migration and invasion in the most common subtype of lung cancer, non-small-cell lung cancer (NSCLC), through an unexpected nuclear function. We show that TIAM1 interacts with TRIM28, a master regulator of gene expression, in the nucleus of NSCLC cells. We reveal that a TIAM1-TRIM28 complex promotes epithelial-to-mesenchymal transition, a phenotypic switch implicated in cell migration and invasion. This occurs through H3K9me3-induced silencing of protocadherins and by decreasing E-cadherin expression, thereby antagonizing cell-cell adhesion. Consistently, TIAM1 or TRIM28 depletion suppresses the migration of NSCLC cells, while migration is restored by the simultaneous depletion of protocadherins. Importantly, high nuclear TIAM1 in clinical specimens is associated with advanced-stage lung adenocarcinoma, decreased patient survival, and inversely correlates with E-cadherin expression.

EGFR/MEK inhibitor therapy induces a distinct inflammatory hair follicle response that includes a collapse of immune privilege.

AIMS: Inhibitors of epidermal growth factor receptor (EGFRi) or mitogen-activated protein kinase (MEKi) induce a folliculitis in 75-90% of patients, whose pathobiology remains insufficiently understood. OBJECTIVES: (1) Characterize changes in the skin immune status and global transcriptional profile of EGFRi-treated patients (2) Probe whether EGFRi affects the hair follicle's (HF) immune privilege (IP) (3) Identify early pro-inflammatory signals induced by EGFRi/MEKi in human scalp HFs ex vivo. METHODS: Scalp biopsies were taken from long-term EGFRi-treated patients exhibiting folliculitis (Chronic-EGFRi, n=9) vs normal scalp skin (n=9) and patients prior to commencing EGFRi therapy and after two weeks of EGFRi therapy (Acute-EGFRi, n=5). Healthy organ-cultured scalp HFs were exposed to EGFRi (Erlotinib) or MEKi (Cobimetinib) (n=5 patients, each). Samples were assessed by quantatitive immunohistomorphometry, RNAseq and in situ hybridization. RESULTS: The Chronic-EGFRi cohort showed CD8+ T cell infiltration of the bulge alongside a partial collapse of the HF's IP, evidenced by upregulated MHC class I, ß2-microglobulin and MHC class II and decreased TGF-ß1 protein expression. Healthy HFs treated with EGFRi/MEKi ex vivo also showed partial HF IP collapse and increased transcription of HLA-A, HLA-DR, ß2-microglobulin transcripts. RNAseq anlysis showed increased transcription of chemokines (CXCL1, CXCL13, CCL18, CCL3, CCL7) and IL-26 in Chronic-EGFRi biopsies, as well as increased interlukin IL-33 and decreased IL-37 expesssion in both Acute-EGFRi biopsies and organ-cultured HFs. CONCLUSION: These data show that EGFRi/MEKi compromise the physiological IP of human scalp HFs and suggest that future clinical management of EGFRi/MEKi-induced folliculitis requires HF IP protection and inhibition of IL-33.

Corrigendum: Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

This corrects the article DOI: 10.1038/nature22364.

REFINE-Lung implements a novel multi-arm randomised trial design to address possible immunotherapy overtreatment.

Increasing evidence suggests that some immunotherapy dosing regimens for patients with advanced cancer could result in overtreatment. Given the high costs of these agents, and important implications for quality of life and toxicity, new approaches are needed to identify and reduce unnecessary treatment. Conventional two-arm non-inferiority designs are inefficient in this context because they require large numbers of patients to explore a single alternative to the standard of care. Here, we discuss the potential problem of overtreatment with anti-PD-1 directed agents in general and introduce REFINE-Lung (NCT05085028), a UK multicentre phase 3 study of reduced frequency pembrolizumab in advanced non-small-cell lung cancer. REFINE-Lung uses a novel multi-arm multi-stage response over continuous interventions (MAMS-ROCI) design to determine the optimal dose frequency of pembrolizumab. Along with a similarly designed basket study of patients with renal cancer and melanoma, REFINE-Lung and the MAMS-ROCI design could contribute to practice-changing advances in patient care and form a template for future immunotherapy optimisation studies across cancer types and indications. This new trial design is applicable to many new or existing agents for which optimisation of dose, frequency, or duration of therapy is desirable.

A cross-sectional analysis of treatment patterns in small-cell lung cancer in five European countries.

Aim: To investigate changes in treatment patterns in extensive-stage small-cell lung cancer (ES-SCLC) in France, Germany, Italy, Spain and the UK (EU5) between 2018 and 2021. Methods: Cross-sectional data from an oncology database were analyzed retrospectively. Results: Of 5832 eligible patients, 88.4% had stage IV disease at diagnosis. Among patients receiving first-line treatment, 91.8% (1079 /1176) received the platinum-etoposide (PE) combination in 2018 which decreased to 42.3% (509/1203) by 2021. Usage of the PE-atezolizumab combination increased from 0 to 41.2% during the same timeframe. Topotecan monotherapy remained the most widely used second-line treatment regardless of patients' platinum sensitivity. Conclusion: The first-line standard of care for ES-SCLC has evolved in EU5 with the PE-atezolizumab/durvalumab combination gradually superseding PE usage.

Lung cancer is the leading cause of cancer-related deaths. Small-cell lung cancer (SCLC) is fast-growing type of lung cancer. New treatments for SCLC using medicines that stimulate the immune system to kill cancer cells (called immunotherapies) have recently been approved for use in Europe. The purpose of the study was to describe the type of treatments that patients received in five European countries before and after the introduction of these new treatments to determine how quickly these new treatments were adopted in a real-world setting. This study found that most patients treated between 2018 and 2020 still received a platinum-based chemotherapy as their first anticancer therapy, but immunotherapies were used more often in later years and became the most common first treatment in 2021 for patients who had never been treated for their cancer. Topotecan, a type of chemotherapy, was the most used treatment for patients whose cancer came back after treatment. There is still a clear unmet need for new, safe and effective therapies for the treatment of patients with SCLC whose cancer comes back again after treatment.

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

Aprepitant for Cough in Lung Cancer. A Randomized Placebo-controlled Trial and Mechanistic Insights.

Rationale: Effective cough treatments are a significant unmet need in patients with lung cancer. Aprepitant is a licensed treatment for nausea and vomiting, which blocks substance P activation of NK-1 (neurokinin 1) receptors, a mechanism also implicated in cough.Objectives: To assess aprepitant in patients with lung cancer with cough and evaluate mechanisms in vagal nerve tissue.Methods: Randomized double-blind crossover trial of patients with lung cancer and bothersome cough. They received 3 days of aprepitant or matched placebo; after a 3-day washout, patients crossed to the alternative treatment. The primary endpoint was awake cough frequency measured at screening and Day 3 of each treatment; secondary endpoints included patient-reported outcomes. In vitro, the depolarization of isolated guinea pig and human vagus nerve sections in grease-gap recording chambers, indicative of sensory nerve activation, was measured to evaluate the mechanism.Measurements and Main Results: Twenty patients with lung cancer enrolled, with a mean age 66 years (±7.7); 60% were female and 80% had non-small cell cancer, 50% had advanced stage, and 55% had World Health Organization performance status 1. Cough frequency improved with aprepitant, reducing by 22.2% (95% confidence interval [CI], 2.8-37.7%) over placebo while awake (P = 0.03), 30.3% (95% CI, 12.7-44.3) over 24 hours (P = 0.002), and 59.8% (95% CI, 15.1-86.0) during sleep (P = 0.081). Patient-reported outcomes all significantly improved. Substance P depolarized both guinea pig and human vagus nerve. Aprepitant significantly inhibited substance P-induced depolarization by 78% in guinea pig (P = 0.0145) and 94% in human vagus (P = 0.0145).Conclusions: Substance P activation of NK-1 receptors appears to be an important mechanism driving cough in lung cancer, and NK-1 antagonists show promise as antitussive therapies.

Large cell neuroendocrine lung carcinoma: consensus statement from The British Thoracic Oncology Group and the Association of Pulmonary Pathologists.

Over the past 10 years, lung cancer clinical and translational research has been characterised by exponential progress, exemplified by the introduction of molecularly targeted therapies, immunotherapy and chemo-immunotherapy combinations to stage III and IV non-small cell lung cancer. Along with squamous and small cell lung cancers, large cell neuroendocrine carcinoma (LCNEC) now represents an area of unmet need, particularly hampered by the lack of an encompassing pathological definition that can facilitate real-world and clinical trial progress. The steps we have proposed in this article represent an iterative and rational path forward towards clinical breakthroughs that can be modelled on success in other lung cancer pathologies.

Validation of ROS1 by immunohistochemistry against fluorescent in situ hybridisation on cytology and small biopsy samples in a large teaching hospital.

OBJECTIVE: Rearranged ROS1, present in 1%-2% of non-small cell lung cancer (NSCLC) patients, usually young, never or light smokers, is assessed by fluorescence in situ hybridization (FISH) to determine eligibility for tyrosine kinase inhibitors (TKI). Immunohistochemistry (IHC) for the protein product of ROS1 rearrangement, a cost-effective alternative, is validated on cytology and small biopsy samples. METHODS: From 1 March to 31 December 2019, cytology cell blocks and small biopsy samples from a selected cohort of NSCLC patients were concurrently tested for ROS1 gene rearrangement by Vysis 6q22 Break Apart FISH probe and IHC using Cell Signalling D4D6 antibody. Mismatch cases were tested by an RNA fusion next generation sequencing (NGS) panel. RESULTS: In a prospective population of 95 cases, 91 were negative and two were positive by both FISH and IHC. Both dual positive cases were female never smokers and benefited from TKI treatment. Another two cases were positive by FISH but negative by IHC and repeat by NGS showed one to be negative but one failed. Turnaround time for IHC was 0 to 8 days from request to authorisation, whilst that of FISH was 9 to 42 days at a cost of £51 and £159 respectively. CONCLUSION: IHC to assess for the protein product of ROS1 gene rearrangement on cytology cell blocks and small biopsy samples in a routine setting is a promising screening method to assess eligibility for TKI treatment with positive and indeterminate cases confirmed by FISH or NGS as it has good negative predictive value, faster turnaround time and is cost effective, with proven technical and clinical validation.

Cumulative Antibiotic Use Significantly Decreases Efficacy of Checkpoint Inhibitors in Patients with Advanced Cancer.

BACKGROUND: With the advent of immunotherapy, substantial progress has been made in improving outcomes for patients with advanced cancer. However, not all patients benefit equally from treatment, and confounding immune-related issues may have an impact. Several studies suggest that antibiotic use (which alters the gut microbiome) may result in poorer outcomes for patients treated with immune checkpoint inhibitors (ICI). MATERIALS AND METHODS: This is a large, single-site retrospective review of n = 291 patients with advanced cancer treated with ICI (n = 179 melanoma, n = 64 non-small cell lung cancer, and n = 48 renal cell carcinoma). Antibiotic use (both single and multiple courses/prolonged use) during the periods 2 weeks before and 6 weeks after ICI treatment was investigated. RESULTS: Within this cohort, 92 patients (32%) received antibiotics. Patients who did not require antibiotics had the longest median progression-free survival (PFS), of 6.3 months, and longest median overall survival (OS), of 21.7 months. With other clinically relevant factors controlled, patients who received a single course of antibiotics had a shorter median OS (median OS, 17.7 months; p = .294), and patients who received multiple courses or prolonged antibiotic treatment had the worst outcomes overall (median OS, 6.3 months; p = .009). Progression-free survival times were similarly affected. CONCLUSION: This large, multivariate analysis demonstrated that antibiotic use is an independent negative predictor of PFS and OS in patients with advanced cancer treated with ICIs. This study highlighted worse treatment outcomes from patients with cumulative (multiple or prolonged courses) antibiotic use, which warrants further investigation and may subsequently inform clinical practice guidelines advocating careful use of antibiotics. IMPLICATIONS FOR PRACTICE: Antibiotic use is negatively associated with treatment outcomes of immune checkpoint inhibitors (ICI) in advanced cancer. Cumulative antibiotic use is associated with a marked negative survival outcome. Judicious antibiotic prescribing is warranted in patients receiving treatment with ICI for treatment of advanced malignancy.

Tracking the Evolution of Non-Small-Cell Lung Cancer.

BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. METHODS: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival. RESULTS: We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10-4), which remained significant in multivariate analysis. CONCLUSIONS: Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).

A cross sectional study to determine the prevalence of cough and its impact in patients with lung cancer: a patient unmet need.

BACKGROUND: There is absence of literature related to cough prevalence and its characteristics in lung cancer patients, with information deriving only from broader symptoms occurrence studies. The aims of this study were to provide a snapshot of the prevalence of all-cause-cough in lung cancer patients and to characterise cough in terms of its impact and severity. METHODS: A cross-sectional study recruiting consecutive lung cancer patients over a pre-defined period of time and using cough-specific validated tools in a tertiary referral centre in the UK, including a cough severity VAS and the Manchester Cough in Lung Cancer scale (MCLCS). RESULTS: Data was collected from 202 patients. All-cause cough prevalence was 57% (through VAS) both in the screened (N = 223) and research (N = 202) population or 67% (through the MCLCS), and cough severity was moderate at a mean of 32 mm (in a 100 mm VAS). Age, sex, smoking status, lung cancer histology, stage and comorbidities were not associated with cough prevalence. The only variable associated with lower cough reports was being 'on anticancer treatment'; fewer patients on treatment reported a cough (40%) compared to those off treatment (54%) (p = 0.04). The impact of cough (as measured by MCLCS) was also significant (mean score = 22). About 18% of patients felt moderate/severe distress from their cough and about 15% often or always reported disturbed sleep due to coughing. Half the patients felt their cough warranted treatment. CONCLUSIONS: Cough is a common symptom in lung cancer with considerable impact on patients' lives. Cough presence and severity should regularly be assessed in clinical practice. There is an urgent need to focus on developing more potent antitussive treatments and improve the management of this complex and distressing symptom.

Reliability and prognostic value of radiomic features are highly dependent on choice of feature extraction platform.

OBJECTIVE: To investigate the effects of Image Biomarker Standardisation Initiative (IBSI) compliance, harmonisation of calculation settings and platform version on the statistical reliability of radiomic features and their corresponding ability to predict clinical outcome. METHODS: The statistical reliability of radiomic features was assessed retrospectively in three clinical datasets (patient numbers: 108 head and neck cancer, 37 small-cell lung cancer, 47 non-small-cell lung cancer). Features were calculated using four platforms (PyRadiomics, LIFEx, CERR and IBEX). PyRadiomics, LIFEx and CERR are IBSI-compliant, whereas IBEX is not. The effects of IBSI compliance, user-defined calculation settings and platform version were assessed by calculating intraclass correlation coefficients and confidence intervals. The influence of platform choice on the relationship between radiomic biomarkers and survival was evaluated using univariable cox regression in the largest dataset. RESULTS: The reliability of radiomic features calculated by the different software platforms was only excellent (ICC > 0.9) for 4/17 radiomic features when comparing all four platforms. Reliability improved to ICC > 0.9 for 15/17 radiomic features when analysis was restricted to the three IBSI-compliant platforms. Failure to harmonise calculation settings resulted in poor reliability, even across the IBSI-compliant platforms. Software platform version also had a marked effect on feature reliability in CERR and LIFEx. Features identified as having significant relationship to survival varied between platforms, as did the direction of hazard ratios. CONCLUSION: IBSI compliance, user-defined calculation settings and choice of platform version all influence the statistical reliability and corresponding performance of prognostic models in radiomics. KEY POINTS: • Reliability of radiomic features varies between feature calculation platforms and with choice of software version. • Image Biomarker Standardisation Initiative (IBSI) compliance improves reliability of radiomic features across platforms, but only when calculation settings are harmonised. • IBSI compliance, user-defined calculation settings and choice of platform version collectively affect the prognostic value of features.

Direct Ras G12C inhibitors: crossing the rubicon.

Despite its status as the most commonly mutated oncogene in cancer, Ras has long been considered 'undruggable'. In 2019, we will see the first clinical trial results for direct mutant Ras inhibitors, a result of persistent cross-disciplinary research that has been informed by a number of previous clinical and biological failures.

Will liquid biopsies improve outcomes for patients with small-cell lung cancer?

Small-cell lung cancer (SCLC) is an aggressive tumour that seeds metastases early with dismal outcomes. As expected from a disease that is closely associated with smoking, mutation burden in SCLC is high. Intratumoral and intertumoral heterogeneity is a substantial obstacle to successful treatment and the SCLC genomic landscape reveals few targets that are readily druggable. Chemotherapy elicits responses in most patients with SCLC, but their effects are short lived. Multiple clinical trials have been unsuccessful in showing positive survival outcomes and biomarkers to select patients and monitor responses to novel targeted treatments have been lacking, not least because acquisition of tumour biopsies, especially during relapse after chemotherapy, is a substantial challenge. Liquid biopsies via blood sampling in SCLC, notably circulating tumour cells and circulating free tumour DNA can be readily and repeatedly accessed, and are beginning to yield promising data to inform SCLC biology and patient treatment. Primary cell cultures and preclinical mouse models can also be derived from the relatively plentiful SCLC circulating tumour cells providing a tractable platform for SCLC translational research and drug development.

Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.

BACKGROUND: Concurrent chemoradiotherapy is the standard of care in limited-stage small-cell lung cancer, but the optimal radiotherapy schedule and dose remains controversial. The aim of this study was to establish a standard chemoradiotherapy treatment regimen in limited-stage small-cell lung cancer. METHODS: The CONVERT trial was an open-label, phase 3, randomised superiority trial. We enrolled adult patients (aged ≥18 years) who had cytologically or histologically confirmed limited-stage small-cell lung cancer, Eastern Cooperative Oncology Group performance status of 0-2, and adequate pulmonary function. Patients were recruited from 73 centres in eight countries. Patients were randomly assigned to receive either 45 Gy radiotherapy in 30 twice-daily fractions of 1·5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin-etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status. Treatment group assignments were not masked. The primary endpoint was overall survival, defined as time from randomisation until death from any cause, analysed by modified intention-to-treat. A 12% higher overall survival at 2 years in the once-daily group versus the twice-daily group was considered to be clinically significant to show superiority of the once-daily regimen. The study is registered with ClinicalTrials.gov (NCT00433563) and is currently in follow-up. FINDINGS: Between April 7, 2008, and Nov 29, 2013, 547 patients were enrolled and randomly assigned to receive twice-daily concurrent chemoradiotherapy (274 patients) or once-daily concurrent chemoradiotherapy (273 patients). Four patients (one in the twice-daily group and three in the once-daily group) did not return their case report forms and were lost to follow-up; these patients were not included in our analyses. At a median follow-up of 45 months (IQR 35-58), median overall survival was 30 months (95% CI 24-34) in the twice-daily group versus 25 months (21-31) in the once-daily group (hazard ratio for death in the once daily group 1·18 [95% CI 0·95-1·45]; p=0·14). 2-year overall survival was 56% (95% CI 50-62) in the twice-daily group and 51% (45-57) in the once-daily group (absolute difference between the treatment groups 5·3% [95% CI -3·2% to 13·7%]). The most common grade 3-4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia (197 [74%] of 266 patients in the twice-daily group vs 170 [65%] of 263 in the once-daily group). Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiotherapy (129 [49%] vs 101 [38%]; p=0·05). In patients assessed for radiotherapy toxicity, was no difference in grade 3-4 oesophagitis between the groups (47 [19%] of 254 patients in the twice-daily group vs 47 [19%] of 246 in the once-daily group; p=0·85) and grade 3-4 radiation pneumonitis (4 [3%] of 254 vs 4 [2%] of 246; p=0·70). 11 patients died from treatment-related causes (three in the twice-daily group and eight in the once-daily group). INTERPRETATION: Survival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting. FUNDING: Cancer Research UK (Clinical Trials Awards and Advisory Committee), French Ministry of Health, Canadian Cancer Society Research Institute, European Organisation for Research and Treatment of Cancer (Cancer Research Fund, Lung Cancer, and Radiation Oncology Groups).

Randomised Phase 2 study of maintenance linsitinib (OSI-906) in combination with erlotinib compared with placebo plus erlotinib after platinum-based chemotherapy in patients with advanced non-small cell lung cancer.

BACKGROUND: Maintenance therapy is important in advanced/metastatic non-small cell lung cancer (NSCLC). Erlotinib as switch maintenance following platinum-based chemotherapy increases survival. Cross-talk between the epidermal growth factor receptor and insulin-like growth factor receptor (IGFR) pathways mediate resistance to individual receptor blockade. This study compared maintenance linsitinib plus erlotinib vs erlotinib plus placebo in patients with NSCLC. METHODS: In this Phase II randomised trial, patients without progression following four cycles of first-line platinum-based chemotherapy (N=205) received continuous schedule maintenance oral linsitinib 150 mg or placebo BID combined with erlotinib 150 mg QD for 21-day cycles. The primary endpoint was progression-free survival (PFS). RESULTS: The study was unblinded early due to linsitinib non-superiority. No difference was found between the two treatment groups in median PFS of 125 days linsitinib vs 129 days placebo (P=0.601); no difference in overall survival (OS) was observed. Tolerability was similar, although in the linsitinib group, treatment-related adverse events and discontinuations were more frequent. No drug-drug interaction was implicated. CONCLUSIONS: Linsitinib maintenance therapy added to erlotinib did not improve PFS or OS in non-progressing NSCLC patients. This highlights the need for robust biomarkers of response for combinations that incorporate IGFR-targeted therapies in maintenance or other therapeutic settings.

SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting.

BACKGROUND: We investigated selumetinib (AZD6244, ARRY-142886), an oral, potent, and highly selective, allosteric MEK1/2 inhibitor, plus platinum-doublet chemotherapy for patients with advanced/metastatic non-small cell lung cancer. METHODS: In this Phase I, open-label study (NCT01809210), treatment-naïve patients received selumetinib (50, 75, 100 mg BID PO) plus standard doses of gemcitabine or pemetrexed plus cisplatin or carboplatin. Primary objectives were safety, tolerability, and determination of recommended Phase II doses. RESULTS: Fifty-five patients received treatment: selumetinib 50 or 75 mg plus gemcitabine/cisplatin (n=10); selumetinib 50 mg plus gemcitabine/carboplatin (n=9); selumetinib 50, 75 or 100 mg plus pemetrexed/carboplatin (n=21); selumetinib 75 mg plus pemetrexed/cisplatin (n=15). Most frequent adverse events (AEs) were fatigue, nausea, diarrhoea and vomiting. Grade ⩾3 selumetinib-related AEs were reported in 30 (55%) patients. Dose-limiting toxicities (all n=1) were Grade 4 anaemia (selumetinib 75 mg plus gemcitabine/cisplatin), Grade 4 thrombocytopenia/epistaxis and Grade 4 thrombocytopenia (selumetinib 50 mg plus gemcitabine/carboplatin), Grade 4 febrile neutropenia (selumetinib 100 mg plus pemetrexed/carboplatin), and Grade 3 lethargy (selumetinib 75 mg plus pemetrexed/cisplatin). Partial responses were confirmed in 11 (20%) and unconfirmed in 9 (16%) patients. CONCLUSIONS: Standard doses of pemetrexed/carboplatin or pemetrexed/cisplatin were tolerated with selumetinib 75 mg BID. The selumetinib plus gemcitabine-containing regimens were not tolerated.