Advanced Non-small Cell Lung Carcinoma Patients Research Articles

Biomarker Turnaround Times and Impact on Treatment Decisions in Patients with Advanced Non-Small Cell Lung Carcinoma at a Large Canadian Community Hospital with an Affiliated Regional Cancer Centre.

Background: Timely reporting of molecular biomarkers is critical in guiding optimal treatment decisions in patients with advanced non-small cell lung carcinoma (NSCLC). Any delays along the tissue or treatment pathway may be associated with suboptimal treatment/outcomes and a reduced quality of life. For many centres, biomarkers are tested off-site. Methods: A retrospective chart review of 123 patients with advanced NSCLC seen between 1 June 2021 and 30 June 2022 was conducted. With a focus on core biomarkers (PD L1, EGFR, and ALK), the outcome variables were as follows: total turnaround time (total TAT), divided into pre-laboratory, laboratory, and post-laboratory time intervals, as well as time to treatment decision (TOTD) and time to optimal systemic therapy decision (TOTSD). Results: At first consult, only 20.3% of patients had all core biomarker results available. The median total TAT was significantly longer for non-squamous (non-SCC) than squamous cell carcinoma (SCC) specimens (36.5 versus 22 days, p < 0.001). The median pre-laboratory time for the entire cohort was 5 calendar days. The median laboratory testing time was greater for non-SCC compared to the SCC specimens (23 versus 12 days, p < 0.001). The median time from consult to TOTD was 19 calendar days for the entire cohort. Conclusions: This study emphasizes the need for the expansion of regional resources to meet the clinical needs of advanced NSCLC patients treated at a regional cancer centre which uses an off-site molecular laboratory.

Desmoplasia in non-small cell lung carcinomas is associated with low programmed death-ligand 1 expression and the absence of tumor-infiltrating lymphocytes.

Programmed death-ligand 1 (PD-L1) is the most widely utilized predictive marker used to identify non-small cell lung carcinoma (NSCLC) patients most suitable for immunotherapy approaches. The relationship between PD-L1 expression, the presence of CD8+ T cells, and other clinicopathological characteristics of NSCLC patients has not been elucidated yet. In this retrospective study, we immunohistochemically determined PD-L1 expression (using clone 22C3) and CD8+ T cell count (using clone c8/144B) in surgical resection specimens from 698 advanced NSCLC patients. Results of PD-L1 expression and CD8+ T cell count were correlated to various clinicopathological characteristics, including the presence of desmoplasia in NSCLC. Regarding the immunological attributes of the tumor microenvironment, we identified major differences between desmoplastic and non-desmoplastic areas in NSCLC. Tumor areas without desmoplasia were significantly more often PD-L1 positive than tumor cell clusters encased in a dense collagenous stroma (p=0.004). Furthermore, the desmoplastic stroma contained significantly less often an immune cell infiltrate rich in CD8+ T cells (p<0.001). Also, the positivity of PD-L1 significantly correlated with advanced N-stage (p<0.001) and poor differentiation in adenocarcinomas (p=0.032) but not with other clinicopathological characteristics. In conclusion, to our knowledge, this is the first study that points to major differences in terms of immunological attributes between desmoplastic and non-desmoplastic areas in NSCLC. The desmoplastic component, therefore, may represent an immunologically distinct tumor area in which PD-L1 immunohistochemistry and CD8+ T cell count should be evaluated separately.

Identification of molecular biomarkers associated with non-small-cell lung carcinoma (NSCLC) using whole-exome sequencing.

Significant progress has been made in the treatment of patients with pulmonary adenocarcinoma (ADCA) based on molecular profiling. However, no such molecular target exists for squamous cell carcinoma (SQCC). An exome sequence may provide new markers for personalized medicine for lung cancer patients of all subtypes. The current study aims to discover new genetic markers that can be used as universal biomarkers for non-small cell lung cancer (NSCLC). WES of 19 advanced NSCLC patients (10 ADCA and 9 SQCC) was performed using Illumina HiSeq 2000. Variant calling was performed using GATK HaplotypeCaller and then the impacts of variants on protein structure or function were predicted using SnpEff and ANNOVAR. The clinical impact of somatic variants in cancer was assessed using cancer archives. Somatic variants were further prioritized using a knowledge-driven variant interpretation approach. Sanger sequencing was used to validate functionally important variants. We identified 24 rare single-nucleotide variants (SNVs) including 17 non-synonymous SNVs, and 7 INDELs in 18 genes possibly linked to lung carcinoma. Variants were classified as known somatic (n= 10), deleterious (n= 8), and variant of uncertain significance (n= 6). We found TBP and MPRIP genes exclusively associated with ADCA subtypes, FBOX6 with SQCC subtypes and GPRIN2, KCNJ18 and TEKT4 genes mutated in all the patients. The Sanger sequencing of 10 high-confidence somatic SNVs showed 100% concordance in 7 genes, and 80% concordance in the remaining 3 genes. Our bioinformatics analysis identified KCNJ18, GPRIN2, TEKT4, HRNR, FOLR3, ESSRA, CTBP2, MPRIP, TBP, and FBXO6 may contribute to progression in NSCLC and could be used as new biomarkers for the treatment. The mechanism by which GPRIN2, KCNJ12, and TEKT4 contribute to tumorigenesis is unclear, but our results suggest they may play an important role in NSCLC and it is worth investigating in future.

Targeting programmed cell death protein 1 (PD-1) for treatment of non-small-cell lung carcinoma (NSCLC); the recent advances.

The immune system uses various immune checkpoint axes to adjust responses, support homeostasis, and deter self-reactivity and autoimmunity. Nevertheless, non-small-cell lung carcinoma (NSCLC) can use protective mechanisms to facilitate immune evasion, which leads to potentiated cancer survival and proliferation. In this light, many blocking anti-bodies have been developed to negatively regulate checkpoint molecules, in particular, programmed cell death protein 1 (PD-1) / PD-ligand 1 (L1), and bypass these immune suppressive mechanisms. Meanwhile, anti-PD-1 anti-bodies such as nivolumab, pembrolizumab, cemiplimab, and sintilimab have shown excellent competence in successfully inspiring immune responses versus NSCLC. Accordingly, the United States Food and Drug Administration (FDA) has recently approved nivolumab (alone or in combination with ipilimumab) and pembrolizumab (alone or in combination with chemotherapy) as first-line treatment for advanced NSCLC patients. However, PD-1 blockade monotherapy remains inefficient in more than 60% of NSCLC patients, and many patients don't respond or acquire resistance to this modality. Also, toxicities related to anti-PD-1 anti-body have been progressively identified in clinical trials and oncology practice. Herein, we will outline the clinical benefits of PD-1 blockade therapy alone or in combination with other treatments (e.g., chemotherapy, radiotherapy, anti-angiogenic therapy) in NSCLC patients. Moreover, we will take a glimpse into the recently identified predictive biomarkers to determine patients most likely to suffer serious adverse events to decrease untoward toxicity risk and diminish treatment costs.

Neutrophil to lymphocyte ratio, platelet to lymphocyte ratio and one year survival of lung cancer in Sanglah hospital

Background: Lung cancer is ranked third as the most common cancer in Indonesia. The one-year survival rate of advanced-stage non-small cell lung carcinoma (NSCLC) patient is quite low, that is 24.6%. Effective and inexpensive prognostic markers need to be further studied due to an increasing incidence of cancer. Inflammation plays an important role in tumorigenesis and research showed an association of NLR and PLR values with poor prognosis in patients with various solid tumors, but current cut off values still vary. This study wanted to determine the value of NLR, PLR and their relationship with the survival rate of advanced stage NSCLC patients at Sanglah hospital.Methods: A retrospective cohort study using the medical record of 96 advanced-stage NSCLC patients who underwent treatment since January 2018 in Sanglah hospital, was closely monitored for a year since diagnosed. Analysis was performed with ROC, Kaplan Meier analysis, log rank test, and time independent cox regression model.Results: The one-year survival rate of advanced stage NSCLC patient is 14.6%, with median survival 3.26 months. Cut off NLR&gt; 3.37, median survival 2.66, p=0.00. Cut off PLR&gt;178.55, median survival 3.26, p=0.35. Multivariate analysis showed that NLR, HR=2.75 and performance status, HR=1.78 were associated with survival.Conclusions: NLR with cut off &gt;3.37 is associated with one-year survival rate of advanced-stage NSCLC patient. PLR did not have any significant association with one-year survival rate of advanced-stage NSCLC patient.

Pathological Response and Immune Biomarker Assessment in Non-Small-Cell Lung Carcinoma Receiving Neoadjuvant Immune Checkpoint Inhibitors.

Simple SummaryRecently, the U.S. Food and Drug Administration (FDA) approved neoadjuvant immunotherapy plus chemotherapy for the treatment of resectable non-small-cell lung carcinoma (NSCLC) due to the clinical benefits reported in several clinical trials. In these settings, the pathological assessment of the tumor bed to quantify a pathological response has been used as a surrogate method of clinical benefit to neoadjuvant therapy. In addition, several clinical trials are including the assessment of tissue-, blood-, or host-based biomarkers to predict therapy response and to monitor the response to neoadjuvant treatment. In this manuscript, we provide an overview of current recommendations for the evaluation of pathological response and describe potential biomarkers used in clinical trials of neoadjuvant immunotherapy in resectable NSCLC.Lung cancer is the leading cause of cancer incidence and mortality worldwide. Adjuvant and neoadjuvant chemotherapy have been used in the perioperative setting of non-small-cell carcinoma (NSCLC); however, the five-year survival rate only improves by about 5%. Neoadjuvant treatment with immune checkpoint inhibitors (ICIs) has become significant due to improved survival in advanced NSCLC patients treated with immunotherapy agents. The assessment of pathology response has been proposed as a surrogate indicator of the benefits of neaodjuvant therapy. An outline of recommendations has been published by the International Association for the Study of Lung Cancer (IASLC) for the evaluation of pathologic response (PR). However, recent studies indicate that evaluations of immune-related changes are distinct in surgical resected samples from patients treated with immunotherapy. Several clinical trials of neoadjuvant immunotherapy in resectable NSCLC have included the study of biomarkers that can predict the response of therapy and monitor the response to treatment. In this review, we provide relevant information on the current recommendations of the assessment of pathological responses in surgical resected NSCLC tumors treated with neoadjuvant immunotherapy, and we describe current and potential biomarkers to predict the benefits of neoadjuvant immunotherapy in patients with resectable NSCLC.

Efficacy of pembrolizumab combined with anlotinib in 3 patients with advanced non-small cell lung cancer

Non-small-cell lung carcinoma (NSCLC) is any type of epithelial lung cancer and accounts for about 85% of all lung cancers. Pembrolizumab, a PD-1 inhibitor, is approved to treat patients with advanced NSCLC. Anlotinib, a multi-target tyrosine kinase inhibitor, is approved in China for treating patients with advanced NSCLC with progression or recurrence after ≥ 2 lines of systemic chemotherapy. Whether pembrolizumab combined with anlotinib has synergistic effects on treating advanced NSCLC patients remains unclear. Here we reported that three cases of patients with advanced NSCLC had a good response and a long time of PR to pembrolizumab combined with anlotinib treatment, indicating that combined administration of pembrolizumab and anlotinib can be optional management for advanced NSCLC.

ENose analysis for early immunotherapy response monitoring in non-small cell lung cancer

ObjectivesExhaled breath analysis by electronic nose (eNose) has shown to be a potential predictive biomarker before start of anti-PD-1 therapy in patients with non-small cell lung carcinoma (NSCLC). We hypothesized that the eNose could also be used as an early monitoring tool to identify responders more accurately at early stage of treatment when compared to baseline. In this proof-of-concept study we aimed to definitely discriminate responders from non-responders after six weeks of treatment. Materials and MethodsThis was a prospective observational study in patients with advanced NSCLC eligible for anti-PD-1 treatment. The efficacy of treatment was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 3-month follow-up. We analyzed SpiroNose exhaled breath data of 94 patients (training cohort n = 62, validation cohort n = 32). Data analysis involved signal processing and statistics based on Independent Samples T-tests and Linear Discriminant Analysis (LDA) followed by Receiver Operating Characteristic (ROC) analysis. ResultsIn the training cohort, a specificity of 73% was obtained at a 100% sensitivity level to identify objective responders. The Area Under the Curve (AUC) was 0.95 (CI: 0.89–1.00). In the validation cohort, these results were confirmed with an AUC of 0.97 (CI: 0.91–1.00). ConclusionExhaled breath analysis by eNose early during treatment allows for a highly accurate, non-invasive and low-cost identification of advanced NSCLC patients who benefit from anti-PD-1 therapy.

Results from a phase II study of eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab in patients with PD-L1 unselected metastatic non-small cell lung carcinoma.

9046 Background: Eftilagimod alpha (efti) is a soluble LAG-3 protein that binds to a subset of MHC class II molecules to mediate antigen presenting cell (APC) activation and CD8 T-cell activation. The stimulation of the dendritic cell network and subsequent T cell recruitment with efti may lead to stronger anti-tumor responses in combination than observed with pembrolizumab alone. We hereby report results of the 1st line non-small cell lung carcinoma (NSCLC) part of the phase II trial (NCT03625323). Methods: Patients (pts) with untreated, immunotherapy naïve, advanced NSCLC unselected for PD-L1 expression were recruited into part A. The study used a Simon's 2-stage design (17 pts planned for stage 1 and 19 pts for stage 2), with objective response rate (ORR) by iRECIST as the primary endpoint (EP). Secondary EPs include tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS), PK, PD and immunogenicity. Efti is administered as 30 mg subcutaneous injection every 2 wks for 8 cycles and then every 3 wks for 9 cycles with pembrolizumab (200 mg intravenous infusion every 3 wks for up to 2 yrs). Imaging was performed every 8 weeks locally and with blinded independent central review (BICR) retrospectively. The study was approved by ethic committees and institutional review boards. Results: In total 36 pts were enrolled. At data cut-off (Jan 2021; median FU of 14 months), the median age was 69 yrs (range 53-84) and 69 % were male. The ECOG PS 0 and 1 was 42% and 58% respectively. Patients had squamous (42%) and non-squamous (58%) NSCLC and 95% presented with metastatic disease. All PD-L1 subgroups (TPS &lt; 1 %, ≥ 1 % to ≤49 %; ≥50 %) were represented with 36% pts having ≥50% TPS. Pts received a median of 7.0 (range 1 – 31) pembrolizumab and 11.5 (range 1-22) efti administrations. Responses as per BICR and local read are shown in the table. ORR (local, iRECIST) by different PD-L1 subgroups was 27% for pts with TPS&lt;1%, 39 % for TPS ≥1 %and 54% for ≥50 % TPS. Median PFS (n=36) was 8.2 months while median OS was not yet reached. The most common (&gt; 20 %) treatment emergent adverse events (AEs) were asthenia (47 %), cough (36 %), decreased appetite (36 %), dyspnea (32 %), pruritus (31 %), fatigue (28 %), diarrhea (25 %), anemia (25 %), constipation (25 %) and back pain (22%). Two patients discontinued treatment due to adverse reactions (Grade 4 immune-mediated hepatitis, Grade 3 AST+ALT increase). Conclusions: Efti in combination with pembrolizumab is safe and shows encouraging antitumor activity in 1st line advanced NSCLC patients across all PD-L1 (TPS) levels. Clinical trial information: NCT03625323. [Table: see text]

Next-Generation Sequencing with Liquid Biopsies from Treatment-Naïve Non-Small Cell Lung Carcinoma Patients.

Simple SummaryScreening for genomic alterations in treatment-naïve non-small cell lung carcinoma (NSCLC) is mainly done by tissue biopsy (TB), an invasive approach. However, it may not be possible to obtain a TB, the patient does not consent to it and/or the extracted nucleic acids are of poor quantity and/or quality for further genomic analyses, so a liquid biopsy (LB) is the only option to detect molecular target(s) for first-line treatment in these patients. However, a LB at diagnosis is still not often used in clinical centers since a TB is currently the gold standard approach for histological diagnosis, assessment of the PD-L1 status on tumor cells and evaluation of the molecular alterations. A number of different approaches are already available for the assessment of genetic abnormalities with LB, but next-generation sequencing (NGS) is the most promising. This review provides an overview of the main studies currently using LB NGS at diagnosis for NSCLC. We discuss its advantages and limitations in comparison with a TB and the perspectives for the future.Recently, the liquid biopsy (LB), a non-invasive and easy to repeat approach, has started to compete with the tissue biopsy (TB) for detection of targets for administration of therapeutic strategies for patients with advanced stages of lung cancer at tumor progression. A LB at diagnosis of late stage non-small cell lung carcinoma (NSCLC) is also being performed. It may be asked if a LB can be complementary (according to the clinical presentation or systematics) or even an alternative to a TB for treatment-naïve advanced NSCLC patients. Nucleic acid analysis with a TB by next-generation sequencing (NGS) is gradually replacing targeted sequencing methods for assessment of genomic alterations in lung cancer patients with tumor progression, but also at baseline. However, LB is still not often used in daily practice for NGS. This review addresses different aspects relating to the use of LB for NGS at diagnosis in advanced NSCLC, including its advantages and limitations.

Abstract PO-063: Extracellular vesicle miRNAs and autophagic CTCs: Predictive and prognostic biomarkers in radiotherapy treated NSCLC patients

Abstract Introduction: Most non-small cell lung carcinoma (NSCLC) patients are diagnosed at advanced stages, when the prognosis is dismal. Thoracic irradiation in combination with chemotherapy have demonstrated to increase the survival of these patients, however, progression is still developed early. The failure of the treatment may be caused by inaccurate patient stratification due to the heterogeneous and evolving nature of tumors that tissue biopsy fails to reflect. Therefore, real-time predictive and prognostic biomarkers are needed to improve the survival of NSCLC patients. In this context, miRNAs are potential markers as they regulate the expression of cancer genes and can be selectively encapsulated into extracellular vesicles (EVs) by cancer cells and found in blood circulation. Similarly, circulating tumor cells (CTCs) are a key event in the metastatic process that shredded into the circulation resemble the features of the tissue of origin. Thus, CTCs can act as tissue surrogates and potential predictive and prognostic factors in these irradiated patients. Recent evidence has associated autophagy activation to an increased resistance to radiotherapy and chemotherapy. However, controversial reports showed a dual role of autophagy during tumor cell survival, thus requiring further research to be done. In this work, we aimed to identify the predictive and prognostic role of specific EV miRNAs and autophagic CTCs in advanced NSCLC patients under concomitant radio-chemotherapy. Methods: This study prospectively enrolled 38 locally advanced NSCLC patients under concomitant radio-chemotherapy (cisplatin-vinorelbine/carboplatin-taxol). Peripheral blood samples were drawn before, during, and after the treatment. CTCs were immunomagnetically isolated and autophagic activity was characterized by immunofluorescence. EVs were isolated by ultracentrifugation methods and specific miRNAs were analyzed by RT-PCR. Internal validation of the predictive model was performed by bootstrap approach. Results: The increase of EV-miR-375 and miR-200c was associated with the reduction of autophagic CTCs along the treatment (p=0.013 &amp; p=0.025). Moreover, baseline levels of EV-miR-375, miR-200c, and miR-30c predicted the response to the treatment with an area under the curve (AUC) of 86%. The presence of autophagic CTCs and low EV-miR-30c were independent prognostic biomarkers for shorter relapse-free survival (p=0.002 &amp; p=0.002) and overall survival (p=0.012 &amp; p&amp;lt;0.001). The analysis of miRNA targets showed that miR-375, miR-200c, and mir30c regulate genes involved in autophagy and cell division such as PIK3CA, potentially modulating radio-chemotherapy resistance. Conclusion: This study reports for the first time that EV-miRNAs and autophagic CTCs are predictive and prognostic biomarkers in advanced NSCLC patients under concomitant radio- chemotherapy. Their identification could serve as tumor surrogates for a real-time treatment stratification of NSCLC patients and might also benefit new combinatory strategies based on autophagy inhibition or immunotherapy. Citation Format: Diego de Miguel Perez, Rosario Guerrero Tejada, Alessandro Russo, Francisco Gabriel Ortega, Antonio Martínez-Única, Muthukumar Gunasekaran, Jose Antonio Lorente, Jose Exposito, Maria Jose Serrano Fernandez, Christian Rolfo. Extracellular vesicle miRNAs and autophagic CTCs: Predictive and prognostic biomarkers in radiotherapy treated NSCLC patients [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-063.

Blood T cell diversity associated with the prognosis of advanced non-small cell lung carcinoma treated with first-line pemetrexed based chemotherapy.

BackgroundThe tumor microenvironment is associated with prognosis in advanced non‐small cell lung carcinoma (NSCLC). The aim of this study was to explore the relationship between blood T cell diversity and survival of patients treated with pemetrexed‐based chemotherapy for nonsquamous NSCLC.MethodsThis prospective clinical study enrolled 26 patients with advanced NSCLC treated with 4–6 cycles of first‐line pemetrexed combined with platinum‐based therapy. The complementarity‐determining region 3 (CDR3) located in the T cell receptor beta chain (TCR β chain) was captured and deeply sequenced using next‐generation sequencing (NGS) technology, and the correlation between TCR changes and efficacy after chemotherapy was analyzed.ResultsPatients with an inferior quarter diversity index showed a significantly shorter progression‐free survival (PFS) than the others (median, 5.0 months vs. 8.1 months, P = 0.014). After two cycles of chemotherapy, the TCR diversity was significantly higher than the baseline (P = 0.034). Just as with the baseline, patients with an inferior quarter diversity index at the endpoint of cycle 2 showed a shorter progression‐free survival (PFS) than the others (median, 5.0 months vs. 8.4 months, P = 0.024).ConclusionsIn advanced NSCLC patients treated with first‐line pemetrexed combined with platinum, the low level of blood TCR diversity at baseline with an endpoint of two cycles of chemotherapy was correlated with a poor prognosis.

Soluble High Mobility Group Box 1 (HMGB1) Is a Promising Biomarker for Prediction of Therapy Response and Prognosis in Advanced Lung Cancer Patients.

Background: High mobility group box 1 protein (HMGB1) is known for its significant elevation in a multitude of tumors and benign diseases. In this study, we investigated the relevance of soluble HMGB1 for the prediction and monitoring of therapy response as well as the estimation of prognosis in advanced lung cancer. Materials and Methods: In a retrospective study, HMGB1 levels were assessed by an enzyme-linked immunosorbent assay (ELISA) in the sera of 96 patients with advanced lung cancer (79 non-small-cell lung carcinoma (NSCLC); 14 small cell lung carcinoma (SCLC), 3 Mesothelioma) prior to cycles 1, 2, and 3 of chemotherapy and correlated with radiological therapy response after 2 and 4 cycles as well as with overall survival. In addition, HMGB1 was compared with established tumor markers cytokeratin 19-fragments (CYFRA 21-1), carcinoembryonic antigen (CEA) and neuron specific enolase (NSE). Results: While pretherapeutic HMGB1 levels were not predictive or prognostically relevant in NSCLC patients, HMGB1 values prior to cycles 2 and 3 as well as kinetics from cycle 1 to 2 discriminated significantly between patients with good (remission and stable disease) and poor response (progression). Performance of HMGB1 in receiver operating characteristic (ROC) analyses of NSCLC patients, with areas under the curve (AUCs) of 0.690 at cycle 2 and 0.794 at cycle 3 as well as sensitivities of 34.4% and 37.5%, respectively, for progression at 90% specificity, was comparable with the best tumor-associated antigen CYFRA 21-1 (AUCs 0.719 and 0.799; sensitivities of 37.5% and 41.7%, respectively). Furthermore, high concentrations of HMGB1 at cycles 2 and 3 were associated with shorter overall survival in NSCLC patients. Conclusion: Soluble HMGB1 is a promising biomarker for prediction of therapy response and prognosis in advanced NSCLC patients.

Real-world effectiveness of nab-paclitaxel plus carboplatin as first-line therapy for patients with advanced NSCLC: Results of the second interim analysis of the NEPTUN study.

e21611 Background: Collecting real-world evidence is required not only to evaluate effectiveness and safety in routine clinical practice, but to improve clinical cancer outcomes. Methods: NEPTUN is a prospective, multicenter, non-interventional study designed to evaluate effectiveness, safety and quality of life (QoL) of first-line nab-Paclitaxel plus carboplatin in patients (pts) with advanced or metastatic non-small cell lung carcinoma (NSCLC) in the real-world setting in Germany. The primary endpoint was 6-months progression free survival rate (PFSR). Descriptive statistics were used to analyze data. Results: Between August 2016 and June 2019, 408 pts were enrolled at 75 active sites, 373 pts started treatment according to label. The cut-off date for this interim analysis (07 Dec 2019) was after all pts were observed for at least 6 months. The 6-months PFSR was 40.8% (95% CI, 35.3-46.2), median PFS 5.2 months (95% CI, 4.5-5.7). Overall response rate was 41.5% (95% CI, 36.3-46.8) with a complete response documented in 6 pts (1.7%) and a partial response in 142 pts (39.8%). Disease control rate was 61.6% (95% CI, 56.4-66.7). Employing a multivariable cox regression model for PFS adjusted for ECOG, histology, age group, renal impairment, and smoking status, elderly patients and patients with squamous histology were identified as being of favorable risk (HR squamous vs. non-squamous histology 0.76 (95% CI, 0.58-1.01); HR for ≥70 vs. &lt; 70 years of age 0.80 (95% CI, 0.59-1.08)). Median overall survival (OS) was 10.5 months (95% CI, 9.2-11.6) with 9.6 months (95% CI, 7.7-11.2) for non-squamous and 11.8 months (95% CI, 9.2-13.8) for squamous histology. 12-months OS rate was 43.1% (95% CI, 37.3-48.7). The most common treatment-emergent AEs (TEAEs) were anemia (26.5%), leukopenia (25.7%) and thrombocytopenia (16.6%). Polyneuropathy was documented for 11.3% of pts. 54.2% of pts developed TEAE grade 3/4 including leukopenia (10.2%), anemia (8.6%) and pneumonia (5.1%). 9.9% pts discontinued nab-paclitaxel due to nab-paclitaxel-related TEAEs. EQ-5D-5L visual analogue scale and FACT-L total score remained stable during therapy. Conclusions: nab-Paclitaxel plus carboplatin given first-line according to German SmPC in advanced NSCLC patients in a real-world clinical setting is an effective and safe therapy commonly applied. These results were similar to those reported in the phase iii clinical trial setting. QoL scores remained stable during first-line treatment. No new safety signals emerged. Clinical trial information: NCT02799862.

Neo-adjuvant chemotherapy followed by either continuous hyper-fractionated accelerated radiation therapy week-end less or conventional chemo-radiotherapy in locally advanced NSCLC-A randomised prospective single institute study.

Better locoregional control and increased overall survival by continuous hyper fractionated accelerated radiotherapy have been shown in unresectable nonsmall cell lung carcinoma (NSCLC). Dose escalation and neoadjuvant chemotherapy (NACT) along with continuous hyperfractionated accelerated radiotherapy week end-less (CHARTWEL) were also tried for improved survival. In this present study, we compared the results of NACT followed by CHARTWEL against NACT followed by conventional concurrent chemo-radiation therapy. The aim of this study is to compare the locoregional control and toxicities in NSCLC Stage IIIA and B in both arms. Randomized, prospective single-institutional study with a study population comprising all locally advanced unresectable NSCLC patients enrolled in 2014 at our institute. All enrolled patients were randomized into two arms-CHARTWEL and concomitant chemo-radiotherapy (CCRT), after three weeks of the fourth cycle of NACT. In CHARTWEL arm 30 patients received two-dimensional radiotherapy (RT) 58.5 Gy/39 fr/2.5 weeks while in CCRT arm 30 received 66 Gy/33 fr/6.5 weeks. Disease response was evaluated at 6 months and toxicity assessment during and after treatment completion. Data were analyzed using tools such as percentage, mean, Chi-square test and P value. Chi-square and P value was calculated by statistical online software (http://quantpsy.org). 28% of patients in study arm and 20% in control arm had complete response at 6 months after RT. Locoregional disease control was observed in 44% in study arm and 32% in control arm of patients. There was no statistical difference in grades of toxicities or overall survival (OS)/disease-free survival except persistent esophagitis Grade III seen in two patients of study arm. Study suggests that CHARTWEL in combination with NACT is an effective strategy to treat patients with locally advanced lung cancer with the advantage of a smaller dose and shorter duration. Although large multivariate studies still needed.

Abstract 4067: PD-L1 expression, CD8 cells and MHC-class-1 Beta-2-microglobulin expression in advanced non-small lung cancer

Abstract Introduction: PD-L1 expression has been approved as predictive biomarker for immune checkpoint inhibitors (ICI) in non-small cell lung carcinoma (NSCLC). In case of lack of PD-L1 expression in tumor biopsies, 8-10% of patients will respond to ICI. However, in case of &amp;gt; 50% PD-L1 tumor expression half of patients show no response. Tumor immune escape phenotypes are characterized by loss of MHC-class-I and a lower grade of CD8 T-cell infiltration, despite upregulation of PD-L1 expression. At least one of the four phenotypes of MHC-class-I and PD-L1 co-expression is considered responsible for non-responsiveness. We investigated the frequency of PD-L1, MHC-class-I β2-microglobulin (β-2M) co-expression and presence of CD8 cells in advanced NSCLC. Methods: Analysis was performed on formalin fixed, paraffin embedded (FFPE) transbronchial or transthoracic tumor biopsies of 27 patients with advanced NSCLC. Immunohistochemistry was performed using Ventana Benchmark Ultra immunostainer. PD-L1 was detected using Ventana PD-L1 (SP263) Assay (CE IVD), CD8 by Ventana CONFIRM anti-CD8 (SP57) antibody and MHC-class I β2-M by Agilent-Dako polyclonal rabbit anti-human beta-2-Microglobulin. PDL1 expression was scored as percentage positive tumor cells according to the manufacturers guideline, β2-M was scored as positive or negative in tumor cells and CD8 cells as low (+), intermediate (++) or high (+++) numbers in tumor or peritumoral stroma. Results: In 27 patients IHC staining was performed. PDL1 expression was scored as &amp;lt;1%, 1-49% and ≥50% in 17, 3, and 7 patients, respectively. PD-L1 positive (&amp;gt;1%) patients had positive β-2M in 10 of 10 cases. PD-L1 negative tumors showed presence of β-2M in 10 of 17 cases. Seven out of 27 cases (26%) were β-2M negative; all of them were PD-L negative cases. Low CD8 score was seen in 7 patients and 2 of these patients have a PD-L1 expression &amp;gt;1% and positive β-2M. Conclusion: In this ongoing study one quarter of advanced NSCLC patients had no tumor MHC-class-1 β-2M expression. In our cohort β-2M negative phenotype was associated with lack of PD-L1 tumor expression. Citation Format: Lucie Hijmering-Kappelle, Jeroen Hiltermann, Birgitta Hiddinga, Anthonie van der Wekken, Nils 't Hart, Harry Groen, Wim Timens. PD-L1 expression, CD8 cells and MHC-class-1 Beta-2-microglobulin expression in advanced non-small 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 4067.

EGFR exon 20 insertion mutations and response to osimertinib in non-small-cell lung cancer

BackgroundEpidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations represent approximately 4–12% of EGFR mutations and are generally refractory to the 1st and 2nd generation EGFR tyrosine kinase inhibitors (TKIs). Development of effective therapies for patients with EGFRex20ins mutant non-small-cell lung carcinoma (NSCLC) represents a great unmet need. Preclinical models have shown that osimertinib is active in NSCLC harboring EGFRex20ins, while the antitumor activity of osimertinib remains to be evaluated in patients with EGFRex20ins mutations.MethodsTumor genotyping was performed in 2316 Chinese NSCLC cases with targeted next generation sequencing (NGS) covering the whole exons of EGFR gene. The frequency and genetic characteristics of EGFRexon20ins mutations were analyzed. Furthermore, six patients with specific EGFRexon20ins mutations and receiving osimertinib 80 mg once daily were retrospectively included to assess the antitumor activity and safety of monotherapy osimertinib.ResultsEGFRex20ins mutations were identified in 4.8% (53/1095) of EGFR mutant NSCLC and 2.3% (53/2316) of all NSCLC cases. The most frequently identified EGFRexon20ins is A767_V769dup (17/53,32.1%). We found that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Four patients with osimertinib therapy achieved partial response and the rest stable disease. Median progression free survival (PFS) was 6.2 months (95% confidence interval 5.0–12.9 months; range 4.9–14.6 months). The most common adverse events (AEs) were diarrhea (2/6), pruritis (2/6), stomatitis (1/6) and nausea (1/6). No grade 3 or more AEs were documented.ConclusionsThis study revealed that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Furthermore, our study firstly demonstrated promising antitumor activity of osimertinib in certain EGFRex20ins mutant advanced NSCLC patients, indicating that osimertinib treatment for EGFRex20ins positive patients deserves further study.

P3.01-99 Effect of Pembrolizumab on Patients Harboring Uncommon Epidermal Growth Factor Receptor Mutations

The characteristics of non-small cell lung carcinoma (NSCLC) patients harboring uncommon epidermal growth factor receptor (EGFR) mutations differ from those of patients with common EGFR mutations. For example, male smokers were more common among patients with uncommon mutations. The efficacies of non-afatinib treatment strategies for patients harboring uncommon EGFR mutations are uncertain. The efficacy of immune checkpoint inhibitors (ICIs) in advanced NSCLC patients with EGFR mutations is limited. Furthermore, the efficacy of ICIs in patients harboring uncommon EGFR mutations is unknown. We retrospectively reviewed five NSCLC cases with uncommon EGFR mutations and high program death (PD)-ligand (L)1 expression (> 50%) on tumor cells that were treated with the ICI pembrolizumab in our institute from April 2017 to April 2018. We collected data include sex, age, performance status, smoking history, PD-L1 expression, EGFR mutations status and clinical outcome. Four cases were male, median age was 68 (45-78), 4 cases were former/current smokers, 1 case was stage IIIC, 2 cases were stage IVA and 2 cases were stage IVB, 4 cases had G719X and 1 case had both exon 19 deletion and T790M. Four cases were treated with pembrolizumab as first line treatment and 1 case were treated as second line treatment after afatinib. Median number of pembrolizumab doses were 4 (1-7) and best responses were 2 partial response (PR), 2 stable disease (SD) and 1 progressive disease (PD). As adverse events, 1 case had grade 3 colitis and 1 case had grade 1 pneumonitis. Four patients with the G719X mutation were male former/current smokers and were effectively treated (PR of SD) with pembrolizumab. However, one patient with both common mutation and de novo T790M did not respond to pembrolizumab (PD). ICI-based treatment for patients harboring uncommon EGFR mutations may be one of the treatment option.

Role of VEGF gene polymorphisms in the clinical outcome of non-small cell lung cancer.

This report details a study conducted to assess the role of VEGF gene polymorphisms in the prognosis of advanced non-small cell lung carcinoma (NSCLC). Samples obtained from 210 advanced NSCLC patients admitted at the Huaihe Hospital of Henan University between January 2010 and December 2011 were recruited for this study. The VEGF -2578C/A (rs699947), +936C/T (rs3025039), and -634G/C (rs2010963) genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism. We discovered, by logistic regression analysis, that the TT genotype of VEGF +936C/T was associated with more complete response + partial response to chemotherapy, compared to the CC genotype (odds ratio (OR) = 4.78, 95% confidence interval (CI) = 1.34-25.85). We also found a correlation between the TT genotype of VEGF +936C/T and lower risk of death from all causes compared to the CC genotype (OR = 0.26, 95%CI = 0.10-0.69), using the Cox proportional hazard model (after adjusting for potential confounding factors). In conclusion, we discovered that the VEGF +936C/T gene polymorphism influences the response to chemotherapy and overall survival of NSCLC patients.

A prospective study of the efficacy of a combination of autologous dendritic cells, cytokine-induced killer cells, and chemotherapy in advanced non-small cell lung cancer patients

Dendritic cells (DC) play a crucial role in the induction of an effective antitumor immune response. Cytokine-induced killer (CIK) cells, a subset of T lymphocytes, have the capacity to eliminate cancer cells. This study was to evaluate the correlation between the frequency of DC/CIK immunotherapies following regular chemotherapy, the time-to-progression (TTP), and overall survival (OS) of advanced non-small lung cancer patients. Sixty patients with IIIB-IV non-small-cell lung carcinoma (NSCLC) were enrolled from August 2007 to December 2009 and were randomized into two groups. All 60 patients received four courses of navelbine-platinum (NP) chemotherapy. In one group, 30 patients were treated with adoptive autologous DC/CIK cell transfusion twice every 30 days. In the other group, the patients received immunotherapies more than twice every 30 days. The adverse effects, TTP, and OS were evaluated between the two groups. Median survival time of all 60 patients was 13.80 months. The 1-, 2-, and 3-year overall survival rates were 60.0, 21.7, and 15.0 %, respectively. The 1-, 2-, and 3-year overall survival rates of patients receiving more than two immunotherapies were 63.3, 30.0, and 23.3 %, and the rates of those receiving two immunotherapies were 56.7, 13.3, and 6.7 %, respectively. The difference between the two groups was statistically significant (P = 0.037). Compared with patients in the fewer immunotherapies group, TTP in the group receiving more immunotherapies significantly prolonged, with the median improving from 6.2 months (95 % CI, 5.35-9.24) to 7.3 months (95 % CI, 5.45-6.95; P = 0.034). The adverse effects of chemoimmunotherapy were tolerable. Advanced NSCLC patients can benefit from the combination of DC/CIK immunotherapies following conventional chemotherapy. More than two immunotherapies improved TTP and OS of those patients in this study.