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The management of non-small cell lung cancer (NSCLC) has changed significantly with the discovery of specific drug targets. These drugs have helped transform patient care and outcomes. BRAF mutated NSCLC is now recognised as a rare form of lung cancer. Data has begun to emerge supporting the use of BRAF/MEK inhibitors that target BRAF(V600E) mutations in the mitogen-activated protein kinase (MAPK) pathway. Multiple phase 2 studies have been performed assessing the effectiveness of single agent BRAF inhibition and combination BRAF/MEK inhibition in pretreated and untreated patient populations. Consistently overall response rate (ORR) and progression free survival (PFS) are improved with the addition of a MEK inhibitor. A 2-cohort phase 2 study demonstrated an ORR of 33% vs. 67% and PFS of 5.5 vs. 10.2 months in those treated with single agent dabrafenib vs. dabrafenib and trametinib respectively. A similar ORR of 63% and PFS of 10.9 months was seen in a separate phase 2 study in patients treated with Dabrafenib and Trametinib in the first line setting. Immunotherapy is beginning to show promise as an active therapy in BRAF mutated NSCLC in both V600E and non-V600E subtypes; however, this requires further study and clarification. BRAF(V600E) mutated NSCLC treated with chemotherapy have been widely reported to be associated with worse outcomes when compared to those without a mutation. With efficacy of combination BRAF/MEK established and early evidence of immune checkpoint inhibitor activity careful consideration should be given when choosing the most appropriate therapy in this select patient cohort.

Background: Studies suggest that combining radiotherapy (RT) with programmed cell death protein 1 (PD-1) blockade may elicit a synergistic antitumor response. We aimed to assess whether prior or concurrent RT was associated with improved disease control in patients with metastatic non-small cell lung cancer (NSCLC) treated with nivolumab. Methods: We conducted a retrospective study of patients receiving nivolumab as second or subsequent line therapy for metastatic NSCLC. Patients were categorized into those who received any RT for NSCLC prior to or during nivolumab therapy, and those with no history of RT for NSCLC. Results: A total of 85 patients received nivolumab between July 2015 and December 2016 and were followed up for a median of 15 months. Sixty-five patients (76.4%) received RT prior to or during nivolumab and 20 patients (23.6%) received nivolumab alone. Baseline characteristics of age, performance status, histology, smoking status and previous therapy were similar between the two groups. Prior or concurrent RT was associated with a superior PFS, median 2.8 months with RT versus 1.3 months without RT (Hazard Ratio (HR) = 0.494; 95% Confidence Interval (CI), 0.279-0.873; P = 0.02). The median OS of the group receiving RT was 6.4 months versus 4.2 months for the no RT group (P = 0.20). RT was not associated with an increase in toxicity. Conclusion: RT prior to or concurrent with nivolumab for metastatic NSCLC was associated with a modest improvement in PFS over nivolumab alone with no evidence of increase in adverse effects. RT may potentiate the effect of anti-PD-1 immunotherapy in NSCLC.

Objectives The majority of patients with non-small cell lung cancer (NSCLC) present with advanced stage disease, at which time chemotherapy is usually the most common treatment option. While somewhat effective, patients treated with platinum-based regimens will eventually develop resistance, with others presenting with intrinsic resistance. Multiple pathways have been implicated in chemo-resistance, however the critical underlying mechanisms have yet to be elucidated. The aim of this project was to determine the role of inflammatory mediators in cisplatin-resistance in NSCLC. Materials and methods Inflammatory mediator, NF-κB, and its associated pathways were investigated in an isogenic model of cisplatin-resistant NSCLC using age-matched parental (PT) and corresponding cisplatin-resistant (CisR) sublines. Pathways were assessed using mass spectrometry, western blot analysis and qRT-PCR. The cisplatin sensitizing potential of an NF-κB small molecule inhibitor, DHMEQ, was also assessed by means of viability assays and western blot analysis. Results Proteomic analysis identified dysregulated NF-κB responsive targets in CisR cells when compared to PT cells, with increased NF-κB expression identified in four out of the five NSCLC sub-types examined (CisR versus PT). DHMEQ treatment resulted in reduced NF-κB expression in the presence of cisplatin, and re-sensitized CisR cells to the cytotoxic effects of the drug. Conclusion This study identified NF-ĸB as a potential therapeutic target in cisplatin-resistant NSCLC. Furthermore, inhibition of NF-ĸB using DHMEQ re-sensitized chemo-resistant cells to cisplatin treatment.

PURPOSE CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non–small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients. CONCLUSION Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.

Chemotherapy is used as a standard-of-care against cancers that display high levels of inherent genome instability. Chemotherapy induces DNA damage and intensifies pressure on the DNA repair pathways that can lead to deregulation. There is an urgent clinical need to be able to track the emergence of DNA repair driven chemotherapy resistance and tailor patient staging appropriately. There have been numerous studies into chemoresistance but to date no study has elucidated in detail the roles of the key DNA repair components in resistance associated with the frontline clinical combination of anthracyclines and taxanes together. In this study, we hypothesized that the emergence of chemotherapy resistance in triple negative breast cancer was driven by changes in functional signaling in the DNA repair pathways. We identified that consistent pressure on the non-homologous end joining pathway in the presence of genome instability causes failure of the key kinase DNA-PK, loss of p53 and compensation by p73. In-turn a switch to reliance on the homologous recombination pathway and RAD51 recombinase occurred to repair residual double strand DNA breaks. Further we demonstrate that RAD51 is an actionable target for resensitization to chemotherapy in resistant cells with a matched gene expression profile of resistance highlighted by homologous recombination in clinical samples.

Non-small cell lung cancer (NSCLC) is one of the most common cancers globally and has a 5-year survival rate ~20%. Immunotherapies have demonstrated long-term and durable responses in NSCLC patients, although they appear to be effective in only a subset of patients. A more comprehensive understanding of the underlying tumour biology may contribute to identifying those patients likely to achieve optimal outcomes. Profiling the tumour microenvironment (TME) has shown to be beneficial in addressing fundamental tumour-immune cell interactions. Advances in multiplexing immunohistochemistry and molecular barcoding has led to recent advances in profiling genes and proteins in NSCLC. Here, we review the recent advancements in spatial profiling technologies for the analysis of NSCLC tissue samples to gain new insights and therapeutic options for NSCLC. The combination of spatial transcriptomics combined with advanced imaging is likely to lead to deep insights into NSCLC tissue biology, which can be a powerful tool to predict likelihood of response to therapy.

Background In the absence of targetable mutations or immune checkpoints, cisplatin-doublet chemotherapy remains the standard of care in non-small cell lung cancer (NSCLC). Drug resistance has however become a significant clinical challenge. Exploring a role for small non-coding microRNAs (miRNA) as biomarker candidates in cisplatin resistant (CisR) lung cancer is lacking and warrants further investigation. Methods miRNA expression profiling was assessed in a panel of cisplatin sensitive and resistant NSCLC cell lines and validated by qPCR. Modulation of altered miRNAs was studied using antagomiRs and pre-miRs while functional assays were used to assess cisplatin response. The translational relevance of these miRNAs as potential biomarkers was assessed in serum and matched normal and tumour lung tissues from chemo-naive NSCLC patients, in addition to xenograft formalin-fixed paraffin-embedded (FFPE) tumours derived from cisplatin sensitive and resistant cell lines. Results Differential expression of a 5-miR signature (miR-30a-3p, miR-30b-5p, miR-30c-5p, miR-34a-5p, miR-4286) demonstrated their ability to distinguish between normal and tumour lung tissue and between NSCLC histologies. In squamous cell carcinoma (SqCC), tissue miRNA expression was associated with poor survival. miR-4286 showed promise as a blood-based diagnostic biomarker that could distinguish between adenocarcinoma and SqCC histologies. In a xenograft model of cisplatin resistance, using 7-9 week old female NOD/SCID mice (NOD.CB17-Prkdcscid/NCrCrl), a 5-miRNA panel showed altered expression between sensitive and resistant tumours. Conclusions This study identified a panel of miRNAs which may have diagnostic and prognostic potential as novel biomarkers in lung cancer and furthermore, may have a predictive role in monitoring the emergence of resistance to cisplatin.

Platinum-based chemotherapy remains the cornerstone of treatment for most non-small cell lung cancer (NSCLC) cases either as maintenance therapy or in combination with immunotherapy. However, resistance remains a primary issue. Our findings point to the possibility of exploiting levels of cell division cycle associated protein-3 (CDCA3) to improve response of NSCLC tumours to therapy. We demonstrate that in patients and in vitro analyses, CDCA3 levels correlate with measures of genome instability and platinum sensitivity, whereby CDCA3high tumours are sensitive to cisplatin and carboplatin. In NSCLC, CDCA3 protein levels are regulated by the ubiquitin ligase APC/C and cofactor Cdh1. Here, we identified that the degradation of CDCA3 is modulated by activity of casein kinase 2 (CK2) which promotes an interaction between CDCA3 and Cdh1. Supporting this, pharmacological inhibition of CK2 with CX-4945 disrupts CDCA3 degradation, elevating CDCA3 levels and increasing sensitivity to platinum agents. We propose that combining CK2 inhibitors with platinum-based chemotherapy could enhance platinum efficacy in CDCA3low NSCLC tumours and benefit patients., Kildey et al find that high levels of mitotic regulator CDCA3 correlates with sensitivity to platinum agents in non-small cell lung cancer patients and cell lines. They show that interfering with CDCA3 degradation through CK2 inhibition enhances CDCA3 levels and increases sensitivity to platinum agents suggesting a therapeutic route.

Simple Summary PIM kinases interact with major oncogenic players, including the PI3K/Akt pathway, and provide an escape mechanism leading to drug resistance. This study examined PIM kinase expression in NSCLC and the potential of PIM1 as a prognostic marker. The effect on cell signaling of novel preclinical PI3K/mTOR/PIM kinase inhibitor IBL-301 was compared to PI3K/mTOR inhibition in vitro and ex vivo. PI3K-mTOR inhibitor sensitive (H1975P) and resistant (H1975GR) cells were compared for altered IL6/STAT3 pathway expression and sensitivity to IBL-301. All three PIM kinases are expressed in NSCLC and PIM1 is a marker of poor prognosis. IBL-301 inhibited c-Myc, the PI3K-Akt and JAK/STAT pathways in vitro and in NSCLC tumor tissue explants. IBL-301 also inhibited secreted pro-inflammatory cytokine MCP-1. PIM kinases were activated in H1975GR cells which were more sensitive to IBL-301 than H1975P cells. A miRNA signature of PI3K-mTOR resistance was validated. Co-targeting PIM kinase and PI3K-mTOR warrants further clinical investigation. Abstract PIM kinases are constitutively active proto-oncogenic serine/threonine kinases that play a role in cell cycle progression, metabolism, inflammation and drug resistance. PIM kinases interact with and stabilize p53, c-Myc and parallel signaling pathway PI3K/Akt. This study evaluated PIM kinase expression in NSCLC and in response to PI3K/mTOR inhibition. It investigated a novel preclinical PI3K/mTOR/PIM inhibitor (IBL-301) in vitro and in patient-derived NSCLC tumor tissues. Western blot analysis confirmed PIM1, PIM2 and PIM3 are expressed in NSCLC cell lines and PIM1 is a marker of poor prognosis in patients with NSCLC. IBL-301 decreased PIM1, c-Myc, pBAD and p4EBP1 (Thr37/46) and peIF4B (S406) protein levels in-vitro and MAP kinase, PI3K-Akt and JAK/STAT pathways in tumor tissue explants. IBL-301 significantly decreased secreted pro-inflammatory cytokine MCP-1. Altered mRNA expression, including activated PIM kinase and c-Myc, was identified in Apitolisib resistant cells (H1975GR) by an IL-6/STAT3 pathway array and validated by Western blot. H1975GR cells were more sensitive to IBL-301 than parent cells. A miRNA array identified a dysregulated miRNA signature of PI3K/mTOR drug resistance consisting of regulators of PIM kinase and c-Myc (miR17-5p, miR19b-3p, miR20a-5p, miR15b-5p, miR203a, miR-206). Our data provides a rationale for co-targeting PIM kinase and PI3K-mTOR to improve therapeutic response in NSCLC.

Genomic stability is critical for normal cellular function and its deregulation is a universal hallmark of cancer. Here we outline a previously undescribed role of COMMD4 in maintaining genomic stability, by regulation of chromatin remodelling at sites of DNA double-strand breaks. At break-sites, COMMD4 binds to and protects histone H2B from monoubiquitination by RNF20/RNF40. DNA damage-induced phosphorylation of the H2A-H2B heterodimer disrupts the dimer allowing COMMD4 to preferentially bind H2A. Displacement of COMMD4 from H2B allows RNF20/40 to monoubiquitinate H2B and for remodelling of the break-site. Consistent with this critical function, COMMD4-deficient cells show excessive elongation of remodelled chromatin and failure of both non-homologous-end-joining and homologous recombination. We present peptide-mapping and mutagenesis data for the potential molecular mechanisms governing COMMD4-mediated chromatin regulation at DNA double-strand breaks., Amila Suraweera et al. use a range of biochemical and in vitro cellular assays to examine the role of the COMMD4 in DNA repair. Their results suggest that COMMD4 interacts with the histone H2A-H2B during repair of double-stranded DNA breaks, thereby maintaining genomic stability by regulating chromatin structure.

Purpose/Objective(s) Synergy and abscopal phenomena have been observed with radiation and immunotherapy in pre-clinical and early clinical studies. Nivolumab, a PD-1 receptor antibody, improved overall survival in advanced NSCLC progressing after chemotherapy. We hypothesized that the addition of SABR might increase the activity of nivolumab. The aim of NIVORAD was to determine the activity and safety of treating a site of disease with a single fraction of SABR during therapy with nivolumab in advanced NSCLC progressing after 1 or 2 lines of chemotherapy. Materials/Methods Adults with metastatic NSCLC progressing after 1 or 2 lines of chemotherapy and a disease site suitable for SABR were randomly assigned (2:1) to either nivolumab 240mg 2-weekly until disease progression or prohibitive toxicity given together with a single fraction of SABR (18-20 Gy on day 8-14 of cycle 1); or, the same regimen of nivolumab without SABR. The primary endpoint was progression-free survival (PFS) at 6 months. Secondary endpoints included objective tumor response rate (OTRR), overall survival (OS), PFS at 1 year and 2 years, and adverse events (AEs). The planned sample size of 120 provided 80% power with a 1-sided type 1 error rate of 5% to distinguish the observed proportions alive and progression free at 6 months from benchmarks of 50% (worthy of pursuit) versus 35%. The study was closed early because of slow accrual. Results Fifty of the planned 120 participants were recruited from MAR2017 to JUN2019 (median age 66 years; male 58%; ECOG PS 0 32%, PS 1 68%; current smoker 30%) and randomly assigned to either nivolumab plus SABR (n = 34) or nivolumab alone (n = 16). Median follow-up was 25 months. PFS was similar among those assigned nivolumab plus SABR versus nivolumab alone (HR = 0.82, 95% CI 0.44 to 1.54, P = 0.6; PFS at 6mo 44% vs 43%, at 1y 27% vs 19%, and at 2y 16% vs 6%, respectively). OTRR (8/34 [24%] vs 4/16 [25%]) and OS (HR 0.94, P = 0.9) were also similar in the two treatment groups, as were the numbers of participants with grade 3-4 AEs: 24/30 (80%) vs 12/16 (75%) respectively. There were no treatment-related deaths in either arm. Conclusion Nivolumab plus SABR demonstrated similar activity and safety to nivolumab alone in NSCLC progressing after 1 or 2 lines of chemotherapy, with a potential signal of long-term efficacy, although the study was underpowered to detect this. Research should focus on identifying more active regimens of SABR and immunotherapy worthy of further evaluation.

DNA repair and metabolic pathways are vital to maintain cellular homeostasis in normal human cells. Both of these pathways, however, undergo extensive changes during tumorigenesis, including modifications that promote rapid growth, genetic heterogeneity, and survival. While these two areas of research have remained relatively distinct, there is growing evidence that the pathways are interdependent and intrinsically linked. Therapeutic interventions that target metabolism or DNA repair systems have entered clinical practice in recent years, highlighting the potential of targeting these pathways in cancer. Further exploration of the links between metabolic and DNA repair pathways may open new therapeutic avenues in the future. Here, we discuss the dependence of DNA repair processes upon cellular metabolism; including the production of nucleotides required for repair, the necessity of metabolic pathways for the chromatin remodeling required for DNA repair, and the ways in which metabolism itself can induce and prevent DNA damage. We will also discuss the roles of metabolic proteins in DNA repair and, conversely, how DNA repair proteins can impact upon cell metabolism. Finally, we will discuss how further research may open therapeutic avenues in the treatment of cancer.

BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged in late 2019 has spread globally, causing a pandemic of respiratory illness designated coronavirus disease 2019 (COVID-19). A better definition of the pulmonary host response to SARS-CoV-2 infection is required to understand viral pathogenesis and to validate putative COVID-19 biomarkers that have been proposed in clinical studies.MethodsHere, we use targeted transcriptomics of formalin-fixed paraffin-embedded tissue using the NanoString GeoMX platform to generate an in-depth picture of the pulmonary transcriptional landscape of COVID-19, pandemic H1N1 influenza and uninfected control patients.ResultsHost transcriptomics showed a significant upregulation of genes associated with inflammation, type I interferon production, coagulation and angiogenesis in the lungs of COVID-19 patients compared to non-infected controls. SARS-CoV-2 was non-uniformly distributed in lungs (emphasising the advantages of spatial transcriptomics) with the areas of high viral load associated with an increased type I interferon response. Once the dominant cell type present in the sample, within patient correlations and patient–patient variation, had been controlled for, only a very limited number of genes were differentially expressed between the lungs of fatal influenza and COVID-19 patients. Strikingly, the interferon-associated gene IFI27, previously identified as a useful blood biomarker to differentiate bacterial and viral lung infections, was significantly upregulated in the lungs of COVID-19 patients compared to patients with influenza.ConclusionCollectively, these data demonstrate that spatial transcriptomics is a powerful tool to identify novel gene signatures within tissues, offering new insights into the pathogenesis of SARS-COV-2 to aid in patient triage and treatment.

Circulating tumor cells (CTCs) carry a wealth of information on primary and metastatic tumors critical for precise cancer detection, monitoring, and treatment. Numerous microfluidic platforms have been developed in the past few years to capture these rare cells in patient bloodstream for deciphering the critical information needed. However, the practical need for a high-quality method of CTC isolation remains to be met. Herein, we demonstrate a novel multi-flow microfluidic device that is able to sensitively provide high purity (>87%) of separation outcome without labeling. Our device is constructed and configured based on the phenomenal effect of size-dependent inertial migration. The recovery rate of >93% has been achieved using spiked cancer cells at clinically relevant concentrations (10 cells per 5 mL and above). We have also successfully detected CTCs from 6 out of 8 non-small-cell-lung-cancer (NSCLC) patients, while none for 5 healthy control subjects. With these results, we envision our approach is a promising alternative for reliable CTC capture, and thus for facilitating the progress of extracting information from CTCs to personalize treatment strategies for solid tumor patients.

TPS8599 Background: Combination PD1/CTLA4 immune checkpoint blockade and platinum-pemetrexed (CP) chemotherapy are standard first-line options for the treatment of unresectable malignant pleural mesothelioma (MPM). Two recent, single-arm, phase 2 trials (DREAM and PrE0505) combining the PD-L1 inhibitor durvalumab and standard first line CP both exceeded pre-specified efficacy criteria. The Phase 3 DREAM3R trial aims to determine the effectiveness of including durvalumab with first line CP chemotherapy in advanced MPM. Methods: Treatment-naïve patients with advanced MPM will be randomized (2:1) to either durvalumab 1500 mg every 3 weeks plus chemotherapy (cisplatin 75 mg/m2 or carboplatin AUC 5 and pemetrexed 500 mg/m2) every 3 weeks for 4-6 cycles (Arm A), followed by durvalumab 1500 mg every 4 weeks until disease progression, unacceptable toxicity or patient withdrawal, versus doublet chemotherapy alone for 4-6 cycles with all patients monitored for progression. The target sample size is 480 patients recruited over 27 months, with follow up for an additional 24 months. This provides over 85% power if the true hazard ratio for overall survival (OS) is 0.70, with 2-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Key eligibility criteria include: MPM of any histological subtype; measurable disease per RECIST 1.1 modified for mesothelioma (mRECIST 1.1); ECOG PS 0-1; and adequate hematologic, renal, and liver function. Exclusions: Prior systemic anticancer treatment for MPM, diagnosis based solely on cytology or fine needle aspiration biopsy, contraindication to immunotherapy or conditions requiring immunosuppressive agents or corticosteroids. Patients will be further stratified at randomization by: Age (18-70 years vs. > 70), sex, histology (epithelioid vs. non-epithelioid), planned platinum (cisplatin vs. carboplatin) and geographic region (USA vs. ANZ). The primary endpoint is OS. Secondary endpoints include progression-free survival; objective tumor response; adverse events; health-related quality of life; and healthcare resource use in ANZ. Tertiary correlative objectives aim to further explore and validate potential prognostic and/or predictive biomarkers (including those identified in the DREAM and PrE0505 studies, PD-L1 expression, tumor mutation burden, genomic characteristics, and HLA subtypes) via tissue and serial blood samples. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma. The study is active and enrolling in both ANZ and in the US. Clinical trial information: NCT04334759 and ACTRN 12620001199909.

Introduction In CheckMate 227 (NCT02477826), patients with treatment-naive stage IV or recurrent NSCLC and 1% or greater tumor programmed death ligand 1 expression had significantly improved overall survival with nivolumab plus ipilimumab versus chemotherapy. We present the patient-reported outcomes (PROs). Methods Patients (N = 1189) were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy. PROs were exploratory. Changes in Lung Cancer Symptom Scale (LCSS) average symptom burden index, LCSS 3-item global index, EQ-5D visual analog scale (VAS), and EQ-5D utility index were analyzed descriptively. Mixed-effect model repeated measures and time-to-first deterioration and improvement analyses were conducted. Results PRO completion rates were generally greater than 80%. On-treatment improvements from baseline in LCSS measures of symptom burden and global health status with nivolumab plus ipilimumab generally met or exceeded the minimal important difference (smallest clinically meaningful change) from weeks 24 and 30, respectively; improvements with chemotherapy generally remained below the minimal important difference. Mean on-treatment EQ-5D VAS scores for both treatments approached the U.K. population norm at week 24, remaining so throughout the treatment period. Mixed-effect model repeated measures analyses revealed numerically greater improvements from baseline with nivolumab plus ipilimumab versus chemotherapy across LCSS average symptom burden index and 3-item global index, and EQ-5D VAS and utility index. Nivolumab plus ipilimumab had delayed time-to-first deterioration (hazard ratio [95% confidence interval] 0.74 [0.56 to 0.98]) and a trend for more rapid time-to-first improvement (1.24 [0.98 to 1.59]) versus chemotherapy. Conclusions Nivolumab plus ipilimumab revealed delayed deterioration and numerical improvement in symptoms and health-related quality of life versus chemotherapy in patients with advanced NSCLC and 1% or greater programmed death ligand 1 expression.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in late 2019 has spread globally, causing a pandemic of respiratory illness designated coronavirus disease 2019 (COVID-19). Robust blood biomarkers that reflect tissue damage are urgently needed to better stratify and triage infected patients. Here, we use spatial transcriptomics to generate an in-depth picture of the pulmonary transcriptional landscape of COVID-19 (10 patients), pandemic H1N1 (pH1N1) influenza (5) and uninfected control patients (4). Host transcriptomics showed a significant upregulation of genes associated with inflammation, type I interferon production, coagulation and angiogenesis in the lungs of COVID-19 patients compared to non-infected controls. SARS-CoV-2 was non-uniformly distributed in lungs with few areas of high viral load and these were largely only associated with an increased type I interferon response. A very limited number of genes were differentially expressed between the lungs of influenza and COVID-19 patients. Specific interferon-associated genes (includingIFI27) were identified as candidate novel biomarkers for COVID-19 differentiating this COVID-19 from influenza. Collectively, these data demonstrate that spatial transcriptomics is a powerful tool to identify novel gene signatures within tissues, offering new insights into the pathogenesis of SARS-COV-2 to aid in patient triage and treatment.

Cancer is a leading cause of death worldwide. As a common characteristic of cancer, hypoxia is associated with poor prognosis due to enhanced tumor malignancy and therapeutic resistance. The enhanced tumor aggressiveness stems at least partially from hypoxia-induced genomic instability. Therefore, a clear understanding of how tumor hypoxia induces genomic instability is crucial for the improvement of cancer therapeutics. This review summarizes recent developments highlighting the association of tumor hypoxia with genomic instability and the mechanisms by which tumor hypoxia drives genomic instability, followed by how hypoxic tumors can be specifically targeted to maximize efficacy.

Background: Circulating tumour DNA (ctDNA) has emerged as a promising biomarker for monitoring non-small-cell lung cancer (NSCLC). This has enabled the monitoring of clinically actionable mutations over the course of therapy. Case presentation: We present the case of a 74-year-old female who was treated with EGFR inhibitors for NSCLC which later transformed to SCLC. The kinetics of ctDNA was monitored by measuring the EGFR Exon 19 mutant L747–A750 > P and PIK3CA E545K over the course of therapy. Stabilisation of the PIK3CA mutation was found in response to therapy, however there appeared to be increasing levels of the EGFR mutant, potentially reflective of untreated EGFR-driven disease. Conclusion: The key finding described here, revealed by mutational tracking of mutations from the blood, is that clinically actionable mutations are assessable and may demonstrate clinical utility in measuring disease burden, multiple clones and progression non-invasively for lung cancer.

Background Profiling the tumour microenvironment (TME) has been informative in understanding the underlying tumour-immune interactions. Multiplex immunohistochemistry(mIHC) coupled with molecular barcoding technologies have revealed greater insights into the TME. Methods In this study, we utilised the Nanostring GeoMX Digital Spatial Profiler (DSP) platform to profile a NSCLC tissue microarray for protein markers across immune cell profiling, immuno-oncology(IO) drug target, immune activation status, immune cell typing, and pan-tumour protein modules. Regions of interest (ROIs) were selected that described tumour, TME and normal adjacent tissue (NAT) compartments. Results Our data revealed that paired analysis (n=18) of patient matched compartments indicated that the TME was significantly enriched in CD27, CD3, CD4, CD44, CD45, CD45RO, CD68, CD163, and VISTA relative to tumour. Unmatched analysis indicated that the NAT(n=19) was significantly enriched in CD34, fibronectin, IDO1, LAG3, ARG1 and PTEN when compared to the TM E(n=32). Univariate Cox proportional hazards indicated that the presence of cells expressing CD3 (HR:0.5, p=0.018), CD34(HR:0.53, p=0.004) and ICOS (HR:0.6, p=0.047) in tumour compartments were significantly associated with improved overall survival (OS). Conclusions We implemented both high-plex and high-throughput methodologies to the discovery of protein biomarkers and molecular phenotypes within biopsy samples and demonstrate the power of such tools for a new generation of pathology research. Acknowledgements This study was funded by the Princess Alexandra Hospital Foundation grant for KOB. AK is supported by an NHMRC ECF Fellowship (APP1157741) and Cure Cancer (APP1182179). Ethics Approval The study was approved by the QUT Human Research Ethics Board

Objectives: Assess computed tomography texture analysis of patients likely to benefit from nivolumab. Materials & methods: Texture analysis was used to quantify heterogeneity within the largest tumor before immunotherapy. Histogram analysis was classified as hyperdense (positive skewness) or hypodense (negative skewness) and subclassified on median standard deviation value or entropy measurement. Results: 47 patients were included. At a median follow-up of 18 months, statistical significant differences in progression-free survival were observed when stratified by positive skewness with low entropy, hazard ratio: 0.43 (0.19–0.95); p = 0.036, and positive skewness with low standard deviation, hazard ratio: 0.42 (0.18–0.96); p = 0.04. Conclusion: Patients who derive a clinical benefit to Nivolumab show a computed tomography texture of a hyperdense yet homogenous tumor.

A 69-year-old male presented with early stage non-small cell lung cancer in 2016. The tumor was resected; however, the patient experienced recurrence 2 years later and subsequently received paclitaxel/carboplatin concurrently with radiotherapy. Within weeks of completing this treatment, he developed a symptomatic pancoast tumor secondary to disease progression and commenced second line nivolumab. Following the second dose of nivolumab, he developed acute unilateral right hearing loss. He commenced intravenous methylprednisolone followed by a slow taper of oral prednisolone. With steroids, he noted a gradual improvement in hearing, confirmed by audiology. Restaging imaging post-nivolumab demonstrated a complete metabolic response. Two prior cases have reported bilateral sensorineural hearing loss post-immune checkpoint inhibitor (ICI). We postulate the hearing impairment relates to the development of autoimmune inner ear disease. To our knowledge, this is the only case of a patient experiencing unilateral loss of hearing following an ICI.

Epidermal growth factor receptor (EGFR) mutations are the most common oncogenic drivers in non-small-cell lung cancer (NSCLC). Significant developments have taken place which highlight the differences in tumor biology that exist between the mutant and wild-type subtypes of NSCLC. Patients with advanced EGFR-mutant NSCLC have a variety of EGFR-targeting agents available proven to treat their disease. This has led to superior patient outcomes when used as a monotherapy over traditional cytotoxic systemic therapy. Attempts at combining EGFR agents with other anticancer systemic treatment options, such as chemotherapy, antiangiogenic agents, and immunotherapy, have shown varied outcomes. Currently, no specific combination stands out to cause a shift away from the use of single-agent EGFR inhibitors in the first-line setting. Similarly, adjuvant EGFR inhibitors, are yet to significantly add to patient overall survival if used at earlier timepoints in the disease course. Liquid biopsy is an evolving technology with potential promise of being incorporated into the management paradigm of this disease. Data are emerging to suggest that this technique may be capable of identifying early resistance mechanisms and consequential disease progression on the basis of the analysis of blood-based circulating tumor cells.

Despite advances in our understanding of the molecular biology of the disease and improved therapeutics, lung cancer remains the most common cause of cancer-related deaths worldwide. Therefore, an unmet need remains for improved treatments, especially in advanced stage disease. Genomic instability is a universal hallmark of all cancers. Many of the most commonly prescribed chemotherapeutics, including platinum-based compounds such as cisplatin, target the characteristic genomic instability of tumors by directly damaging the DNA. Chemotherapies are designed to selectively target rapidly dividing cells, where they cause critical DNA damage and subsequent cell death (1, 2). Despite the initial efficacy of these drugs, the development of chemotherapy resistant tumors remains the primary concern for treatment of all lung cancer patients. The correct functioning of the DNA damage repair machinery is essential to ensure the maintenance of normal cycling cells. Dysregulation of these pathways promotes the accumulation of mutations which increase the potential of malignancy. Following the development of the initial malignancy, the continued disruption of the DNA repair machinery may result in the further progression of metastatic disease. Lung cancer is recognized as one of the most genomically unstable cancers (3). In this review, we present an overview of the DNA damage repair pathways and their contributions to lung cancer disease occurrence and progression. We conclude with an overview of current targeted lung cancer treatments and their evolution toward combination therapies, including chemotherapy with immunotherapies and antibody-drug conjugates and the mechanisms by which they target DNA damage repair pathways.

Tumor tissue biopsy is often limited for non-small cell lung cancer (NSCLC) patients and alternative sources of tumoral information are desirable to determine molecular alterations such as anaplastic lymphoma kinase (ALK) rearrangements. Circulating tumor cells (CTCs) are an appealing component of liquid biopsies, which can be sampled serially over the course of treatment. In this study, we enrolled a cohort of ALK-positive (n = 8) and ALK-negative (n = 12) NSCLC patients, enriched for CTCs using spiral microfluidic technology and performed DNA fluorescent in situ hybridization (FISH) for ALK. CTCs were identified in 12/20 NSCLC patients ranging from 1 to 26 CTCs/7.5 mL blood. Our study revealed that 3D imaging of CTCs for ALK translocations captured a well-defined separation of 3′ and 5′ signals indicative of ALK translocations and overlapping 3′/5′ signal was easily resolved by imaging through the nuclear volume. This study provides proof-of-principle for the use of 3D DNA FISH in the determination of CTC ALK translocations in NSCLC.

Background An increasing number of anti-cancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Successful use of these therapies is dependent on the presence or absence of somatic mutations within the patient’s tumor that can confer clinical efficacy or drug resistance. Methods The aim of our study was to determine the type, frequency, overlap and functional proteomic effects of potentially targetable recurrent somatic hotspot mutations in 47 cancer-related genes in multiple disease sites that could be potential therapeutic targets using currently available agents or agents in clinical development. Results Using MassArray technology, of the 1300 patient tumors analysed 571 (43.9%) had at least one somatic mutation. Mutations were identified in 30 different genes. KRAS (16.5%), PIK3CA (13.6%) and BRAF (3.8%) were the most frequently mutated genes. Prostate (10.8%) had the lowest number of somatic mutations identified, while no mutations were identified in sarcoma. Ocular melanoma (90.6%), endometrial (72.4%) and colorectal (66.4%) tumors had the highest number of mutations. We noted high concordance between mutations in different parts of the tumor (94%) and matched primary and metastatic samples (90%). KRAS and BRAF mutations were mutually exclusive. Mutation co-occurrence involved mainly PIK3CA and PTPN11, and PTPN11 and APC. Reverse Phase Protein Array (RPPA) analysis demonstrated that PI3K and MAPK signalling pathways were more altered in tumors with mutations compared to wild type tumors. Conclusions Hotspot mutational profiling is a sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular based therapeutics for treatment of cancer, and could potentially be of use in identifying novel opportunities for genotype-driven clinical trials.

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor protein that has roles in key cellular processes including apoptosis and cellular proliferation. As these cellular processes are frequently disrupted in human tumours and little is known about the role of SASH1 in the pathogenesis of the disease, we analysed the prognostic value of SASH1 in non-small cell lung cancers using publicly available datasets. Here, we show that low SASH1 mRNA expression is associated with poor survival in adenocarcinoma. Supporting this, modulation of SASH1 levels in a panel of lung cancer cell lines mediated changes in cellular proliferation and sensitivity to cisplatin. The treatment of lung cancer cells with chloropyramine, a compound that increases SASH1 protein concentrations, reduced cellular proliferation and increased sensitivity to cisplatin in a SASH1-dependent manner. In summary, compounds that increase SASH1 protein levels could represent a novel approach to treat NSCLC and warrant further study.

Immunotherapies have shown long‐lasting and unparalleled responses for cancer patients compared to conventional therapy. However, they seem to only be effective in a subset of patients. Therefore, it has become evident that a greater understanding of the tumor microenvironment (TME) is required to understand the nuances which may be at play for a favorable outcome to therapy. The immune contexture of the TME is an important factor in dictating how well a tumor may respond to immune checkpoint inhibitors. While traditional immunohistochemistry techniques allow for the profiling of cells in the tumor, this is often lost when tumors are analysed using bulk tissue genomic approaches. Moreover, the actual cellular proportions, cellular heterogeneity and deeper spatial distribution are lacking in characterisation. Advances in tissue interrogation technologies have given rise to spatially resolved characterisation of the TME. This review aims to provide an overview of the current methodologies that are used to profile the TME, which may provide insights into the immunopathology associated with a favorable outcome to immunotherapy., In this review, we discuss spatial analysis tools that can be used to characterise the tumor microenvironment. We present a number of technologies that are transforming the field and providing insights into the immunopathology associated with a favorable outcome to immunotherapy.

Genomic stability is critical for normal cellular function and its deregulation is a universal hallmark of cancer. Here we outline a previously undescribed role of COMMD4 in maintaining genomic stability, by regulating of chromatin remodelling at sites of DNA double strand breaks (DSBs). We demonstrate that COMMD4 is initially recruited to DSBs by a direct-interaction with phosphorylated hSSB1. At break-sites, COMMD4 binds to and protects histone H2B from monoubiquitination by RNF20/RNF40. DNA damage-induced phosphorylation of the H2A-H2B heterodimer disrupts the dimer allowing COMMD4 to preferentially bind H2A. Displacement of COMMD4 from H2B allows RNF20/40 to monoubuquitinate H2B and for remodelling of the break-site. Consistent with this critical function, COMMD4-defficient cells show excessive elongation of remodelled chromatin and failure of both non-homologous-end-joining and homologous recombination. We present a model, developed by molecular dynamic simulation, peptide-mapping and mutagenesis for the potential molecular mechanisms governing COMMD4-mediated chromatin regulation at DSBs.

Background: Cisplatin and pemetrexed chemotherapy provides modest survival benefits for malignant pleural mesothelioma (MPM). This study evaluated cisplatin and pemetrexed with, and followed by, the anti-PD-L1 (programmed death ligand-1) antibody durvalumab in advanced MPM. Methods: DREAM was a single-arm, multicentre open label phase 2 study in patients with treatment-naive advanced MPM. Eligible patients had Eastern Cooperative Oncology Group performance status 0 or 1 and measurable disease. The first six patients were treated on a two-cycle safety lead-in. All patients received cisplatin 75mg/m2, pemetrexed 500mg/m2, and durvalumab 1125mg fixed dose on day 1 of a three-weekly schedule to maximum six cycles chemotherapy. Change from cisplatin to carboplatin AUC5 was permitted. Durvalumab was continued to complete up to 12 months total treatment. The primary endpoint was progression-free survival at six months (PFS6); secondary outcomes included objective tumour response rate (RR), overall survival (OS), and adverse event (AE) rates. Findings: Fifty-four patients were registered and treated. Most were male (83%), with epithelioid subtype (83%), and a median age of 68 years. The proportion alive and progression-free at six months was 54%; median PFS was 6.9 months (95% CI 5.5–9.0). Median OS was 18.4 months (95% CI 13.1–24.8). RR according to modified RECIST for MPM was 48% (95% CI 36–61%), with partial responses in 26 (48%) and stable disease in 21 (37%) patients, respectively. AEs reflected the expected toxicities of combining chemotherapy and durvalumab. None of the five deaths during study treatment were attributed to durvalumab. There was no association between tumour expression of PD-L1 and PFS. Interpretation: This single-arm phase 2 trial demonstrated that the combination of durvalumab, cisplatin, and pemetrexed has promising activity and safety to warrant the conduct of a randomised phase 3 trial. Funding: AstraZeneca provided study drug and funding. Declaration of Interest: The other authors declared no conflicts of interest. Ethical Approval: DREAM conformed to ethical principles of the Declaration of Helsinki and the International Council on Harmonization guidelines on Good Clinical Practice. The protocol was approved by a central Human Research Ethics Committee (HREC), and all site HRECs. All patients provided written informed consent before any screening procedures. Patients confirmed eligible after screening were registered to the study.

Tumor biopsy is the gold standard for the assessment of clinical biomarkers for treatment. However, tumors change dynamically in response to therapy, and there remains a need for a more representative biomarker that can be assayed over the course of treatment. Circulating tumor cells (CTCs) may provide clinically important and comprehensive tumoral information that is predictive of treatment response and outcome. Blood samples were processed for CTCs from 56 patients using the ClearCell FX system. Captured cells were phenotyped for CTC clusters and markers for immunotherapy (PD‐L1) CTC chromosomal architecture (ALK, EGFR). CTCs were isolated in 11/23 (47.8%) of head and neck cancer (HNC) patients and 17/33 (51.5%) of non‐small‐cell lung cancer (NSCLC) patients. CTCs were determined to be PD‐L1‐positive in 6/11 (54.4%) HNC and 11/17 (64.7%) NSCLC cases, respectively. 3D chromosomal DNA FISH for ALK and EGFR molecular targets showed better resolution than in 2D when imaging CTCs. HNC CTC‐positive patients had shorter progression‐free survival (PFS) (hazard ratio[HR]: 4.946; 95% confidence internal[CI]:1.571‐15.57; P = 0.0063), and PD‐L1‐positive CTCs were found to be significantly associated with worse outcome ([HR]:5.159; 95% [CI]:1.011‐26.33; P = 0.0485). In the advanced stage NSCLC patient cohort, PFS was not found to be associated with CTCs prior to therapy ([HR]:2.246; 95% [CI]:0.9565‐5.273; P = 0.0632), nor the presence of PD‐L1 expression ([HR]:1.646; 95% [CI]:0.5128‐5.283; P = 0.4023). This study demonstrated that CTCs are predictive of poorer outcomes in HNC and provides distinct and separate utility for CTCs in HNC and NSCLC, which may be more representative of the disease burden and overall survival than the parameters used to measure them.

Introduction There is no approved second-line treatment for malignant pleural mesothelioma (MPM). On the basis of promising early results, pembrolizumab was used off-label in Switzerland and Australia. We investigated outcomes in association with clinicopathological features and expression of programmed death ligand 1 (PD-L1). Methods Registry data in Australia and Switzerland were pooled. Patient characteristics, including age, sex, histological subtype, and previous treatments were captured. Outcomes were assessed locally. PD-L1 expression was categorized as negative ( Results A total of 93 patients (48 from Switzerland and 45 from Australia) were treated; 68 patients (73%) had epithelioid MPM, and 67 (72%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Pembrolizumab was the second-line treatment in 48 of 93 patients (52%). PD-L1 expression results were available for 66 patients (71%). Most (68%) were negative, 18% were intermediate, and 14% were high for PD-L1 expression. In the full cohort, the overall response rate (ORR) was 18%, the median progression-free survival (mPFS) was 3.1 months, and the median overall survival was 7.2 months. In patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and only one previous systemic treatment (n = 35), the ORR was 37%, the mPFS was 3.7 months, and the median overall survival was 10.2 months. The nonepitheloid histological subtype showed an improved ORR (24% versus 16% [p = 0.54) and mPFS (5.6 versus 2.8 months [p = 0.02]). Compared with intermediate and negative PD-L1 expression, high PD-L1 expression was associated with an improved ORR (44% versus 42% versus 11% [p = 0.01]) and mPFS (6.2 versus 3.9 versus 2.7 months [p = 0.04]). Toxicity was as expected. Conclusion These real-world data demonstrate similar response rates but inferior survival compared with those in early-phase trials. High PD-L1 expression and nonepitheloid histological subtype were associated with greater activity. Anti–PD-L1 immunotherapy is a reasonable second-line therapy in patients with MPM.

BACKGROUND: Nivolumab plus ipilimumab showed promising efficacy for the treatment of non-small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (≥10 mutations per megabase). METHODS: We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx assay. RESULTS: Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P

Simple Summary Resistance to tyrosine kinase inhibitors (TKIs) that target common non-small-cell lung cancer mutations within the epidermal growth factor receptor (EGFR) is a primary clinical issue. The aim of our study was to determine whether the protein cell division cycle-associated protein 3 (CDCA3) might be a biomarker for TKI response in EGFR mutant lung cancer. Our previous work has demonstrated that CDCA3 is a marker of chemotherapy sensitivity in lung cancer. We provide evidence that CDCA3 levels are increased in EGFR mutant lung cancer and these levels are associated with sensitivity to TKIs. In addition, increasing the levels of CDCA3 enhances TKI sensitivity in models of TKI-resistant EGFR mutant lung cancer. Our findings propose that strategies to upregulate CDCA3 levels might improve TKI response in EGFR mutant lung cancer. Abstract Tyrosine kinase inhibitors (TKIs) are the first-line therapy for non-small-cell lung cancers (NSCLC) that harbour sensitising mutations within the epidermal growth factor receptor (EGFR). However, resistance remains a key issue, with tumour relapse likely to occur. We have previously identified that cell division cycle-associated protein 3 (CDCA3) is elevated in adenocarcinoma (LUAD) and correlates with sensitivity to platinum-based chemotherapy. Herein, we explored whether CDCA3 levels were associated with EGFR mutant LUAD and TKI response. We demonstrate that in a small-cohort tissue microarray and in vitro LUAD cell line panel, CDCA3 protein levels are elevated in EGFR mutant NSCLC as a result of increased protein stability downstream of receptor tyrosine kinase signalling. Here, CDCA3 protein levels correlated with TKI potency, whereby CDCA3high EGFR mutant NSCLC cells were most sensitive. Consistently, ectopic overexpression or inhibition of casein kinase 2 using CX-4945, which pharmacologically prevents CDCA3 degradation, upregulated CDCA3 levels and the response of T790M(+) H1975 cells and two models of acquired resistance to TKIs. Accordingly, it is possible that strategies to upregulate CDCA3 levels, particularly in CDCA3low tumours or upon the emergence of therapy resistance, might improve the response to EGFR TKIs and benefit patients.

Introduction In LUX-Lung 3 and LUX-Lung 6, afatinib significantly improved progression-free survival (PFS) versus chemotherapy in patients with tumors harboring common epidermal growth factor receptor (EGFR) mutations (Del19/L858R) and significantly improved overall survival (OS) in patients with tumors harboring Del19 mutations. Patient-reported outcomes stratified by EGFR mutation type are reported. Patients and Methods Lung cancer symptoms and health-related quality of life (QoL) were assessed every 21 days until progression using the EORTC Quality of Life Core Questionnaire C30 and its lung cancer-specific module, LC13. Analyses of cough, dyspnea, and pain were prespecified and included analysis of percentage of patients who improved on therapy, time to deterioration of symptoms, and change over time. Global health status (GHS)/QoL was also assessed. Analyses were conducted for all patients with tumors harboring Del19 or L858R mutations and were exploratory. Results Compared with chemotherapy, afatinib more commonly improved symptoms of, delayed time to deterioration for, and was associated with better mean scores over time for cough and dyspnea in patients with Del19 or L858R mutations. All three prespecified analyses of pain showed a trend favoring afatinib over chemotherapy. In both Del19 and L858R mutations, afatinib was also associated with improvements in GHS/QoL. Longitudinal analyses demonstrated statistically significant improvements in GHS/QoL for afatinib over chemotherapy for patients with tumors harboring Del19 mutations or L858R mutations. Conclusions These exploratory analyses suggest first-line afatinib improved lung cancer-related symptoms and GHS/QoL compared with chemotherapy in patients with non-small-cell lung cancer with tumors harboring common EGFR mutations, with benefits in both Del19 and L858R patients. When considered with OS (Del19 patients only) and PFS benefits, these findings substantiate the value of using afatinib over chemotherapy in these patient groups. Electronic supplementary material The online version of this article (10.1007/s40271-017-0287-z) contains supplementary material, which is available to authorized users.

Purpose Patients with squamous non–small-cell lung cancer (NSCLC) have poor prognosis and limited treatment options. This randomized, double-blind, phase III study investigated the efficacy and safety of first-line ipilimumab or placebo plus paclitaxel and carboplatin in advanced squamous NSCLC. Patients and Methods Patients with stage IV or recurrent chemotherapy-naïve squamous NSCLC were randomly assigned (1:1) to receive paclitaxel and carboplatin plus blinded ipilimumab 10 mg/kg or placebo every 3 weeks on a phased induction schedule comprising six chemotherapy cycles, with ipilimumab or placebo from cycles 3 to 6 and then, after induction treatment, ipilimumab or placebo maintenance every 12 weeks for patients with stable disease or better. The primary end point was overall survival (OS) in patients receiving at least one dose of blinded study therapy. Results Of 956 randomly assigned patients, 749 received at least one dose of blinded study therapy (chemotherapy plus ipilimumab, n = 388; chemotherapy plus placebo, n = 361). Median OS was 13.4 months for chemotherapy plus ipilimumab and 12.4 months for chemotherapy plus placebo (hazard ratio, 0.91; 95% CI, 0.77 to 1.07; P = .25). Median progression-free survival was 5.6 months for both groups (hazard ratio, 0.87; 95% CI, 0.75 to 1.01). Rates of grade 3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and TRAEs leading to discontinuation were numerically higher with chemotherapy plus ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo. Conclusion The addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma studies. Ongoing studies are evaluating ipilimumab in combination with nivolumab in this population.

Non-small cell lung cancer (NSCLC) accounts for a large proportion of cancer deaths and is characterized by low treatment response rates and poor overall prognosis. In the absence of specific treatable mutations, cisplatin-based chemotherapy plays an important role in the treatment of this disease. Unfortunately, the development of resistance has become a major therapeutic challenge in the use of this cytotoxic drug. Elucidating the mechanisms underlying this resistance phenotype, may result in the development of novel agents that enhance sensitivity to cisplatin in lung cancer patients. In this study, targeting the cancer stem cell activity of aldehyde dehydrogenase 1 (ALDH1) was investigated as a strategy to overcome chemoresistance in NSCLC. Tumors from NSCLC patients showed an increase in their profile of pluripotent stemness genes. Cisplatin exposure induced the emergence or expansion of an ALDH1-positive subpopulation in cisplatin sensitive and resistant NSCLC cell lines, respectively, further enhancing cisplatin resistance. Using the Aldefluor assay and FACS analysis, ALDH1 subpopulations were isolated and evaluated in terms of stem cell characteristics. Only ALDH1-positive cells exhibited asymmetric division, cisplatin resistance and increased expression of stem cell factors in vitro. Xenograft studies in NOD/SCID mice demonstrated efficient tumorigenesis from low cell numbers of ALDH1-positive and ALDH1-negative subpopulations. Targeting ALDH1 with Diethylaminobenzaldehyde (DEAB) and Disulfiram, significantly re-sensitized resistant lung cancer cells to the cytotoxic effects of cisplatin. Our data demonstrate the existence of a lung CSC population and suggest a role for targeting ALDH1 as a potential therapeutic strategy in re-sensitizing NSCLC cells to the cytotoxic effects of cisplatin.

Immune checkpoint inhibitors have recently emerged as an exciting new treatment paradigm across a broad spectrum of malignancies. This new class of agents also challenges oncologists with a unique set of immune-based toxicities. Early recognition and precise management of these toxicities can result in better outcomes, with minimization of toxicity and harm to the patient. This article provides a comprehensive review of immune-based toxicities caused by immune checkpoint inhibitors, including recommendations for their investigation and guidelines for specific management.

INTRODUCTION NSCLC is the leading cause for cancer-related deaths worldwide. New therapeutic targets are needed, as development of resistance to current treatment, such as platinum-based chemotherapy, is inevitable. The purpose of this study was to determine the functional relevance and therapeutic potential of cell division cycle associated 3 protein (CDCA3) in NSCLC. METHODS The expression of CDCA3 in squamous and nonsquamous NSCLC was investigated by using bioinformatics, Western blot analysis of matched tumor and normal tissue, and immunohistochemistry of a tissue microarray. The function of CDCA3 in NSCLC was determined by using several in vitro assays with small interfering RNA depleting CDCA3 in a panel of three immortalized human bronchial epithelial cell (HBEC) lines and seven NSCLC cell lines. RESULTS In this study, cell division cycle associated 3 gene (CDCA3) transcripts were identified as highly increased in NSCLC versus in nonmalignant tissue, with high levels of CDCA3 being associated with poor patient prognosis. CDCA3 protein was also increased in NSCLC tissue and expression was limited to tumor cells. CDCA3 expression was similarly increased in a panel of NSCLC cell lines compared with in three HBEC lines. Although depletion of CDCA3 in the HBEC lines did not affect cellular proliferation, depletion of CDCA3 expression markedly reduced the proliferation of all NSCLC cell lines. CDCA3 depletion caused a defective G2/M-phase cell cycle progression, upregulation of p21 independent of p53, and induction of cellular senescence. CONCLUSIONS Our findings highlight CDCA3 as a prognostic factor and potential novel therapeutic target in NSCLC through inhibition of tumor growth and promotion of tumor senescence.

This work was supported by a National Health and Medical Research Council project grant [1066550], an Australian Research Council project grant [DP 120103099] and by a Queensland Health Senior Clinical Research Fellowship awarded to K.J.O. This work was also supported by the Wellcome Trust [094476/Z/10/Z], which funded the purchase of the TripleTOF 5600 mass spectrometer at the BSRC Mass Spectrometry and Proteomics Facility, University of St Andrews. NWA was supported by a scholarship awarded by Cancer Council Queensland. E.B. is supported by an Advance Queensland Research Fellowship. The maintenance of genomic stability is essential for cellular viability and the prevention of diseases such as cancer. Human single-stranded DNA-binding protein 1 (hSSB1) is a protein with roles in the stabilisation and restart of stalled DNA replication forks, as well as in the repair of oxidative DNA lesions and double-strand DNA breaks. In the latter process, phosphorylation of threonine 117 by the ATM kinase is required for hSSB1 stability and efficient DNA repair. The regulation of hSSB1 in other DNA repair pathways has however remained unclear. Here we report that hSSB1 is also directly phosphorylated by DNA-PK at serine residue 134. While this modification is largely suppressed in undamaged cells by PPP-family protein phosphatases, S134 phosphorylation is enhanced following the disruption of replication forks and promotes cellular survival. Together, these data thereby represent a novel mechanism for hSSB1 regulation following the inhibition of replication. Publisher PDF

Introduction Nivolumab est approuve a la dose de 240 mg Q2S dans l’Union europeenne dans le traitement de 2e ligne du CBNPC avance. La modelisation pharmacocinetique dans diverses tumeurs predit que l’exposition, l’efficacite et la tolerance peuvent etre maintenues avec une dose Q4S. Nous presentons ici une analyse intermediaire des donnees d’efficacite et de tolerance de l’etude de phase 3b/4 CheckMate 384. Methodes Des pts deja traites pour un CBNPC de stade IIIb/IV histologiquement confirme ou recurrent, avec un statut de performance ECOG de 0 a 2, un traitement anterieur par nivolumab 3 mg/kg ou 240 mg Q2S ≤ 12 mois et un minimum de 2 evaluations consecutives mettant en evidence une reponse complete/partielle ou une maladie stable, ont ete randomises (1 :1) en 2 bras : nivolumab 480 mg Q4S ou 240 mg Q2S. Les criteres principaux d’evaluation etaient les taux de survie sans progression (SSP) post-randomisation a 6 mois et a 1 an. La tolerance etait un critere de jugement secondaire. En raison des changements dans les algorithmes de traitement du CBNPC, les analyses statistiques ont ete modifiees pour reduire la taille de l’echantillon. Les analyses presentees sont descriptives. Resultats Sur 166 et 163 pts randomises aux doses de 480 mg Q4S et de 240 mg Q2S, 164 et 161 ont ete respectivement traites. Le suivi median etait de 9,5 mois (480 mg Q4S) et de 10,2 mois (240 mg Q2S). Les caracteristiques a l’inclusion etaient equilibrees entre les 2 bras de traitement. Les taux de SSP stratifiee post-randomisation a 6 mois et a 1 an etaient comparables entre les 2 bras de traitement (voir le Tableau 1 ). Les effets indesirables de tous grades lies au traitement et ceux ayant entraine l’arret du traitement ont ete rapportes respectivement chez 48 % vs 61 % et 6 % vs 9 % des patients. Aucun deces lie au traitement n’a ete rapporte. Conclusion Nivolumab 480 mg Q4S presente une efficacite et une tolerance similaires a celles de nivolumab 240 mg Q2S chez les patients avec une maladie controlee par nivolumab, soutenant l’utilisation potentielle de 480 mg Q4S comme dose de nivolumab plus pratique dans le traitement du CBNPC avance de 2e ligne.