Inhibitors In Non-small Cell Lung Cancer Research Articles

Tepotinib in patients (pts) with advanced non-small cell lung cancer (NSCLC) with MET amplification (METamp).

9021 Background: METamp is an oncogenic driver occurring in 1–5% of NSCLCs that confers a poor prognosis and lacks approved targeted therapies. Tepotinib, a highly selective MET inhibitor, provided durable response in NSCLC with MET exon 14 ( METex14) skipping in Cohort A of the Phase II VISION trial (NCT02864992). VISION Cohort B evaluated tepotinib in pts with advanced NSCLC and METamp, as detected by a convenient and minimally invasive liquid biopsy assay, in the absence of METex14 skipping. Methods: Pts with locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, 0–2 prior lines of therapy, EGFR/ ALK wild-type status, no METex14 skipping, and METamp by liquid biopsy (Guardant360®; MET gene copy number ≥2.5) received oral tepotinib 500 mg QD (450 mg active moiety). The primary endpoint was objective response (RECIST v1.1) by independent review committee (IRC). Secondary endpoints included duration of response (DOR), progression-free survival (PFS) and safety. The data cut-off was July 1, 2020. Results: Among 24 enrolled pts, median age was 63.4 years (range: 38–73), 21 pts (88%) were male, 21 (88%) had ECOG PS 1 and 21 (88%) were smokers. Tepotinib was given to 7 pts (29%) in first line (1L), 10 pts (42%) in second line (2L) and 7 pts (29%) in third line (3L). As of November 2020, treatment was ongoing for > 1 year in 5 pts (1L, n = 2; 2L, n = 2; 3L, n = 1). Objective response rate (ORR) by IRC was 42% (10/24 pts) overall, 71% (5/7 pts) in 1L, 30% (3/10 pts) in 2L and 29% (2/7 pts) in 3L (Table). Median DOR by IRC was not estimable (NE; 95% confidence interval [CI]: 2.8 months–NE). Investigator-assessed outcomes were similar. Five pts (20.8%) discontinued due to adverse events (AEs), which were considered unrelated to tepotinib. Treatment-related AEs were reported in 16 pts (67%; Grade 3/4, 7 pts [29%]) and included peripheral edema (9 pts [38%]; Grade 3/4, 2 pts [8%]), generalized edema (4 pts [17%]; Grade 3/4, 2 pts [8%]) and constipation (4 pts [17%]; Grade 3/4, 0 pts). Conclusions: In the first study of a MET inhibitor in NSCLC with METamp prospectively detected by liquid biopsy, tepotinib showed high and clinically meaningful activity, especially in 1L, and was generally well tolerated. Tepotinib warrants further evaluation in NSCLC with METamp. Clinical trial information: NCT02864992. [Table: see text]

Circulating tumor cell proportion scoring (CTPS) based PD-L1 assessment and clinical application of circulating tumor cells (CTCs) on stage IV non-small cell lung cancer (NSCLC) through liquid biopsy.

e15031 Background: Stage IV lung cancer is the most advanced lung cancer state accompanied by metastasized to the area around the lungs or distant major organs. The most common type of lung cancer is non-small cell lung cancer, which is more aggressive and may spread quickly due to organ-specific complex networks such as lymph and major blood vessels. Thus, only precise diagnostic strategy approaches will determine the effectiveness of the actual and successful clinical treatment. Until a recent date, Immunohistochemistry (IHC) for programmed death-ligand 1(PD-L1) test is the only available biomarker test that purpose diagnostics (CDx) and guide the treatment with immune checkpoint inhibitors in NSCLC. Methods: Given that CDx strategy, tissue biopsy has inevitable limitations, including patient risk, repetitive examination, sample preparation, sensitivity, and accuracy. For this reason, our research team contrived the best strategy for biomarker, PD-L1-specific CTCs in stage IV NSCLC group (N = 30) compared to pulmonary inflammatory patient groups (N = 30) CytoGen Smart biopsy platform. Herein, we removed false-positive cells for the first strategy of distinguishing between lymphoid/myeloid cells and the enriched-CTCs. And the second strategic approach is to calculate the pure CTCs (without false-positive cells) and then CTPS) as measured by the PD-L1 expression among pure-CTCs. That application is the percentage of viable CTCs showing partial or complete stained cells at the deducted cut-off value in each fluorescence, respectively. Results: Consequently, we demonstrated over 80% of the concordance rate between VENTANA PD-L1(SP263) and DAKO PD-L1(SP263) assay tested by the PD-L1 expression on stage IV NSCLC in tissue and pure-CTCs based CTPS from the blood. In contrast, pure-CTCs based CTPS in the pulmonary inflammatory group were all negative (recorded as zero). Conclusions: Conclusively, this study implicates that pure-CTCs based CTPS could be deployed for innovative diagnosis strategies as alternatives for tissue biopsy. Our clinical study's data suggested that the possibility for prompt decision for diagnosis and gain powerful insights to guide the personalized treatment in NSCLCs. Clinical trial information: 2020-0553.

Effects of histone deacetylase inhibitors Tricostatin A and Quisinostat on tight junction proteins of human lung adenocarcinoma A549 cells and normal lung epithelial cells.

Histone deacetylase (HDAC) inhibitors have a potential therapeutic role for non-small cell lung cancer (NSCLC). However, more preclinical studies of HDAC inhibitors in NSCLC and normal lung epithelial cells are required to evaluate their antitumor activities and mechanisms. The bicellular tight junction molecule claudin-2 (CLDN-2) is highly expressed in lung adenocarcinoma tissues and increase the proliferation of adenocarcinoma cells. Downregulation of the tricellular tight junction molecule angulin-1/LSR induces malignancy via EGF-dependent CLDN-2 and TGF-β-dependent cellular metabolism in human lung adenocarcinoma cells. In the present study, to investigate the detailed mechanisms of the antitumor activities of HDAC inhibitors in lung adenocarcinoma, human lung adenocarcinoma A549 cells and normal lung epithelial cells were treated with the HDAC inibitors Trichostatin A (TSA) and Quisinostat (JNJ-2648158) with or without TGF-β. Both HDAC inhibitors increased anguin-1/LSR, decrease CLDN-2, promoted G1 arrest and prevented the migration of A549 cells. Furthermore, TSA but not Quisinostat with or without TGF-β induced cellular metabolism indicated as the mitochondrial respiration measured using the oxygen consumption rate. In normal human lung epithelial cells, treatment with TSA and Quisinostat increased expression of LSR and CLDN-2 and decreased that of CLDN-1 with or without TGF-β in 2D culture. Quisinostat but not TSA with TGF-β increased CLDN-7 expression in 2D culture. Both HDAC inhibitors prevented disruption of the epithelial barrier measured as the permeability of FD-4 induced by TGF-β in 2.5D culture. TSA and Quisinostat have potential for use in therapy for lung adenocarcinoma via changes in the expression of angulin-1/LSR and CLDN-2.

High expression of hypoxia inducible factor 1\u03b1 related with acquired resistant to EGFR tyrosine kinase inhibitors in NSCLC

The acquired resistance of the first generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is a main factor leading to poor prognosis of non-small cell lung cancer (NSCLC), so we researched whether the high expression of hypoxia-inducible factor-1α (HIF-1α) in EGFR-TKIs sensitive NSCLC tissue tends to induce the acquired resistance. We detected the HIF-1α in normal lung tissue, EGFR-TKIs sensitive NSCLC tissue, the first generation EGFR-TKIs acquired resistant NSCLC tissue and acquired EGFR T790M mutation NSCLC tissue with the method of immunohistochemistry. Then, we compared the expression of HIF-1α in these tissues, and evaluate the effect of HIF-1α expression to the occurrence of acquired resistance. The expression of HIF-1α was much higher in the EGFR-TKIs sensitive NSCLC tissue than that in normal lung tissue. HIF-1α level became higher after the occurrence acquired resistance. There was negative correlation between HIF-1α level before receiving treatment and the time of acquired resistance occurring as well as the acquired EGFR T790M mutation occurring. As the treatment going on, EGFR-TKIs sensitivity rate of low HIF-1α level group was much higher than that of high level group. The high expression of HIF-1α related with the acquired resistance of the first generation EGFR-TKIs, and HIF-1α can be a biomarker to predict the early occurrence of acquired resistance.

AZD9291 Resistance Reversal Activity of a pH-Sensitive Nanocarrier Dual-Loaded with Chloroquine and FGFR1 Inhibitor in NSCLC.

AZD9291 can effectively prolong survival of non‐small cell lung cancer (NSCLC) patients. Unfortunately, the mechanism of its acquired drug resistance is largely unknown. This study shows that autophagy and fibroblast growth factor receptor 1 signaling pathways are both activated in AZD9291 resistant NSCLC, and inhibition of them, respectively, by chloroquine (CQ) and PD173074 can synergistically reverse AZD9291 resistance. Herein, a coloaded CQ and PD173074 pH‐sensitive shell–core nanoparticles CP@NP‐cRGD is developed to reverse AZD9291 resistance in NSCLC. CP@NP‐cRGD has a high encapsulation rate and stability, and can effectively prevent the degradation of drugs in circulation process. CP@NP‐cRGD can target tumor cells by enhanced permeability and retention effect and the cRGD peptide. The pH‐sensitive CaP shell can realize lysosome escape and then release drugs successively. The combination of CP@NP‐cRGD and AZD9291 significantly induces a higher rate of apoptosis, more G0/G1 phase arrest, and reduces proliferation of resistant cell lines by downregulation of p‐ERK1/2 in vitro. CQ in CP@NP‐cRGD can block protective autophagy induced by both AZD9291 and PD173074. CP@NP‐cRGD combined with AZD9291 shows adequate tumor enrichment, low toxicity, and excellent antitumor effect in nude mice. It provides a novel multifunctional nanoparticle to overcome AZD9291 resistance for potential clinical applications.

Transformation or Progression from Adenocarcinoma to Small Cell Lung Cancer Detected by Serially Tracking Mutations in the Blood

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.

Inhibition of ELF3 confers synthetic lethality of PARP inhibitor in non-small cell lung cancer

Background E74 Like ETS Transcription Factor 3 (ELF3) functions as a transcriptional factor to regulate non-small cell lung cancer (NSCLC) differentiation and progression. Poly(ADP-ribose) polymerase (PARP) inhibitors demonstrate anti-tumor effect in NSCLC. This study aimed to investigate whether ELF3 confers synthetic lethal with PARP inhibitor in NSCLC. Materials and methods The sensitivity of PARP inhibitor, Olaparib, to different NSCLC cell lines was determined by half maximal inhibitory concentration (IC50). Expression of ELF3 in NSCLC cell lines was evaluated by western blot. The effects of ELF3 on cytotoxicity of Olaparib to NSCLC were investigated by MTT (3-(4,5- di methyl thiazol −2-yl)-2,5-di phenyl tetrazolium bromide) and colony formation assays. The underlying mechanism involved in synthetic lethality with ELF3 and PARP inhibitors in NSCLC were detected by immunofluorescence and Western blot. Results ELF3 was up-regulated in NSCLC cell lines exhibiting resistance to PARP inhibitor, Olaparib. Knock down of ELF3 decreased the sensitivity and enhanced cytotoxicity of Olaparib to NSCLC cells. Moreover, knock down of ELF3 increased S139 phosphorylated histone H2AX (γH2AX), and inhibited homologous recombination activity via down-regulation of DNA repair protein RAD51 homolog 1 (RAD51), thus showing deficiency in DNA damage repair. Over-expression of ELF3 could up-regulate phosphorylation of AKT (Protein kinase B), while knock down of ELF3 regulated homologous recombination-mediated DNA repair via down-regulation of phosphorylation of AKT. Conclusion Knock down of ELF3 revealed homologous recombination deficiency via AKT signaling pathway, and synthetic lethality with ELF3 inhibition and PARP inhibitor indicated the clinical significance of PARP inhibitor in ELF3-deficient NSCLC.

Abstract 5885: The impact of genomic mutational status and correlation with tumor mutation burden in non-small cell lung cancer of Xuanwei, Yunnan Province, China

Abstract Background: Xuanwei County in Yunnan Province is one of the regions with the highest lung cancer mortality rates in China, the mortality rate in female lung cancer ranks first in China. Our previous study identified a higher mutation frequency of KRAS (25%) and EGFR uncommon mutations (56.4%) in a Xuanwei cohort compared to a large cohort of Chinese patients(pts) with non-small cell lung cancer (NSCLC) (n=1200). Tumor mutation burden (TMB) is a predictive biomarker for immune checkpoint inhibitors in NSCLC. The aim of this study was to explore gene mutations and the correlation with TMB in Xuanwei NSCLC pts. Materials and Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor samples and matched blood samples of 111 Xuanwei NSCLC pts were collected for 450 cancer gene next-generation sequencing (NGS) targeted panel assay. Genomic alterations (GAs), including single base substitution, short and long insertion/deletions, copy number variations, gene fusions, and rearrangements, and TMB values were assessed with a mean coverage of 1000X. Results: Tumor samples were lung adenocarcinoma (LUAD) (n=99, 89.2%), lung squamous cell carcinoma (LUSC) (n=6, 5.4%), or others (n=6, 5.4%). The cohort included 58 males (52.3%) and 53 females (47.7%) with a median age of 54 years (range 36-78). In total, 73.8% of the pts had one or more actionable GAs. The most common were TP53 (51%), EGFR (49%), KRAS (28%), LRP1B (26%), SPTA1 (23%), NF1 (18%), MED12 (14%), RBM10 (14%), and KMT2C (13%). TMB high (TMB-H) (≥10 muts/Mb) was seen in 58.5% (65/111) of the Xuanwei cohort compared with 29.4% of the Chinese cohort(P <0.001), and the Xuanwei cohort had a higher median TMB than the Chinese cohort (13.1 vs 4.6 muts/Mb, respectively, P <0.001). A higher TMB was associated with higher age, and TMB was higher in males and current/former smokers. Genomic alterations associated with TMB were analysised. Among the common actionable mutations. KRAS mutation cases had a higher median TMB than KRAS wildtype (21.1 vs 9.6 muts/Mb, respectively, P <0.01). TMB-H was seen in 80.6% (25/31) of the Xuanwei KRAS mutation cohort. KRAS G12C (61.3%, 19/31) was the most common mutation and these cases showed lower TMB than non-KRAS G12C cases (P<0.05). EGFR mutations were significantly adversely correlated with TMB (P <0.001). Tumors with the common mutations in EGFR showed significantly lower TMB than those with the uncommon mutations in EGFR (P <0.01). TP53, LRP1B, SPTA1, NF1, and KMT2C mutations frequently occurred in NSCLC pts and were significantly positively correlated with TMB(p<0.001, p<0.001, p<0.001, p<0.001, and p<0.001, respectively). Conclusions: The Xuanwei NSCLC cohort had a higher median TMB than the Chinese NSCLC cohort. KRAS, TP53, LRP1B, SPTA1, NF1, and KMT2C mutations positively correlated with TMB while EGFR mutations were significantly adversely correlated with TMB. NGS revealed potential immunotherapy biomarkers for Xuanwei NSCLC pts. Citation Format: Yinqiang Liu, Jin Liang, Juan Zhao, Shuirong Zhang, Shiyue Zhang, Yunfei Shi, Ruoshan Huang, Xiaojie Wang. The impact of genomic mutational status and correlation with tumor mutation burden in non-small cell lung cancer of Xuanwei, Yunnan Province, China [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5885.

Adverse cardiac events in the treatment of non-small cell lung cancer with programmed death-1and programmed death-ligand 1 inhibitors: A protocol for systematic review and meta-analysis.

Background:Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors are immune therapies that have shown great promise in the treatment of multiple cancers. However, immune-related adverse events of PD-1 and PD-L1 inhibitors may limit their use in non-small cell lung cancer (NSCLC). Given the rising number of clinical trials in recent years, it is essential to perform a meta-analysis to provide assess the cardiotoxicity of PD-1/ PD-L1 inhibitors in NSCLC therapy.Method and analysis:The ClinicalTrials.gov, Embase, PubMed, and Cochrane Central Register of Controlled Trials repositories will be searched from their inception to December 2019. The bibliography of the searching process will be imported into Endnote X9 software. Two reviewers independently will screen the literature, extract data, and conduct the risk of bias for every added study. The data analysis will be analyzed using Stata15.0 software. Specific adverse cardiac events will be identified, with particular attention on atrial fibrillation, cardiac arrest, cardiac failure, and pericarditis. This review will be performed as per the Preferred Reporting Item for Systematic Review and meta-analysis statement recommendations.Ethics and dissemination:This study will provide support for the cardiotoxicity linked to the treatment of NSCLC using PD-1/PD-L1 inhibitors. The data in the meta-analysis will be retrieved from completed and published clinical trials; therefore, ethical review and patient informed consent will not be required.PROSPERO number:CRD42020156397.

EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer

Most patients with KRAS G12C-mutant non-small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRASG12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRAS G12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRAS G12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRASG12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRASG12C blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRASG12C inhibitors. The combinatorial targeting of EGFR and KRASG12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRAS G12C colorectal cancer. SIGNIFICANCE: The efficacy of KRASG12C inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRASG12C inhibition in colorectal cancer. EGFR and KRASG12C should be concomitantly inhibited to overcome resistance to KRASG12C blockade in colorectal tumors.See related commentary by Koleilat and Kwong, p. 1094.This article is highlighted in the In This Issue feature, p. 1079.

Utilization patterns of immune checkpoint inhibitors (ICI) for non-small cell lung cancer (NSCLC) within the veterans health administration (VHA).

e21630 Background: ICI are used routinely for treatment of lung cancer. We investigated the utilization of PD-1/PD-L1 inhibitors for NSCLC in the VHA. Methods: The VHA Corporate Data Warehouse was queried for data on ICI utilization in NSCLC [IRB #00113521]. The first date of any ICI dispensed was January 6, 2015 and therefore this investigation evaluated all patients diagnosed with NSCLC between 2015 –2019. Results: A total of 27,586 Veterans were diagnosed with NSCLC during the study period with demographics: 76.3% Caucasian, 16.3% black; 97.0% male; median age 71 years. Stage distribution was 27.9%, 7.9%, 15.8%, and 27.0% for stage I, II, III, or IV, respectively. A total of 3,990 patients were identified to have received any ICI, representing 20.1% of patients diagnosed with stage IV; 159 patients received more than one ICI. The median time from stage IV diagnosis to receipt of ICI was 5 months (IQR: 2-9 months). ICI was dispensed in 83.7% for duration of < 1 year, 13.3% for 1-2 years, and 3% for > = 2 years. The median duration of ICI receipt (with IQR in months): Nivolumab = 2.0 (0.5-5.5), Pembrolizumab = 2.1 (0.3-5.9), Durvalumab = 5.1 (1.8-9.2), and Atezolizumab = 0.3 (0.1-2.1). Multivariable analyses demonstrated female, not married, 0 comorbidity, and higher stage (II-IV) were independently associated with shorter time to receipt of ICI. Conclusions: The use of ICI for NSCLC is increasing within this integrated healthcare system and commonly prescribed within 5 months of stage IV diagnosis. Further investigations of this cohort using available clinical, pharmaceutical, and genomic data within the VHA present an opportunity to enhance our understanding of the efficacy of ICI for NSCLC. [Table: see text]

The safety of first and subsequent lines of PD-1/PD-L1 inhibitors monotherapy in non-small cell lung cancer patients: a meta-analysis.

BackgroundIn both first or subsequent therapy of patients with non-small cell lung cancer (NSCLC), some programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors have shown prominent efficacy and safety. However, the disease spectra of side effects in different therapy time might exist heterogeneity. In this meta-analysis, we assessed and compared the safety of PD-1/PD-L1 inhibitors in first or subsequent line therapy. And the system-specific disease spectra of both treatment-related adverse events (trAEs) and immune-related adverse events (irAEs) were summarized.MethodsWe performed a comprehensive search of online databases. Incidence and its 95% confidence interval (95% CI) were chosen as the main outcome to assess safety. The incidence of trAEs/irAEs was calculated, including discontinuation and death results. Besides, the most common trAEs/irAEs and system-specific treatment-related/immune-related disease spectra in different therapy lines were also collected.ResultsIn total, 18 studies (5,649 patients) were included. First-line therapy had a higher risk of high-grade trAEs, any-grade irAEs and high-grade irAEs comparing with subsequent therapy (19.4% vs. 13.0%, P<0.001; 30.1% vs. 16.9%, P<0.001; 9.9% vs. 2.4%, P<0.001). The rate of discontinuation in first-line therapy were also higher (9.5% vs. 5.2%, P<0.001). However, the common system-specific trAEs of first-line and subsequent therapy were semblable, including gastrointestinal disorders, general disorders, skin and subcutaneous tissue disorders, investigations. As for irAEs, the frequent system-specific adverse events related to different therapy lines were also similar, including endocrine adverse events, dermatologic adverse events, pulmonary adverse events, and gastrointestinal adverse events. Especially, the incidence of pneumonitis always ranks high in most of the analyses, while for the high-grade toxicities, first-line therapy focuses more on liver-related disorders in trAEs/irAEs.ConclusionsIn summary, the incidence of trAEs in first-line therapy of PD-1/PD-L1 inhibitors in NSCLC is similar to the one in subsequent therapy, while the rate of having any-grade irAEs and high-grade trAEs/irAEs in first-line therapy is higher than the one in subsequent therapy. Meanwhile, there is no obvious heterogeneity for disease spectra in different therapy lines.

Research Progress of CDK4/6 Inhibitors in Non-small Cell Lung Cancer

肺癌是全球癌症相关死亡的首要原因，非小细胞肺癌（non-small cell lung cancer, NSCLC）占肺癌的80%-85%。恶性肿瘤可以无限增殖，细胞周期失调控是恶性肿瘤特征之一。细胞周期依赖激酶（cyclin D-dependent kinase, CDK）4/6抑制剂能阻滞肿瘤细胞通过G1期进入S期从而抑制肿瘤增殖，该药物在激素受体阳性乳腺癌中取得了良好的疗效，联合内分泌治疗成为这类患者一线标准治疗。细胞周期失控在NSCLC中比较常见，发生率约为22%-45%，CDK4/6抑制剂也进行了一系列的探索研究，并取得一定的效果，将来有可能成为新的治疗手段。本文重点讨论CDK4/6抑制剂在NSCLC的研究进展，包括作用机制、获批药物、在NSCLC中的临床研究进展、疗效预测生物标记物及局限性等。

Predictive value of CD73 expression for the efficacy of immune checkpoint inhibitors in NSCLC.

BackgroundCD73 induces the dephosphorylation of adenosine monophosphate converting it to adenosine, enabling malignancies to escape from immune surveillance. Although CD73 overexpression has been reported to be a poor prognostic factor in several malignancies including non‐small cell lung cancer (NSCLC), its predictive relevance in NSCLC patients receiving immune checkpoint inhibitors is unknown. The present research was conducted to investigate the prognostic significance of CD73 expression in NSCLC patients receiving immune checkpoint inhibitors (ICIs).MethodsWe screened 91 patients with advanced or recurrent NSCLC who received immune checkpoint inhibitors. CD73 expression was evaluated immunohistochemically using tissue specimens obtained just before treatment with ICIs.ResultsAnalysis of progression‐free survival (PFS) and overall survival (OS) in relation to several levels of CD73 expression (1%, 10%, 30%, and 50%) showed that both tended to be more favorable as expression of CD73 increased. PFS and OS were longer for patients in whom at least 50% of the tumor cells expressed CD73 than for those in whom <50% of the tumor cells did so. In patients who were positive for EGFR mutation, immune checkpoint inhibitors were significantly more effective in those with high CD73 expression, whereas CD73 expression did not significantly affect the efficacy in patients with EGFR mutation‐negative NSCLC. Furthermore, CD73 expression was predictive factor for the PFS independent of PD‐L1 expression in patients with EGFR mutation.ConclusionsHigh CD73 expression may predict a favorable response to ICIs in NSCLC patients, especially those harboring EGFR mutations.Key pointsSignificant findings of the study: In patients who were positive for EGFR mutation, immune checkpoint inhibitors (ICIs) were significantly more effective in those with high CD73 expression, whereas CD73 expression did not significantly affect the efficacy in patients with EGFR mutation‐negative NSCLC.What this study adds: High CD73 expression may predict a favorable response to immune checkpoint inhibitors in NSCLC patients, especially those harboring EGFR mutations.

Baseline Serum Interleukin-6 Levels Predict the Response of Patients with Advanced Non-small Cell Lung Cancer to PD-1/PD-L1 Inhibitors.

Although various studies on predictive markers in the use of PD-1/PD-L1 inhibitors are in progress, only PD-L1 expression levels in tumor tissues are currently used. In the present study, we investigated whether baseline serum levels of IL-6 can predict the treatment response of patients with advanced non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors. In our cohort of 125 NSCLC patients, the objective response rate (ORR) and disease control rate (DCR) were significantly higher in those with low IL-6 (<13.1 pg/ml) than those with high IL-6 (ORR 33.9% vs. 11.1%, p=0.003; DCR 80.6% vs. 34.9%, p<0.001). The median progression-free survival was 6.3 months (95% confidence interval [CI], 3.9–8.7) in the low IL-6 group, significantly longer than in the high IL-6 group (1.9 months, 95% CI, 1.6–2.2, p<0.001). The median overall survival in the low IL-6 group was significantly longer than in the high IL-6 group (not reached vs. 7.4 months, 95% CI, 4.8–10.0). Thus, baseline serum IL-6 levels could be a potential biomarker for predicting the efficacy and survival benefit of PD-1/PD-L1 inhibitors in NSCLC.

Non-small cell lung cancer cells with deficiencies in homologous recombination genes are sensitive to PARP inhibitors

Lung cancer is the leading cause of cancer death worldwide. PARP inhibitors have become a new line of cancer therapy and a successful demonstration of the synthetic lethality concept. The mechanism and efficacy of PARP inhibitors have been well studied in some cancers, especially homologous recombination (HR)-deficient ovarian cancer and breast cancer, yet such studies are still relatively fewer in lung cancer. Here we found that HR genes are frequently mutated in lung cancer patients, exposing a window for targeted therapies by PARP inhibitors. We depleted BRCA1 and BRCA2 in non-small cell lung cancer (NSCLC) cancer cells and found these cells are hypersensitive to the PARP inhibitor olaparib in cell viability and clonogenic survival assays. Olaparib specifically induces apoptosis in A549 cells with BRCA1 or BRCA2 depletion, as determined by positive Annexin-V staining. In addition, we show that A549 cells with ATM shRNA knockdown are also hypersensitive to Olaparib. In summary, our data support the potential use of PARP inhibitors in NSCLC with HR deficiency.

CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC.

Although EGFR mutant-selective tyrosine kinase inhibitors (TKI) are clinically effective, acquired resistance can occur by reactivating ERK. We show using in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype that CXCR7, an atypical G protein-coupled receptor, activates the MAPK-ERK pathway via β-arrestin. Depletion of CXCR7 inhibited the MAPK pathway, significantly attenuated EGFR TKI resistance, and resulted in mesenchymal-to-epithelial transition. CXCR7 overexpression was essential in reactivation of ERK1/2 for the generation of EGFR TKI-resistant persister cells. Many patients with non-small cell lung cancer (NSCLC) harboring an EGFR kinase domain mutation, who progressed on EGFR inhibitors, demonstrated increased CXCR7 expression. These data suggest that CXCR7 inhibition could considerably delay and prevent the emergence of acquired EGFR TKI resistance in EGFR-mutant NSCLC. SIGNIFICANCE: Increased expression of the chemokine receptor CXCR7 constitutes a mechanism of resistance to EGFR TKI in patients with non-small cell lung cancer through reactivation of ERK signaling.

SRC and MEK Co-inhibition Synergistically Enhances the Anti-tumor Effect in Both Non-small-cell Lung Cancer (NSCLC) and Erlotinib-Resistant NSCLC

Non-small-cell lung cancer (NSCLC) is the predominant form of lung cancer, and it is regulated by a complex signal transduction network. Single-agent targeted therapy often results in acquired resistance, which leads to treatment failure. In this study, we demonstrated that a combination of the kinase inhibitors trametinib and bosutinib can synergistically suppress the growth of NSCLC by inhibiting both the mitogen-activated protein kinase (MAPK) and proto-oncogene tyrosine-protein kinase (SRC) pathways. The combination was profiled against a panel of 22 NSCLC cell lines, including one erlotinib-resistant cell line, and this combination was found to show synergistic effects against 16 cell lines. NSCLC cell lines (HCC827, HCC827-erlotinib-resistant, and H1650) were treated with trametinib, bosutinib, or a combination of these drugs. The drug combination inhibited colony formation and induced cell apoptosis. A mechanism study showed that the phosphorylation of multiple kinases in the epidermal growth factor receptor (EGFR) signaling pathway in NSCLC was down-regulated. In addition, the combination significantly attenuated tumor growth of HCC827 xenografts with low toxicity. Our findings provide a theoretical basis for further study of the combination of MAPK and SRC pathway inhibitors in NSCLC, especially in the treatment of erlotinib-resistant NSCLC.

Abstract 3804: The potent AXL kinase inhibitor, TP-0903, is active in pre-clinical models of EGFR positive non-small cell lung cancer

Abstract Lung cancer is the leading cause of cancer related death in the US (2017). Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancer cases. While EGFR inhibitors (EGFRi) have shown activity in NSCLC, single agent response rates often do not exceed 10%. EGFR mutation is a common oncogenic driver in NSCLC, appearing in between 13% and 47% of all NSCLC patients depending on ethnicity. Third generation EGFRis, such as osimertinib, were approved upon demonstrating improved progression-free survival (PFS) rates versus standard therapy. However, EGFR inhibitor resistance, including resistance to osimertinib, has been reported to result from the epithelial-to-mesenchymal transition (EMT) that is coincident with increased AXL kinase expression. The AXL RTK drives EMT and constitutes a bypass survival pathway for tumor cells under EGFRi treatment pressure. We have shown that treatment with TP-0903, our potent AXL inhibitor, leads to a reversal of the mesenchymal phenotype in multiple cancer models. We therefore hypothesized that TP-0903 treatment may potentiate EGFRi treatment in cancer, and in particular EGFR mutant NSCLC. To interrogate our hypothesis, we treated cells with TP-0903 and assessed changes in cell viability with the celltiter-glo assay, changes in mRNA expression using RT-qPCR, and protein expression changes, using standard immunoblotting. In cell viability assays in the H1650 NSCLC cell line, TP-0903 showed an EC50 of 39 nM, while osimertinib showed an EC50 of 2.2 µM. In mRNA and protein assays, we observed changes consistent with a reversal of the mesenchymal phenotype. Following treatment, Slug mRNA expression was inhibited as much as 3.8-fold. However, E-cadherin expression was increased by 1.6-fold. To assess the combination in vivo, we utilized the H1650 xenograft model for NSCLC. In pharmacodynamic assessment of EMT markers in vivo, Snail protein expression was reduced as much as 56% following a single dose of TP-0903 (40 mpk, at 24hrs). In assessment of treatment efficacy in vivo, and with TP-0903 treatment (40 mpk, qd), we observed 60% tumor growth inhibition (%TGI) over the course of a 21-day treatment regimen. With osimertinib treatment (20 mpk, qd), we observed 121 %TGI. However, with the combination, we observed 140 %TGI. Due to its ability to reverse the aggressive mesenchymal phenotype of cancer cells, TP-0903 is a promising agent with the potential to have single agent activity and combined synergy with targeted anti-cancer agents. A Phase I trial with this investigational agent is ongoing, which includes patients with EGFR positive non-small cell lung cancer (clincaltrials.gov, NCT02729298). Taken together, the current study supports continued development of AXL inhibitors in NSCLC, especially in combination with EGFRis. Citation Format: Ryan Mangelson, Ethika Tyagi, Peter Peterson, Adam Siddiqui-Jain, Clifford J. Whatcott, David J. Bearss, Steven L. Warner. The potent AXL kinase inhibitor, TP-0903, is active in pre-clinical models of EGFR positive non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3804.

Is the Blood an Alternative for Programmed Cell Death Ligand 1 Assessment in Non-Small Cell Lung Cancer?

Anti-programmed cell death (PD)-1/PD-ligand 1 (L1) therapies have significantly improved the outcomes for non-small cell lung cancer (NSCLC) patients in recent years. These therapies work by reactivating the immune system and enabling it to target cancer cells once more. There is a general agreement that expression of PD-L1 on tumour cells predicts the therapeutic response to PD-1/PD-L1 inhibitors in NSCLC. Hence, immunohistochemical staining of tumour tissue biopsies from NSCLC patients with PD-L1 antibodies is the current standard used to aid selection of patients for treatment with anti-PD-1 as first line therapy. However, issues of small tissue samples, tissue heterogeneity, the emergence of new metastatic sites, and dynamic changes in the expression of PD-L1 may influence PD-L1 status during disease evolution. Re-biopsy would expose patients to the risk of complications and tardy results. Analysis of PD-L1 expression on circulating tumour cells (CTCs) may provide an accessible and non-invasive means to select patients for anti-PD-1 therapies. Additionally, CTCs could potentially provide a useful biomarker in their own right. Several published studies have assessed PD-L1 expression on CTCs from NSCLC patients. Overall, analysis of PD-L1 on CTCs is feasible and could be detected prior to and after frontline therapy. However, there is no evidence on whether PD-L1 expression on CTCs could predict the response to anti-PD-1/PD-L1 treatment. This review examines the challenges that need to be addressed to demonstrate the clinical validity of PD-L1 analysis in CTCs as a biomarker capable of predicting the response to immune checkpoint blockade.