Subgroup Of Non-small Cell Lung Cancer Patients Research Articles

PD-L1 on large extracellular vesicles is a predictive biomarker for therapy response in tissue PD-L1-low and -negative patients with non-small cell lung cancer.

Immunotherapy has revolutionized the treatment of patients with non-small cell lung cancer (NSCLC). High expression of tissue PD-L1 (tPD-L1) is currently the only approved biomarker for predicting treatment response. However, even tPD-L1 low (1-49%) and absent (<1%) patients might benefit from immunotherapy but, to date, there is no reliable biomarker, that can predict response in this particular patient subgroup. This study aimed to test whether tumour-associated extracellular vesicles (EVs) could fill this gap. Using NSCLC cell lines, we identified a panel of tumour-related antigens that were enriched on large EVs (lEVs) compared to smaller EVs. The levels of lEVs carrying these antigens were significantly elevated in plasma of NSCLC patients (n=108) and discriminated them from controls (n=77). Among the tested antigens, we focused on programmed cell death ligand 1 (PD-L1), which is a well-known direct target for immunotherapy. In plasma lEVs, PD-L1 was mainly found on a population of CD45- /CD62P+ lEVs and thus seemed to be associated with platelet-derived vesicles. Patients with high baseline levels of PD-L1+ lEVs in blood showed a significantly better response to immunotherapy and prolonged survival. This was particularly true in the subgroup of NSCLC patients with low or absent tPD-L1 expression, thus identifying PD-L1-positive lEVs in plasma as a novel predictive and prognostic marker for immunotherapy.

Correlation of Lung Immune Prognostic Index With Efficacy of PD-1/PD-L1 Inhibitor Combined With Chemotherapy and Prognosis in Patients With Advanced Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is a devastating but universal class of lung carcinoma with an unfavorable prognosis. This paper mainly investigated the correlation between lung immune prognostic index (LIPI) score and combined treatment of immune checkpoint inhibitor and chemotherapy (CHT) in patients with advanced NSCLC. Totally, 301 advanced NSCLC patients with programmed death-ligand 1 (PD-L1) expression ≥1% were assigned into good LIPI group (N=113), intermediate LIPI group (N=101), and poor LIPI group (N=87) based on LIPI scoring system, followed by treatment of CHT plus programmed cell death-1 (PD-1)/PD-L1 inhibitor. The differences in clinical parameters between subgroups of NSCLC patients were analyzed by χ 2 test, 1-way analysis of variance, and Kruskal-Wallis H test. All patients were followed up until June 30, 2022, and objective response rate, disease control rate, progression-free survival (PFS), and overall survival (OS) were recorded. The independent associations of LIPI score with PFS and OS were assessed via the Cox regression model. There were evident differences in clinical stage and lymphocyte among the 3 subgroups of NSCLC patients. The efficacy of PD-1/PD-L1 inhibitor combined with CHT was better in patients with good LIPI score, manifested by higher objective response rate and disease control rate. Moreover, LIPI score was an independent factor influencing PFS and OS in patients with advanced NSCLC, with longer PFS and OS in patients with good LIPI score. LIPI score has a predictive value for combination therapy of PD-1/PD-L1 blockade and CHT in advanced NSCLC patients.

Abstract 6116: Ablation of mitotic checkpoint kinase BUB1 sensitizes lung adenocarcinoma to different classes of chemotherapy, radiation, and chemo-radiation

Abstract Lung cancer causes the most cancer associated deaths worldwide. About 80 percent patients with inoperable non-small cell lung cancer (NSCLC) develop local recurrence and about 60 percent distant metastasis. NSCLC subtype, lung adenocarcinoma (LUAD) accounts for about 40% of all lung cancers. Recently, targeted therapy with chemotherapy combination has shown to enhance the pathologic complete response rate in a subgroup of NSCLC patients, but most patients do not benefit from therapy due to development of resistance. Thus, identifying molecular drivers of primary and adaptive chemotherapy resistance that can be effectively targeted represents a critical unmet clinical need. Here we aim to evaluate BUB1 (a mitotic checkpoint kinase) as a viable molecular target for increasing the effectiveness of radiotherapy and chemotherapy in LUAD. Bioinformatic analyses were conducted to evaluate BUB1 expression across lung cancer and normal tissues. BUB1 was found to be overexpressed in LUAD compared to normal tissues and BUB1 expression also correlated with cancer stage and tumor grade. LUAD cell lines A549, H1975 and H2030 were used to study the effect of BUB1 inhibition on chemo-radiosensitization. MTT cell proliferation and clonogenic cell survival studies were conducted with pharmacological (BAY1816032) and genomic (CRISPR) BUB1 ablation in combination with Platinum (Cisplatin), Taxol (Paclitaxel) or a PARP inhibitor (Olaparib) without/with radiation. BUB1 inhibition showed cytotoxicity in LUAD cell lines at micromolar concentration and enhanced the radiation mediated cell killing at nanomolar concentration. Moreover, BUB1 inhibition sensitized LUAD cell lines to Cisplatin, Paclitaxel and Olaparib in double or triple chemotherapy combinations. Additionally, BUB1 inhibition significantly increased LUAD cell death when combined with different classes of chemotherapies with radiation (chemo-radiation). Our preliminary mechanistic studies revealed prolonged presence of γH2AX foci, an indicator of DNA double stand breaks. BLRR DNA damage reporter assay indicated that the non-homologous end joining (NHEJ) pathway was inhibited upon BUB1 ablation. Detailed mechanistic studies combining BUB1 ablation with chemo-radiation are underway to delineate signaling cascades involved in BUB1 driven chemo-radiation sensitization. Our data provides evidence that BUB1 inhibition sensitizes lung adenocarcinoma to radiotherapy, different classes of chemotherapy and chemo-radiation through DNA-double strand break repair pathways and provides rationale for clinical trials that combine BUB1 inhibition with chemo-radiation in NSCLC. Citation Format: Shivani Thoidingjam, Sushmitha Sriramulu, Farzan Siddiqui, Benjamin Movsas, Shirish Gadgeel, Shyam Nyati. Ablation of mitotic checkpoint kinase BUB1 sensitizes lung adenocarcinoma to different classes of chemotherapy, radiation, and chemo-radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6116.

Genome-wide CRISPR/Cas9 screening for therapeutic targets in NSCLC carrying wild-type TP53 and receptor tyrosine kinase genes.

BackgroundTargeted drugs have greatly improved the therapeutic outcome of non‐small cell lung cancer (NSCLC) patients compared with conventional chemotherapy, whereas about one‐third of patients are so far not suitable for targeted therapy due to lack of known driver oncogenes such as a mutated receptor tyrosine kinase (RTK) genes. In this study, we aimed to identify therapeutic targets for this subgroup of NSCLC patients.MethodsWe performed genome‐wide CRISPR/Cas9 screens in two NSCLC cell lines carrying wild‐type TP53 and receptor tyrosine kinase (wtTP53‐RTK) genes using a GeCKO v2.0 lentiviral library (containing 123411 sgRNAs and targeting 19050 genes). MAGeCKFlute was used to analyse and identify candidate genes. Genetic perturbation and pharmacological inhibition were used to validate the result in vitro and in vivo.ResultsThe Genome‐wide CRISPR/Cas9 screening identified MDM2 as a potential therapeutic target for wtTP53‐RTK NSCLC. Genetic and pharmacological inhibition of MDM2 reduced cell proliferation and impaired tumour growth in the xenograft model, thus confirming the finding of the CRISPR/Cas9 screening. Moreover, treatment by a selective MDM2 inhibitor RG7388 triggered both cell cycle arrest and apoptosis in several NSCLC cell lines. Additionally, RG7388 and pemetrexed synergistically blocked the cell proliferation and growth of wtTP53‐RTK tumours but had limited effects for other genotypes.ConclusionsWe identified MDM2 as an essential gene and a potential therapeutic target in wtTP53‐RTK NSCLC via a genome‐wide CRISPR/Cas9 screening. For this subgroup, treatment by RG7388 alone or by its combination with pemetrexed resulted in significant tumour inhibition.

Trial in progress: A phase 2 study of sotorasib as first-line treatment in patients with stage IV non–small cell lung cancer (NSCLC) whose tumors harbor a KRAS p.G12C mutation (CodeBreaK 201).

TPS9150 Background: Chemo-immunotherapy regimens represent a standard of care for the first-line treatment of metastatic NSCLC, yet clinical outcomes in patients bearing tumors that lack PD-L1 expression [PD-L1 Tumor Proportion Score (TPS) &lt; 1%)] or harbor a serine/threonine kinase 11 ( STK11) mutation remain poor. Sotorasib is a selective, irreversible small molecule KRASG12C inhibitor that is approved for the treatment of patients with locally advanced or metastatic KRAS p.G12C-mutated NSCLC following failure of at least one prior line of systemic therapy and has previously demonstrated robust antitumor activity in subgroups of KRAS p.G12C mutant NSCLC with PD-L1 TPS &lt;1% and/or STK11 co-mutations. We hypothesized that sotorasib may represent an effective first-line therapy for subgroups of NSCLC patients who may have suboptimal chemo-immunotherapy outcomes and a high unmet clinical need. Methods: This phase 2, open-label, global study is designed to evaluate the efficacy and safety of sotorasib (960 mg or 240 mg daily) as first-line treatment in approximately 170 patients with KRAS p.G12C-mutated, metastatic NSCLC with PD-L1 TPS &lt;1% as determined by immunohistochemical assay and/or presence of STK11 mutation as determined by next-generation sequencing (NGS). Key eligibility criteria include patients with untreated metastatic NSCLC without active brain metastases. Patients will be stratified by known presence of STK11 mutation. The primary endpoint is objective response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary endpoints include disease control, duration of response, time to response, progression-free survival per RECIST 1.1, overall survival, safety and tolerability, and pharmacokinetic profile. Enrollment began in January 2022 and is ongoing. Contact Amgen Medical Information for more information. Clinical trial information: NCT04933695.

Distinct exhaustion features of T lymphocytes shape the tumor-immune microenvironment with therapeutic implication in patients with non-small-cell lung cancer

BackgroundReinvigoration of T-cell exhaustion with antibodies has shown promising efficacy in patients with non-small-cell lung cancer (NSCLC). However, the characteristics of T-cell exhaustion with regard to tumor-infiltrating lymphocytes (TILs) are...

P50.05 Natural History and Real-World Treatment Outcomes for NSCLC Patients with EGFR Exon 20 Insertion Mutation: An IASLC- ASCO CancerLinQ Study

Epidermal Growth Factor Receptor (EGFR) exon 20 insertion (ex20ins) mutations account for 2-3% all non-small cell lung cancer (NSCLC) patients. Patients with ex20 ins do not respond to standard EGFR TKI therapy. In this work, we have analyzed the characteristics, treatment patterns and outcomes in this subgroup of NSCLC patients. The ASCO CancerLinQ Discovery dataset was queried to identify patients diagnosed with NSCLC between the years 1995-2018 and with EGFR ex20ins mutations. Data were extracted on patient demographics, tumor characteristics, treatments and outcomes, and compared with Chi-square and ANOVA tests. Kaplan-Meier (KM) curves were generated for comparing overall survival with log-rank tests. All analyses were performed using Python 3.6. A total of 357 patients were eligible. Patient characteristics: median age 68 years, female 53.5%, white race 63% and black race 9%. Approximately 62% had stage 4 disease, and 30% had brain metastasis. 54% of the patients were treated with chemotherapy and 15% with immune check point inhibitors (ICI). In patients with brain metastasis, 16% were treated with ICI, 18% targeted therapy and 59% with chemotherapy. The median survival of the entire group is 23.8 months. Among patients with stage 4 disease: 51% were females, 64% white race, 37% had brain metastasis, 18% were treated with ICI, 14% targeted therapy and 60% treated with chemotherapy. In the analysis of stage 4 patients, the median survival of the group was 16.8 months. Stage 4 patients that received ICI had better survival vs. those who did not (29.1 vs. 14.7 months; p=0.01). Stage 4 patients treated with ICI and chemotherapy had better survival compared to those treated with chemotherapy alone (29.1 vs. 16.5 months, p=0.01). Stage 4 patients treated with targeted therapy had better survival compared to those that did not receive targeted therapy (20.6 vs. 16.1 months; p=0.03). Stage 4 NSCLC patients with EGFR ex20ins mutation had favorable real-world survival when treated with ICI and targeted therapy.

How to optimize the incorporation of immunotherapy in trials for oligometastatic non-small cell lung cancer: a narrative review.

Patients with oligometastatic disease (OMD) non-small cell lung cancer (NSCLC) are considered as a subgroup of metastatic NSCLC that can obtain long-term survival or even cure. Oligometastatic refers to a state of a limited number of metastases in a limited number of organs. In clinical guidelines it is stated that patients with oligometastatic NSCLC can benefit from the addition of local radical therapy (LRT) to systemic therapy. With the introduction of minimally invasive surgery, advances in interventional radiology and stereotactic radiotherapy (SRT), LRT is becoming feasible for more and more patients. Furthermore, the introduction of immune checkpoint inhibitors (ICI) in the treatment landscape of advanced NSCLC has improved the survival of these patients. Importantly, the use of ICI in combination with LRT is also of interest in the subgroup of NSCLC patients with OMD. For example, it has been suggested that SRT may synergize with ICI as several preclinical studies reported an increased tumor antigen release, improved antigen presentation, and T-cell infiltration in irradiated tumors. In this narrative review, we describe the current evidence of immunotherapy treatment in OMD NSCLC, with a focus on future trial design and problems that need to be addressed.

Potential Prospective Biomarkers for Non-small Cell Lung Cancer: Mini-Chromosome Maintenance Proteins.

Minichromosome maintenance proteins (MCMs) are considered to be essential factors coupling DNA replication to both cell cycle progression and checkpoint regulation. Previous studies have shown that dysregulation of MCMs are implicated in tumorigenesis of lung cancer. However, the distinct expression/mutation patterns and prognostic values of MCMs in lung cancer have yet to be systematically elucidated. In the present study, we analyzed the transcriptional levels, mutations, and prognostic value of MCM1-10 in non-small cell lung cancer (NSCLC) patients using multiple bioinformatics tools, including ONCOMINE, GEPIA, Kaplan–Meier Plotter, cBioPortal, and GESA. The analysis results from GEPIA dataset showed that MCM2/4/10 was significantly high expressed in both lung adenocarcinoma (LUAD) and squamous cell lung carcinomas (LUSCs). Meanwhile, the expression levels of MCM2/4/6/7/8 were associated with advanced tumor stages. Subsequent survival analysis using the Kaplan–Meier Plotter indicated that high expression levels of MCM1/2/3/4/5/6/7/8/10 were associated with worse overall survival (OS), while high expression level of MCM9 predicted better OS in these patients. Furthermore, we experimentally validated overexpression of MCM2 and MCM4 in NSCLC, thus the results from this study support a view that they may serve as potential prospective biomarkers to identify high-risk subgroups of NSCLC patients.

A narrative review of MET inhibitors in non-small cell lung cancer with MET exon 14 skipping mutations.

Treatment of advanced non-small cell lung cancer (NSCLC) has radically improved in the last years due to development and clinical approval of highly effective agents including immune checkpoint inhibitors (ICIs) and oncogene-directed therapies. Molecular profiling of lung cancer samples for activated oncogenes, including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF, is routinely performed to select the most appropriate up-front treatment. However, the identification of new therapeutic targets remains a high priority. Recently, MET exon 14 skipping mutations have emerged as novel actionable oncogenic alterations in NSCLC, sensitive to MET inhibition. In this review we discuss: (I) MET gene and MET receptor structure and signaling pathway; (II) MET exon 14 alterations; (III) current data on MET inhibitors, mainly focusing on selective MET tyrosine kinase inhibitors (TKIs), in the treatment of NSCLC with MET exon 14 skipping mutations. We identified the references for this review through a literature search of papers about MET, MET exon 14 skipping mutations, and MET inhibitors, published up to September 2020, by using PubMed, Scopus and Web of Science databases. We also searched on websites of main international cancer congresses (ASCO, ESMO, IASLC) for ongoing studies presented as abstracts. MET exon 14 skipping mutations have been associated with clinical activity of selective MET inhibitors, including capmatinib, that has recently received approval by FDA for clinical use in this subgroup of NSCLC patients. A large number of trials are testing MET inhibitors, also in combinatorial therapeutic strategies, in MET exon 14-altered NSCLC. Results from these trials are eagerly awaited to definitively establish the role and setting for use of these agents in NSCLC patients.

Harnessing the epigenome to boost immunotherapy response in non-small cell lung cancer patients.

The introduction of immune checkpoint inhibitor (ICI)-based therapy for non-oncogene addicted non-small cell lung cancer (NSCLC) has significantly transformed the treatment landscape of the disease. Inhibitors of the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint axis, which were initially considered as a late-line treatment option, gradually became the standard of care as first-line treatment for subgroups of NSCLC patients. However, a significant fraction of patients either fails to respond or progresses after a partial response to ICI treatment. Thus, the identification of mechanisms responsible for innate and acquired resistance to immunotherapy within a rapidly evolving tumor microenvironment (TME) is urgently required, as is the identification of reliable predictive biomarkers beyond PD-L1 expression. The deregulation of the epigenome is a key driver of cancer initiation and progression, and it has also been shown to drive therapeutic resistance. Tumor education of infiltrating myeloid cells towards an immuno-suppressive phenotype as well as induction of T-cell dysfunction in the TME is also driven by epigenome reprogramming. As it stands and, given their dynamic nature, epigenetic changes in cancer and non-cancer cells represent an attractive target to increase immunotherapy activity in NSCLC. Accordingly, clinical trials of combinatorial immuno-epigenetic drug regimens have been associated with tumor response in previously immunotherapy-resistant NSCLC patients irrespective of their PD-L1 status. Moreover, epigenetic signatures might represent valuable theragnostic biomarkers as they can be assayed easily in liquid biopsy and provide multiple layers of information. In this review, we discuss the current knowledge regarding the dysregulated epigenetic mechanisms contributing to immunotherapy resistance in NSCLC. Although the clinical data are still maturing, we highlight the attractive perspective that the synergistic model of immuno-epigenetic strategies might overcome the current limitations of immunotherapy alone and will be translated into durable clinical benefit for a broader NSCLC population.

18F-FDG PET/CT Scans Can Identify Sub-Groups of NSCLC Patients with High Glucose Uptake in the Majority of Their Tumor Lesions.

Background: Reprogrammed glucose metabolism is a hallmark of cancer making it an attractive therapeutic target, especially in cancers with high glucose uptake such as non-small cell lung cancer (NSCLC). Tools to select patients with high glucose uptake in the majority of tumor lesions are essential in the development of anti-cancer drugs targeting glucose metabolism. Type 2 diabetes mellitus (T2DM) patients may have tumors highly dependent on glucose uptake. Surprisingly, this has not been systematically studied. Therefore, we aimed to determine which patient and tumor characteristics, including concurrent T2DM, are related to high glucose uptake in the majority of tumor lesions in NSCLC patients as measured by 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) scans.Methods: Routine primary diagnostic 18F-FDG PET/CT scans of consecutive NSCLC patients were included. Mean standardized uptake value (SUVmean) of 18F-FDG was determined for all evaluable tumor lesions and corrected for serum glucose levels according to the European Association of Nuclear Medicine Research Ltd guidelines. Patient characteristics potentially determining degree of tumor lesion glucose uptake in the majority of tumor lesions per patient were investigated.Results: The cohort consisted of 102 patients, 28 with T2DM and 74 without T2DM. The median SUVmean per patient ranged from 0.8 to 35.2 (median 4.2). T2DM patients had higher median glucose uptake in individual tumor lesions and per patient compared to non-diabetic NSCLC patients (SUVmean 4.3 vs 2.8, P < 0.001 and SUVmean 5.4 vs 3.7, P = 0.009, respectively). However, in multivariable analysis, high tumor lesion glucose uptake was only independently determined by number of tumor lesions ≥1 mL per patient (odds ratio 0.8, 95% confidence interval 0.7-0.9).Conclusions: 18F-FDG PET/CT scans can identify sub-groups of NSCLC patients with high glucose uptake in the majority of their tumor lesions. T2DM patients had higher tumor lesion glucose uptake than non-diabetic patients. However, this was not independent of other factors such as the histological subtype and number of tumor lesions per patient.

Identification of a novel subpopulation of Caspase-4 positive non-small cell lung Cancer patients

BackgroundTherapy/prognosis of Non-Small Cell Lung Cancer (NSCLC) patients are strongly related to gene alteration/s or protein expression. However, more than 50% of NSCLC patients are negative to key drugable biomarkers.MethodsWe used human samples of NSCLC and mouse models of lung adenocarcinoma.ResultsWe showed that caspase-4 was highly present in the tumor mass compared to non-cancerous human tissues. Interestingly, the orthologue murine caspase-11 promoted lung carcinogenesis in mice. Carcinogen-exposed caspase-11 knockout mice had lower tumor lesions than wild type mice, due to the relevance of caspase-11 in the structural lung cell as demonstrated by bone marrow transplantation and adoptive transfer experiments. Similarly to what observed in mice, caspase-4 was correlated to the stage of lung cancer in humans in that it induced cell proliferation in a K-Ras, c-MyC and IL-1α dependent manner. Caspase-4 positive adenocarcinoma (79.3%) and squamous carcinoma (88.2%) patients had lower median survival than patients who had lower levels of caspase-4. Moreover, PD-L1 expression and gene mutation (i.e. EGFR) were not correlated to caspase-4 expression. Instead, NSCLC patients who had K-Ras or c-MyC gene alteration were positively correlated to higher levels of caspase-4 and lower survival rate.ConclusionsWe identified a subgroup of NSCLC patients as caspase-4 positive among which double and triple positive caspase-4, K-Ras and/or c-MyC patients which prognosis was poor. Because K-Ras and c-MyC are still undrugable, the identification of caspase-4 as a novel oncoprotein could introduce novelty in the clinical yet unmet needs for NSCLC patients.

Update 2020: Management of Non-Small Cell Lung Cancer.

The past decade has seen a revolution of new advances in the management of non-small cell lung cancer (NSCLC) with remarkable progresses in screening, diagnosis, and treatment. The advances in systemic treatment have been driven primarily by the development of molecularly targeted therapeutics, immune checkpoint inhibitors, and anti-angiogenic agents, all of which have transformed this field with significantly improved patient outcomes. This review will address updates in lung cancer screening, liquid biopsy, and immunotherapy in the front-line setting. We discuss recent advances and highlight the plethora of new approvals of molecular-targeted therapy for subgroups of NSCLC patients with sensitizing EGFR, ALK, ROS1, RET, BRAF V600E, MET, and NTRK alterations.

Excision Repair Cross Complementation Group 1 Single Nucleotide Polymorphisms and Nivolumab in Advanced Non-Small Cell Lung Cancer.

Background: We hypothesized that non-small cell lung cancer (NSCLC) patients with a tumor positive for single nucleotide polymorphisms (SNPs) of the Excision Repair Cross Complementation Group 1 (ERCC-1) gene could be more genetically instable and consequently more responsive to a programmed cell death-1 (PD-1) blockade.Methods: We evaluated the T19007C and C8092A ERCC-1 SNPs by pyrosequencing assay, on tumor specimens from two independent cohorts of patients who relapsed after one or more prior systemic treatments for advanced NSCLC and who received nivolumab (3 mg/kg intravenously every 2 weeks) as part of the Italian Expanded Access Program. We aimed to assess the outcome of enrolled subjects according to the ERCC-1 SNPs status, to evaluate the role of these polymorphisms as putative biomarkers associated with a response/clinical benefit to anti-PD-1 therapies.Results: Of the 45 patients included in the final analysis, 21 (47%) and 16 (36%) were positive for the T19007C and C8092A polymorphic genotype (PG), respectively. In univariate analyses, overall survival (OS) and progression free survival (PFS) were shorter in patients with the T19007C PG, but neither difference achieved statistical significance (P = 0.131 and P = 0.717, respectively). The presence of the C8092A PG was associated with a longer OS and PFS, although statistical significance was only reached for PFS (P = 0.112 and P = 0.025, respectively). These results were confirmed by multivariate analyses. The response rate was only significantly higher in patients with the C8092A PG vs. wild type ERCC-1 (62 vs. 7%, P < 0.001).Conclusions: Results from this hypothesis generating pilot study, provided suggestive evidence that a subgroup of NSCLC patients could benefit differently from nivolumab according to the C8092A ERCC-1 SNP status. However, these data warrant further investigation.

Characterising the impact of pneumonia on outcome in non-small cell lung cancer: identifying preventative strategies.

BackgroundInfections remain a part of the natural course of cancer, and lung cancer patients often present with some form of respiratory infection that can lead to their ultimate demise.MethodsData was gathered concerning all unplanned hospital admissions (UHAs) to our centre from three separate patient cohorts; non-small cell lung cancer (NSCLC) patients (cohort 1), “other cancer” patients (breast, prostate, colon) (cohort 2) and all non-cancer patients (cohort 3).ResultsAcross the three cohorts, there were 455, 1,190 and 54,158 individual patient UHAs to our centre respectively. Within the NSCLC cohort, 164 UHAs were as a direct result of pneumonia (36.0%), compared to 1.3% and 2.2% in the other two cohorts (P<0.0001). In-hospital mortality and length of hospital stay were significantly higher in the pneumonia sub-group of NSCLC patients only compared with the other two patient cohorts (P<0.0001 and P=0.011 respectively). Within the NSCLC cohort, Patient age, pneumococcal vaccination status, pneumonia admission, smoking status and specific tumour stages were identified as significant independent risk factors for in-hospital mortality. Odds ratios of 0.160 for positive vaccination status and 9.522 for pneumonia admission indicate that for NSCLC patients admitted to hospital with a pneumonia without previous pneumococcal vaccination in the last 5 years, the odds of death were almost 60-fold higher.ConclusionsVigilance for infection, early diagnosis with adequate assessment and efforts to identify a culprit organism should be a priority when faced with these patients. Infection prevention strategies should be further explored to address this high mortality risk in NSCLC.

Hyperprogressive Disease upon Immune Checkpoint Blockade: Focus on Non-small Cell Lung Cancer.

Describe the controversial aspects of hyperprogressive disease (HPD) definition, mechanisms, and biomarkers. Although immune checkpoint inhibitors (ICIs) demonstrated a survival benefit in non-small cell lung cancer (NSCLC), an acceleration of tumor growth during ICI, defined as HPD, was reported in ~ 13-26% of NSCLC patients and correlated with worse survival compared with conventional progression. Different criteria have been used for HPD definition. The main limitation for the use of tumor growth rate and tumor growth kinetics variations is its inapplicability for patients without a pre-baseline imaging or progressing on non-measurable lesions. On the contrary, time to treatment failure and clinical criteria (i.e., worsening of performance status, presence of new lesions, or metastatic spread to different sites) can be useful in the above-mentioned settings but do not consent an assessment of tumor growth before ICI initiation. Several mechanisms of HPD have been proposed so far, involving both adaptive and innate immunity or based on cell-autonomous signals of cancer growth triggered by ICI. The characterization of HPD biomarkers and the identification and validation on large series of one or more mechanistic explanations for the HPD phenomenon are of paramount significance to avoid detrimental immunotherapy in a subgroup of patients and exploit novel therapeutic targets for future immunotherapy combinations. HPD occur in a subgroup of NSCLC patients treated with ICI. Several definitions and mechanisms have been proposed and a consensus on HPD criteria and biological bases is currently lacking.

1554P - Genomic and clinical characterization of non-small cell lung cancer (NSCLC) patients harboring mutations in FGFR2 and FGFR3

BackgroundAmplifications in FGFR1are a potential target to therapy with FGFR inhibitors in squamous cell carcinoma NSCLC (SqCC). Recent insights in other entities demonstrate that the efficacy of these inhibitors is not limited to FGFR1 but affects the whole receptor family. We set out this analysis to identify NSCLC patients with mutations in FGFR2 and/or FGFR3 and to describe clinical and genomic characteristics. MethodsWithin the Network Genomic Medicine Lung Cancer (NGM), all stage IV patients underwent genomic testing using a gene panel consistent of 17 potential oncogenes. The panel was implemented in 2015, and data cut-off for this analysis was July 2018. The panel focuses on point mutations or deletions, i. e., rearrangements or copy-number aberrations were not detectable. ResultsOf 6000 patients analyzed, 26 (0.4%) had an FGFR2 mutation and 21 (0.4%) an FGFR3 mutation. 95% of the detected mutations have not been reported so far. Clinically, both subgroups differed from each other, most strikingly in the clinical presentation: The vast majority of FGFR2 mutations were detected in non-SqCC (76.9%), whereas FGFR3 mutations occurred more commonly in SqCC (57.1%). In the FGFR2 group, more female patients were affected (57.7%), contrasting 71.4% male patients in the FGFR3 group. KRAS mutations co-occurred more frequently in the FGFR2 group (23.1% vs 9.5%) and PIK3CA mutations more frequently in the FGFR3 group (19.0% vs 7.7%). For both groups, most mutations did not affect the kinase domain. Patients with FGFR2 mutation seem to have a favorable outcome as compared to FGFR3 patients (median overall survival not reached vs 8.0 months), but follow-up is still immature (p=0.201). ConclusionsPatients with FGFR2 and FGFR3 mutations represent two vastly different subgroups of NSCLC patients. Both mutations are not limited to SqCC and seem to have different prognoses for the outcome of the patients. Further work on the characterization of the different mutations is ongoing. Legal entity responsible for the studyNetwork Genomic Medicine (NGM) Lung Cancer. FundingHas not received any funding. DisclosureM. Scheffler: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: Mediolanum Biosciences; Honoraria (self): Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Takeda; Advisory / Consultancy: BMS. A. Kron: Advisory / Consultancy: BMS; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Novartis. D.S.Y. Abdulla: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Travel / Accommodation / Expenses: AbbVie. R. Riedel: Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly. S. Michels: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim. R.N. Fischer: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Travel / Accommodation / Expenses: Boehringer Ingelheim. S. Merkelbach-Bruse: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis. R. Büttner: Honoraria (self): Pfizer; Honoraria (self): Novartis. L. Nogova: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD. J. Wolf: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AbbVie; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Chugai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ignyta; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.

1240P - TP53 and ATM co-mutation predicts response to immune checkpoint inhibitors in non-small cell lung cancer

BackgroundImmune checkpoint inhibitors (ICIs) elicits durable responses in non–small cell lung cancer (NSCLC), but only a fraction of patients responded. TP53 and ATM co-mutation may lead to genomic instability and hypermutation. However, the prevalence and utility of a TP53/ATM co-mutation as a biomarker to ICIs are not fully understood. MethodsThis was a multiple cohort pooled study, 2020 NSCLC samples from Geneplus Institute, 1031 samples from TCGA, 1567 samples from MSKCC, 853 samples from POLAR/OAK databases were statically analyzed. Next-generation sequencing assays were performed in the Geneplus Institute. Genomic, transcriptomic and clinical data were obtained from the TCGA, MSKCC, POLAR/OAK databases. Comprehensive profiling was performed to determine the prevalence of TP53/ATM co-mutation and correlation with the prognosis and the response to ICIs. ResultsTP53/ATM co-mutation sites were found to be scattered throughout the genes and we did not observe any significant difference in TP53/ATM co-mutated frequency within the histologic subtypes and driver genes. In five independent NSCLC cohorts, TP53/ATM co-mutation contributed to significantly higher tumor mutation burden (TMB) compared to both the sole mutation and both wild type groups. Furthermore, in the MSKCC-IO cohort, a TP53/ATM co-mutation was associated with better OS than sole mutation and both wild type groups, especially in pan-cancer (P=.241, NSCLC and P<.0001, Pan-cancer). Similar results were shown in the POLAR/OAK cohort, the disease control benefit rate, and progression free survival (PFS) and OS were all greater in patients with the TP53/ATM co-mutation compared with the other three groups. GSEA showed that IFN-α response, IFN-γ response, IL6/JAK/STAT3 signaling, and TNF-α signaling pathways had higher levels of activation and there was greater PD-L1 expression in the co-mutated group, compared with solely mutated and both wild type group. ConclusionsOur findings suggest that patients with TP53/ATM co-mutation comprise a special subgroup of NSCLC patients and correlate with increasing TMB and responses to ICIs. It may have implications for potential predictive biomarker in guiding ICIs immunotherapy. Legal entity responsible for the studyJian Ji Pan. FundingNational Natural Science Foundation of China (Grant No. U1705282). DisclosureAll authors have declared no conflicts of interest.

Abstract 4748: RICTOR signaling modulates the activity of EGFR tyrosine kinase inhibitors (TKI) in EGFR-mutated non-small cell lung cancer (NSCLC)

Abstract Background: Molecularly-targeted therapy has significantly improved the therapeutic efficiency and clinical outcome in a subgroup of NSCLC patients. However, drug resistance inevitably emerges, such as resistance to EGFR TKIs in EGFR-mutated NSCLC. RICTOR is a key component of the mTORC2 complex and plays important roles in cell survival, proliferation, migration and invasion. RICTOR has also been suggested to play a part in the regulation of drug resistance to HER2-targeted therapy in HER2-amplified breast cancer, a niche close to EGFR-targeted therapy. In our current study, we hypothesize that RICTOR modulates the activity of EGFR TKIs in EGFR-mutated NSCLC. Co-targeting RICTOR and EGFR signaling pathways could be a new therapeutic strategy for patients with EGFR-mutated lung cancer. Results: Genetically modified EGFR-mutated NSCLC cell lines with different RICTOR expression levels have been developed. RICTOR knockdown significantly increases the sensitivity to all three generations of TKI inhibitors (erlotinib, afatinib and osimertinib), whereas overexpression of RICTOR renders the cells more resistant to EGFR TKIs. In addition, RICTOR knockdown restores the sensitivity of erlotinib-resistant HCC827 cells due to AXL overexpression (IC50: 216µM vs. 0.256 µM with RICTOR knockdown, P&amp;lt;0.001). Pharmacological inhibition of the RICTOR signaling pathway with the mTOR1/2 inhibitor (sapanisertib) also improves EGFR TKI sensitivity. Taken together, RICTOR signaling modulates the efficacy of EGFR TKIs in the EGFR-mutated lung cancer models. Conclusion: Our study provides a new insight into the role of RICTOR signaling modulation in increasing efficacy of EGFR TKI therapy in EGFR-mutated NSCLC. The combination of mTOR1/2 inhibitor and EGFR inhibitor could be a potential novel strategy leading to better therapeutic efficacy. Note: This abstract was not presented at the meeting. Citation Format: Ni Fan, Yiyu Zou, Balazs Halmos, Roman Perez-Soler, Haiying Cheng. RICTOR signaling modulates the activity of EGFR tyrosine kinase inhibitors (TKI) in EGFR-mutated non-small cell lung cancer (NSCLC) [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 4748.