Non-small Cell Lung Cancer Population Research Articles

Blood Tumor Mutational Burden as a Predictive Biomarker in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC).

This study was designed to investigate the impact of blood tumor mutational burden (bTMB) on advanced NSCLC in Southwest China. The relationship between the tTMB estimated by next-generation sequencing (NGS) and clinical outcome was retrospectively analyzed in tissue specimens from 21 patients with advanced NSCLC. Furthermore, the relationship between the bTMB estimated by NGS and clinical outcome was retrospectively assessed in blood specimens from 70 patients with advanced NSCLC. Finally, 13 advanced NSCLC patients were used to evaluate the utility of bTMB assessed by NGS in differentiating patients who would benefit from immunotherapy. In the tTMB group, tTMB ≥ 10 mutations/Mb was related to inferior progression-free survival (PFS) (hazard ratio [HR], 0.30; 95% CI, 0.08-1.17; log-rank P = 0.03) and overall survival (OS) (HR, 0.30; 95% CI, 0.08-1.16; log-rank P = 0.03). In the bTMB group, bTMB ≥ 6 mutations/Mb was associated with inferior PFS (HR, 0.32; 95% CI, 0.14-1.35; log-rank P < 0.01) and OS (HR, 0.31; 95% CI, 0.14-0.7; log-rank P < 0.01). In the immunotherapy section, bTMB ≥ 6 mutations/Mb was related to superior PFS (HR, 0.32; 95% CI, 0.14-1.35; log-rank P < 0.01) and objective response rates (ORRs) (bTMB < 6: 14.2%; 95% CI, 0.03-1.19; bTMB ≥ 6: 83.3%; 95% CI, 0.91-37.08; P = 0.02). These findings suggest that bTMB is a validated predictive biomarker for determining the clinical outcome of advanced NSCLC patients and may serve as a feasible predictor of the clinical benefit of immunotherapies (anti-PD-1 antibody) in the advanced NSCLC population in Yunnan Province.

A Canadian Perspective on the Challenges for Delivery of Curative-Intent Therapy in Stage III Unresectable Non-Small Cell Lung Cancer.

Stage III non-small cell lung cancer (NSCLC) comprises a highly heterogenous group of patients with regards to patient fitness and tumour size and distribution, resulting in a wide range of treatment goals and therapy options. Curative-intent multimodality treatment should be considered in all patients with stage III NSCLC. For patients with unresectable disease who are fit, have adequate lung function, and have a disease that can be encompassed within a radical radiation volume, concurrent chemoradiation therapy (cCRT) is the standard of care and can produce cure rates of 20–30%. Recently, consolidation immunotherapy with durvalumab has been recognized as the standard of care following cCRT based on significant improvement rates in overall survival at 4 years. The large heterogeneity of the stage III NSCLC population, along with the need for extensive staging procedures, multidisciplinary care, intensive cCRT, and now consolidation therapy makes the delivery of timely and optimal treatment for these patients complex. Several logistical, communication, and education factors hinder the delivery of guideline-recommended care to patients with stage III unresectable NSCLC. This commentary discusses the potential challenges patients may encounter at different points along their care pathway that can interfere with delivery of curative-intent therapy and suggests strategies for improving care delivery.

P09.15 Severity of Lung Cancer Disease in Hospitalized Patients During COVID-19

Covid-19 pandemic has drastically changed the management of patients with cancer; however, there is still limited data regarding the real impact of Covid-19 on patient’s outcomes due to delayed diagnosis and treatment of clinical complications. We aimed to assess the prevalence, severity and mortality of clinical complications and oncology emergencies in hospitalized patients in our institution during the Covid19 period vs. the same period of 2019. We conducted a retrospective study of patients with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) who were admitted to the Department of Medical Oncology during Jan-Jun 2019 (before-Covid) and Jan-Jun 2020 (Covid-19 period). Clinical, pathological and biological data were collected. We assessed the clinical severity in both periods including: PS at admission, progression disease (PD), oncologic emergencies (%), start of a systemic therapy or switch to other therapy line. We also analyzed the differences on the 30-day mortality rate since hospitalization between both periods. 229 admissions, 133 during and 93 before Covid-19 pandemic (N=180 patients) were enrolled; the median duration of the hospitalization was 9 days (4-16). Median age was 66 years, 35% were female, 88% with PS≥2, 27% were current smokers; 83% had NSCLC histology. Most of them (82%) had advanced disease at admission; 69% were under systemic therapy (chemotherapy 39%, immunotherapy 17%, targeted therapies 11%). Nine patients (4%) were active covid-19 cases (9 NSCLC, 0 SCLC). The table 1 summarized the most common clinical conditions by histology, in both periods. In NSCLC population, during-Covid, lower rate of admissions were observed (4 cases less per month), with no increase of oncologic emergencies. The PD during hospitalization was slightly higher during vs. before-Covid, but no differences were observed in 30-days mortality rate. In SCLC population, during-Covid, the rate of admissions was doubled (2 cases more per month), with more cases progressing during the hospitalization. (46% during vs. 34% before-Covid). In contrast to NSCLC, the 30-days mortality rate was higher during-Covid (38%) vs. before-Covid (20%). Updated data will be presented in the meeting.Tabled 1NSCLC (N= 190)SCLC (N= 39)During-Covid (2020) N=83 (44%)Before-Covid (2019) N=107 (52%)During-Covid (2020) N=13 (33%)Before-Covid (2019) N=26 (67%)Baseline characteristicsMain reason of hospitalization Dyspnea Fever Pain Neurological symptoms Others27 (33%) 20 (24%) 9 (11%) 11 (13%) 16 (19%)26 (24%) 22 (21%) 16 (15%) 20 (17%) 23 (23%)3 (23%) 3 (23%) 1 (8%) 4 (30%) 2 (16%)11 (42%) 2 (8%) 1 (4%) 6 (23%) 6 (23%)PS at admission 0-1 ≥21 (1%) 82 (99%)22 (21%) 82 (79%)0 (0%) 13 (100%)3 (12%) 23 (88%)Stage at admission Locally Locally advanced Advanced7 (8%) 7 (8%) 69 (84%)7 (7%) 9 (8%) 90 (85%)0 (0%) 4 (30%) 9 (70%)2 (8%) 4 (15%) 20 (77%)N# mets. Sites at admission ≤2 >255 (67%) 28 (33%)64 (60%) 43 (40%)8 (62%) 5 (38%)14 (54%) 12 (46%)Line of therapy (only advanced disease) 0-1 ≥255 (65%) 28 (35%)69 (64%) 38 (36%)10 (76%) 3 (23%)21 (81%) 5 (19%)Disease severityN# AdmissionsN= 83 (14 per month)N=107 (18 per month)N=26 (4 per month)N=13 (2 per month)N# Readmissions21 (25%)22 (21%)1 (8%)5 (19%)Median duration of hospitalization (range)8(1;47)10(1;104)8(1;22)9(1;67)Oncology Emergencies Yes No8 (10%) 75 (90%)22 (20%) 85 (80%)1 (8%) 12 (92%)7 (27%) 19 (73%)Progression during hospitalization Yes No32 (39%) 51 (61%)35 (32%) 72 (68%)6 (46%) 7 (54%)9 (34%) 17 (66%)Early death (30-days mortality rate) Yes No20 (24%) 63 (76%)22 (21%) 84 (79%)5 (38%) 8 (62%)5 (20%) 20 (80%) Open table in a new tab We preliminary observed more aggressive disease with worse outcomes in patients with SCLC hospitalized during-Covid compared to the same period in 2019. No differences were observed in NSCLC. The final outcomes will be assessed in a larger and mature cohort still ongoing.

P02.21 The Impact of Inflammatory Serum Biomarkers in Non-Small Cell Lung Cancer Patients Treated With Immune Checkpoint Inhibitors

The inflammatory serum biomarkers, that are easily accessed in clinical practice, were studied in various types of cancer in patients treated with immune checkpoint inhibitors (ICIs). The ICIs changed how we manage non-small cell lung cancer (NSCLC) in the last years, as in 1st line or as subsequent lines, with an improvement in progression-free survival (PFS), overall survival (OS) and quality of life. Biomarkers for ICIs that have been most explored are PD-L1 expression and tumor mutational burden, nevertheless, there isn’t an ideal biomarker. The objective of the study is to evaluate the predictive and prognostic impact of the following inflammatory serum biomarkers: neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), prognostic nutritional index (PNI) and advanced lung cancer inflammation index (ALI) in advanced NSCLC patients treated with the ICIs (pembrolizumab, nivolumab, atezolizumab). A retrospective study including 52 patients with stage IV NSCLC that started treatment with ICIs between March 2016 and May 2020. The inflammatory serum scores were calculated as following: NLR=total neutrophil count/total lymphocyte count; PLR=total platelet count/total lymphocyte count; PNI=albumin (g/L)+0.005xtotal lymphocyte count/μL; ALI=BMI(Kg/m2)xalbumin(g/dL)/NLR. The cut-offs 5, 200, 50 e 18 were respectively considered. The survival analysis was performed using the Kaplan-Meier method with Log Rank test and Cox regression, with a statistical significance of 5%. Forty-two patients (n=42, 80.8%) were male, 47 (90.4%) had an ECOG performance status between 0-1, and 19 (36.5%) were treated with ICIs as 1st line. The NLR was ≥5 in 34.6% (n=18); PLR was ≥200 in 38.5% (n=20); PNI was <50 in 53.8% (n=28) and ALI was <18 in 59.6% (n=31). The median follow-up period was 15.9 months. The median PFS was 4.97 months (95%CI 3.49-6.44) and the median OS was 10.80 months (95%CI 3.21-18.39). The median PFS was inferior in patients with PLR≥200: 2.13 months versus 6.60 months, HR 2.04 (95%CI 1.03-4.06), p=0.038, and in patients with PNI<50: 2.30 months versus 8.97 months, HR 3.01 (95%CI 1.47-6.20), p=0.002. There were no differences in PFS regarding the NLR and (p=0.077) and the ALI (p=0.150) scores. The median OS was lower in patients with NLR≥5: 1.83 months versus 16.5 months, HR 2.46 (95%CI 1.17-5.16), p=0.014; in patients with PLR≥200: median OS was 4.97 months versus 16.80 months, HR 2.73 (95%CI 1.31-5.72), p=0.005; and in patients with PNI<50: 6.17 months versus 19.87 months, HR 2.86 (95%CI 1.38-5.95), p=0.003. There weren’t differences in OS taking account of the ALI (p=0.083). The PLR≥200 and the PNI<50 were markers of a poorer PFS in our population. The NLR≥5, PLR≥200, and PNI<50 were markers of a worse prognosis in our NSCLC population treated with ICIs. The identification of inflammatory serum biomarkers that are easily accessed in daily practice might be important in the future in the identification and orientation of these patients. Nevertheless, these biomarkers should be prospectively studied in further studies in order to validate these results.

The Prevalence and Concurrent Pathogenic Mutations of KRAS G12C in Northeast Chinese Non-small-cell Lung Cancer Patients.

ObjectiveKRAS mutation is one of important driver genes in non-small-cell lung cancer (NSCLC) and the patients with KRASG12C mutations benefit from the inhibitor AMG510. However, the frequency, concurrent pathogenic mutations, and clinical characteristic of KRASG12C is unknown in the NSCLC population of Northeast China.MethodsThe retrospective analysis was derived from 431 NSCLC patients in Jilin Cancer Hospital between January 2018 and June 2019. The mutation frequency and concurrent mutations of KRASG12C in tumor or peripheral blood was detected by next-generation sequencing (NGS).ResultsThe RAS mutant rate was observed in 10.7% (46/431) of this cohort. All RAS-driver cancers are caused by mutations in the KRAS isoform, while the NRAS and HRAS isoforms were not detected. Among KRAS-mutant patients, 42 (91.3%) showed exon 2 mutation in 12 codon and 13 codon. KRASG12C showed a 4.6% (20/431) mutation rate in this cohort and the highest frequency (43.5%, 20/46) in KRAS-mutant-positive patients. There was no difference between tumor tissue and plasma in terms of either KRAS or KRASG12C mutation. The most frequent co-occurrence mutations with KRASG12C were TP53, followed by PTEN. Furthermore, KRASG12C was exclusive with STK11 mutation. KRASG12C mutation was associated with age, disease stage, and smoking status (P=0.024; P=0.02; P=0.006), smoking remained an independent factor for KRASG12C mutation (P=0.037), and higher mutation frequency in patients older than 60, stage I–III, or smoking in NSCLC (P=0.0151, P=0.0343, P=0.0046, respectively).ConclusionKRAS mutation was the only isoforms of RAS family, of these 43.5% harbored the KRASG12C subtype in northeastern Chinese NSCLC patients. KRASG12C is associated with age, pathological stage and smoking status, more commonly harbored TP53/PTEN mutations, and providing more genome profile for targeted therapy in local clinical practice.

Identification of Stage IIIC/IV EGFR-Mutated Non-Small Cell Lung Cancer Populations Sensitive to Targeted Therapy Based on a PET/CT Radiomics Risk Model

Background: To address the clinical challenges that the progression risk of patients with stage IIIC-IV EGFR-mutated Non-small cell lung cancer (NSCLC) is difficult to accurately quantify and stratify after first-line EGFR-TKI targeted drug therapy, we aimed to construct an individualized PET/CT prognostic biomarker to accurately quantify the progression risk of patients and identify the EGFR-TKI treatment-sensitive population. Methods: 250 patients with stage IIIC-IV EGFR-mutated NSCLC underwent first-line EGFR-TKI drug therapy were included from two institutions (140 patients in training cohort; 60 patients in internal validation cohort, and 50 patients in external validation cohort). 64 patients in the chemotherapy group. 1037 3D radiomics features were extracted to quantify the phenotypic characteristics of the tumor region in PET and CT images. According to the median value of radiomics signature score (Rad-score), patients were divided into low- and high-risk groups. The progression-free survival (PFS) behaviors of the two subgroups were compared with the chemotherapy group by Kaplan–Meier survival analysis. Findings: Higher Rad-scores were significantly associated with worse PFS in the training ( p < 0.0001), internal validation ( p = 0.0153), and external validation ( p = 0.0006) cohorts. Rad-score can effectively identify patients with a high risk of rapid progression, and for these patients. Interpretation: The PET/CT-derived Rad-score can realize the precise quantitative stratification of progression risk after first-line EGFR-TKI drug therapy and identify EGFR-mutated NSCLC populations sensitive to targeted therapy. Funding: National Natural Science Foundation of China; Guangdong Basic and Applied Basic Research Foundation; Science and Technology Planning Project of Guangdong Province. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The Research Ethics Committee of Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences approved this retrospective study and waived the requirement for informed consent from the patients. The approval ID was GDREC2019154H(R1).

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.

EGFR mutation testing and TKI treatment patterns among veterans with stage III and IV non-small cell lung cancer

BackgroundEpidermal growth factor receptor (EGFR) mutation testing is recommended in metastatic non-small cell lung cancer (NSCLC). The objective of this study was to assess changes in EGFR mutation testing patterns and tyrosine kinase inhibitor (TKI) use in US veterans with stage III-IV NSCLC between 2013 and 2017. Patients and MethodsRetrospective study using linked data from Department of Veterans Affairs (VA) Cancer Registry System, Corporate Data Warehouse, commercial laboratories, and clinical notes. Generalized linear mixed models accounting for clustering by VA facility were used to determine factors associated with EGFR mutation testing. ResultsFrom 2013 to 2017, EGFR mutation testing increased from 29.5% to 38.4% among veterans with stage III-IV NSCLC and from 47.0% to 57.4% among veterans with stage IV non-squamous disease. Factors associated with increased odds of testing included being married, Medicare enrollment, and adenocarcinoma histology. Factors associated with decreased odds of testing included Medicaid eligibility, stage III disease, increasing age, being a current or former smoker, increasing Charlson-Deyo comorbidity score, and receiving cancer care in the South. Appropriate use of a TKI rose from 2013 to 2017 (17.2% to 74.1%). ConclusionEGFR mutation testing rates increased to almost 60% in the stage IV non-squamous NSCLC population in 2017, with residual opportunity for further increase. Several sociodemographic characteristics, comorbidities, and geographic regions were associated with EGFR mutation testing suggestive of inequitable testing decisions. Appropriate use of TKI improved drastically from 2013 to 2017 demonstrating rapidly changing practice patterns through the adoption phase of new treatment options.

Decreased Overall Survival in HIV-associated Non–small-cell Lung Cancer

IntroductionThis study aimed to compare demographics, disease characteristics, and outcomes of patients with HIV-infection with non–small-cell lung cancer (NSCLC) with the general NSCLC population. Patients and MethodsA retrospective cohort study was used to compare the HIV-infected and -uninfected groups. Medical records of all patients who were HIV-positive diagnosed with NSCLC between 2000 and 2016 at Yale New Haven Hospital (New Haven, CT) were reviewed and compared with the general Yale NSCLC population regarding demographics, NSCLC characteristics, treatment, and survival. Log-rank tests and Kaplan-Meier curves were used to analyze survival differences. Unadjusted and adjusted Cox proportional hazard models were used to assess predictors of survival. ResultsThirty-five patients with HIV-NSCLC and 5187 general patients with NSCLC were identified. The median age at cancer diagnosis was 54 years (interquartile range [IQR], 49-59 years) for patients with HIV-NSCLC versus 68 years (IQR, 61-76 years) for patients with NSCLC (P < .001). Both groups had high rates of tobacco use. At the time of NSCLC diagnosis, 80% of patients with HIV-NSCLC were on antiretroviral therapy, 60% had an HIV-1 RNA < 400 copies/mL, and their median CD4 was 407 cells/μL (IQR, 218-592 cells/μL). Histology, cancer stage, and first-line cancer treatment regimens were not significantly different between groups. The overall median survival was 12.4 months (95% confidence interval [CI], 7.2-20.4 months) for patients with HIV-NSCLC versus 22.8 months (95% CI, 21.2-24.1 months) for general patients with NSCLC. Patients with HIV-NSCLC had decreased survival at 2 years (P = .028) and 3 years (P = .014) compared with general patients with NSCLC. HIV status was an independent risk factor for poorer outcomes when controlling for other factors (hazard ratio, 1.8; 95% CI, 1.24-2.62). ConclusionDespite similar histology, stage, and treatment between groups, patients with HIV had worse outcomes for NSCLC.

Molecular and clinicopathological characteristics of ROS1-rearranged non-small-cell lung cancers identified by next-generation sequencing.

ROS1 gene rearrangements have been reported in diverse cancer types including non-small-cell lung cancer (NSCLC), and with a notably higher prevalence in lung adenocarcinoma. The tyrosine kinase inhibitors, crizotinib, lorlatinib, and entrectinib, have demonstrated favorable efficacy in treating ROS1-rearranged NSCLCs. Herein, we retrospectively reviewed 17158 NSCLC patients whose tumor specimen and/or circulating cell-free DNA underwent comprehensive genomic profiling. A total of 258 unique patients were identified with ROS1 rearrangements, representing an overall prevalence of approximately 1.5% of ROS1 fusions in newly diagnosed and relapsed NSCLC patients. CD74 (38%) was the most common fusion partner of ROS1, followed by EZR (13%), SDC4 (13%), SLC34A2 (10%), and other recurrent fusion partners with lower frequencies, including TPM3, MYH9, and CCDC6. Variant breakpoints occurred in ROS1 introns 33 (37%), 31 (25%), 32 (17%), and 34 (11%) with no obvious hotspots. CD74 (63%) and EZR (50%) were more frequently fused to ROS1 intron 33 than other introns, while ROS1 intron 31 was most frequently fused with SDC4 (79%) and SLC34A2 (81%). Crizotinib progression-free survival (PFS) was not significantly different between fusion variants involving breakpoints in different ROS1 introns, nor was there a significant difference in PFS between CD74-ROS1 and non-CD74-ROS1 groups of patients. Furthermore, TP53 was most frequently mutated in patients who progressed on crizotinib, and TP53 mutations were significantly associated with shorter crizotinib PFS. ROS1 mutations, including G2032R, were observed in approximately 33% of post-crizotinib samples. Collectively, we report the prevalence of ROS1 fusions in a large-scale NSCLC population and the efficacy of crizotinib in treating patients with ROS1-rearranged NSCLC.

Abstract 741: Molecular and clinicopathological characteristics of Chinese non-small cell lung cancers with ROS1 gene fusions identified by next-generation sequencing

Abstract Background ROS1 gene rearrangements are reported at a prevalence of 1-2% in unselected cancer populations including non-small cell lung cancer (NSCLC), and notably higher in lung adenocarcinoma. More than twenty ROS1 fusion partners have been identified, which continues to increase due to the adoption of next-generation sequencing (NGS) for genetic testing. The tyrosine kinase inhibitors (TKIs) including crizotinib, lorlatinib, and entrectinib, have demonstrated favorable efficacy in the treatment of ROS1-rearranged NSCLCs. Methods A total of 17,158 Chinese non-small cell lung cancer (NSCLC) patients whose tumor specimen and/or circulating cell-free DNA (cfDNA) underwent genomic profiling by hybridization capture-based targeted NGS of exons and introns of cancer related genes were retrospectively reviewed. Clinical characteristics, treatment history, and progression-free survival (PFS) for crizotinib of a subset of 37 patients were further evaluated. Results A total of 288 ROS1-positive NSCLC patients were identified in the cohort at a frequency of 1.7% (288/17158). ROS1 fusions retaining the intact ROS1 kinase domain were confirmed in a subset of 258 patients (1.5%) with the most common fusion partner being CD74 (104/258, 40%), followed by EZR (34/258, 13%), SDC4 (28/258, 11%), SLC34A2 (27/258, 11%), and other recurrent ones at low frequency including TPM3, GOPC, MYH9, and CCDC6. Most frequent breakpoints on ROS1 are spreading in introns 33 (37%), 31 (25%), 32 (17%) and 34 (11%) with no obvious hotspots. 5.4% of cases (14/258) were fused to intergenic regions (IGR), mainly on the same chromosome of ROS1, with unknown fusion products. Notably, CD74 (63%) and EZR (50%) are more frequently fused with ROS1 intron 33, while ROS1 intron 31 was the most common breakpoint region of fusion events involving SDC4 (79%) and SLC34A2 (81%). Median PFS (mPFS) was not significantly different between fusions involving breakpoints in ROS1 introns 31-34 for crizotinib treatment, whereas non-CD74 patients (n=23) trended to demonstrate longer mPFS than that of CD74-ROS1 cases (n=14) (12.0 versus 9.9 months). Previously reported acquired resistance to crizotinib in ROS1-rearranged patients, including ROS1 G2032R and S1986F mutations, were observed in 11 out of 37 patients upon disease progression. In addition, two out of three patients who had uncharacterized fusion partners (IGR-ROS1) achieved durable clinical benefit on crizotinib. Conclusion We hereby report the prevalence of ROS1 fusions of 1.7% in a large Chinses NSCLC population detected by NGS testing and the most frequent fusion partners including CD74, EZR, SDC4, and SLC34A2. Crizotinib has demonstrated robust response in treating ROS1-rearranged NSCLC, particularly in non-CD74 ROS1-positive patients. Keywords ROS1, gene fusion, non-small cell lung cancer, crizotinib, breakpoint, next-generation sequencing Citation Format: Dongling Gao, Yuchen Han, Zhihua Zhao, Qiuxiang Ou, Xiaoling Tong, Ruiying Zhao, Nan Dong, Xue Wu, Wencai Li, Guozhong Jiang. Molecular and clinicopathological characteristics of Chinese non-small cell lung cancers with ROS1 gene fusions identified by next-generation sequencing [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 741.

Abstract 745: Landscape of FGFRactivating aberrations in Chinese non-small cell lung cancer

Abstract Background Dysfunction in fibroblast growth factor receptor (FGFR) signaling has been reported in non-small cell lung cancer (NSCLC), particularly in lung squamous cell carcinoma (LUSC). We hereby assessed the frequency of FGFR aberrations in a large Chinese NSCLC population. Methods A total of 10,966 NSCLCs whose tumor specimen and/or circulating cell-free DNA (cfDNA) underwent hybridization capture-based next-generation sequencing (NGS) of 400+ cancer-related genes were retrospectively reviewed. Patients' clinical characteristics and treatment histories were further evaluated. Results FGFR aberrations, including mutations, fusions, and gene amplifications, were detected in approximately 1.9% (210/10,966) of the population. FGFR abnormalities were more frequently observed in LUSCs (6.8%, 65/954) than lung adenocarcinomas (1.3%, 128/9596). Previously reported FGFR oncogenic mutations were identified in 19 patients (~0.17%), of which, 68% were male LUSC patients. Eleven out of the 19 patients (58%) had concurrent altered PI3K signaling, thus, highlighting an intriguing molecular characteristic and potential combination therapeutic strategy of dual-targeting FGFR and PI3K signaling in those patients. Furthermore, FGFR fusions retaining the intact kinase domain were identified in 12 patients (0.11%), including nine FGFR3-TACC3 cases, one FGFR2-INA fusion, one novel FGFR4-RAPGEFL1 rearrangement event, and one novel gene fusion between FGFR1 and the SLC20A2 5'-untranslated region, which may result in FGFR1 overexpression. Concomitant EGFR mutations or EGFR amplifications were observed in six patients, four of whom were previously treated with EGFR tyrosine kinase inhibitors, suggesting that FGFR fusions may act as acquired resistance to anti-EGFR therapies. In addition, FGFR amplification was detected in 24 patients, with FGFR1 amplification being the most common event. Notably, FGFR oncogenic mutations, fusions, and gene amplifications were almost always mutually exclusive events. Conclusion We herein report an incidence of FGFR anomalies in a large Chinese NSCLC population, including mutations, gene amplifications, and previously characterized and novel FGFR fusions involving TACC3, INA, RAPGEFL1, and SLC20A2. Keywords: FGFR, activating mutation, fusion, gene amplification, NSCLC, FGFR inhibitors Citation Format: Zhen Zhou, Zichuan Liu, Qiuxiang Ou, Xue Wu, Xiaonan Wang, Yang Shao, Hongyan Liu, Yu Yang. Landscape of FGFRactivating aberrations in Chinese non-small cell lung cancer [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 745.

Abstract PR08: Neighborhood-level social determinants impact non-small cell lung cancer aggressive somatic phenotypes

Abstract Background: It is unclear why poor Americans die of non-small cell lung cancer (NSCLC) at a significantly higher rate than their affluent counterparts. We aimed to evaluate the relationship between (1) social determinants of health (SDH) (e.g., pollution, education), (2) cigarette smoke, and (3) aggressive NSCLC somatic biologic phenotypes (e.g., KRAS G12C and G12V and TP53 mutations) in smoking and nonsmoking patients with NSCLC. We hypothesize that adverse social determinants will be associated with more aggressive NSCLC tumor biology. Methods: We conducted a single institutional retrospective cohort study of patients seen at the City of Hope National Medical Center from 2015-2018. Clinical data were obtained from electronic medical records. Risk factor data (air quality measure [PM 2.5 exposure], neighborhood-level income, education, and minority population data) were obtained from the Environmental Protection Agency (EPA). Associations were modeled using logistic regression models, controlling for all demographic variable (TP53) or variables significant on bivariate analyses (KRAS variants G12C and G12V). Results: Of 812 NSCLC patients, 617 (76%) had somatic genomic testing and were included in analyses (mean age 67.6, 53% female, 30% Asian, 4% African American, 64% White, 10% Hispanic, 64.3 % Stage 4, 83% adenocarcinoma, and 38% never smokers). Smokers had a mean pack-year of 20. 22% of patients had KRAS mutations and 42.6% had TP53 mutations. For neighborhood level exposures, the mean PM 2.5 level was 11.7 μg/m3 (US average is 9.5 μg/m3). Patients were almost evenly distributed in the good and moderate PM2.5 risk categories (good 47.6%, moderate 52.4%). There was no overall association between SDH and KRAS mutations. However, multivariable analyses revealed that lower neighborhood education (OR=15.98, 95%CI 1.5-170.4) was associated with KRAS variants G12C and G12V specifically. Poor air quality as measured by PM2.5 was associated with TP53 mutations (OR=2.09, 95%CI 1.33-3.29). Conclusion: Poor air quality is associated with increased risk of TP53 mutations, while low neighborhood-level education is associated with KRAS G12C/G12V mutations. Our study finds a link between adverse neighborhood-level social determinants and aggressive biologic NSCLC behavior. These hypothesis-generating findings suggest a mechanism by which deprived NSCLC populations may experience inferior outcomes. Larger, prospective studies are needed to further evaluate these associations. This abstract is also being presented as Poster C054. Citation Format: Loretta Erhunmwunsee, Hengrui Hu, Catherine Raquel, Lisa N. Lopez, Jenny Shen, Lennie Wong, Jae Y. Kim, Dan J. Raz, Karen L. Reckamp, Ravi Salgia, Stacy W. Gray. Neighborhood-level social determinants impact non-small cell lung cancer aggressive somatic phenotypes [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr PR08.

Does CNS metastases reduce systemic therapy lines for NSCLC patients with EGFR mutation?

e21558 Background: The latest generation tyrosine kinase inhibitor (TKI), Osimertinib, targets the epidermal growth factor receptor (EGFR) despite the T790M mutation status in non-small-cell lung cancer (NSCLC). In cases where there is a detected EGFR mutation on the exon 19-deletion and on the exon 21-L858R in the NSCLC population, studies have demonstrated that Osimertinib has a positive benefit in overall survival and delayed progression of central nervous system (CNS) metastases. Methods: From January 2010 to December 2018, 56 patients with the metastatic NSCLC-EGFR mutation, treated with Osimertinib 80 mg once daily, were included in this analysis. Retrospective data was extracted through the internal administrative databases located at Sunnybrook Hospital. All patients had EGFR mutation positivity by cytology, plasma or tissue sampling. The primary endpoint was to evaluate whether NSCLC patients who were exposed to Osimertinib and had brain metastases underwent fewer systemic therapy lines as compared to those who did not have metastases involving the brain. Results: Eligible patients were analyzed and the median age at the initial diagnosis was 65 years old; 50% (n = 28) of the patients had brain metastases. The median of systemic treatment lines for patients without CNS metastasis was two and for those who have metastases to the brain was three. 82,2% of this cohort received Osimertinib in 2nd line, after development of acquired resistance to first or second TKI generation. Conclusions: Results from this study did not demonstrate that EGFR mutated, NSCLC patients with CNS metastases received less systemic therapy lines to those without metastases involving the brain. A larger cohort for further investigation is warranted.

Clinical and molecular characteristics of TSC1/2 mutant lung cancer.

e21647 Background: Tumor suppressor genes TSC1 and TSC2 inhibit cell growth through inactivation the function of mTORC1. Previous studies have demonstrated that loss of function mutation of either TSC1 or TSC2 gene result in formation of neoplasm in multiple tissues. However, the clinical significance of TSC1 and TSC2 in non-small-cell lung cancer (NSCLC) remains unknown. This study aimed to investigate the clinical and molecular characteristics of TSC1 and TSC2 mutation in NSCLC patients. Methods: We retrieved the clinical and genomic information of 1144 NSCLC from the Pan-Lung cancer dataset through the cBioportal ( www.cbioportal.org) . The cohorts of TSC1 and TSC2 mutant patients were identified. We compared baseline characteristics of patients with the Fisher exact test for categorical data and the Mann-Whitney U test for continuous variables. Overall survival (OS) was estimated with Kaplan-Meier curves, and differences were compared with the log-rank test. Results: Among 1144 patients, 27(2.36%) of them had TSC1 mutation and 40 (3.50%) had TSC2 mutation. Most patients with TSC1 and TSC2 mutations coexisted with other oncogenic gene alterations. TP53 was the most frequent concurrent gene (n = 53), followed with ERBB family genes (n = 24) and KRAS (n = 15). Compared to squamous cell carcinoma, TSC1/2 mutation was slightly more common in adenocarcinoma (53.7% vs 46.3%). 61.2% TSC1/2 mutant patients were male and 88.1% patients had former/current smoking history. Kaplan–Meier analysis showed that the patients harboring TSC1 mutation had a median OS of 14.1 months, whereas patients with TSC2 mutation had a median OS 110.6 months. However, there was not a statistically difference (P = 0.201). Conclusions: TSC1/2 mutation may define a unique population of NSCLC, which often coexists with other oncogenic gene alterations such as TP53 mutation. The function of TSC1/2 mutation and the value of TSC1/2 as therapeutic target in NSCLC are under investigation.

TP53 fusions with next-generation sequencing (NGS) in Chinese non-small cell lung cancer (NSCLC): A multicenter study.

e21742 Background: Currently, with the advances in detection techniques, such as next generation sequencing (NGS), more and more rare or atypical TP53 fusions had been identified. Such as TP53-PSMD14, the importance of EGFR signaling in the pathogenesis of lung cancer and the efficacy of EGFR-TKI treatment had been demonstrated. The aim of this study was to evaluate the prevalence of TP53 fusions in Chinese NSCLC populations, which had not been reported earlier, and to describe targeting potential in Chinese NSCLC populations. Methods: A multicenter study in China was initiated from February 2014, and NSCLC patients have been enrolled as of December 2018. A total of 2743 patients with NSCLC were screened by using next-generation sequencing (NGS)-based 381 genes panel assay for detecting TP53 fusions. Results: Of this entire cohort, just four (0.15%) patients were identified with a TP53 fusion, including DNAH2-TP53 (1), TP53-MPDU1 (1), TP53-FXR2 (1), TP53-VEZF1 (1). Of the TP53 fusion NSCLC patients, 50.00% were detected in female patients. Biopsies were obtained from primary lung tumor (25.00%) and metastatic sites (75.00%). Overall TMB in the TP53 fusion was high, which had more than 20 mut/Mb. Of the TP53 fusion NSCLC, two cases (50.00%) featured EGFR SV alterations. Conclusions: The frequency of TP53 fusions in Chinese populations with NSCLC is extremely rare (0.17%). TP53 fusions may reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions or exon 21 L858R.

PCN14 UPDATED NETWORK META-ANALYSIS OF FIRST-LINE EGFR-TARGETED TYROSINE KINASE INHIBITOR TREATMENTS FOR LOCALLY ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER WITH EGFR-ACTIVATING MUTATIONS

Lung cancer is one of the most common cancers and a worldwide health burden, with 2.1 million new cases reported globally in 2018. The aim of this study was to conduct a network meta-analysis (NMA) utilizing updated/mature randomized controlled trial (RCT) results for overall survival (OS) to examine the efficacy of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) comparators for the treatment of EGFR mutation positive (EGFR+) non-small cell lung cancer (NSCLC). An NMA of EGFR-TKI comparators was previously conducted and published. This updated NMA includes the latest published OS data for dacomitinib and osimertinib. Eleven electronic databases were systematically searched for RCTs of first-line EGFR-TKI therapies that measured OS. Bayesian NMA was used to compare OS among patients receiving afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib in the overall EGFR+ NSCLC population and in subgroup analyses by ethnicity (Asian and non-Asian) and by EGFR mutational status (exon 19 deletion or exon 21 L858R substitution mutations). Based on the NMA dacomitinib demonstrated statistically significant improvement in OS versus gefitinib (hazard ratio (HR): 0.75, 95% credible interval (CrI): 0.59-0.95). Dacomitinib trended toward improved OS versus afatinib (HR:0.87, CrI: 0.61-1.24) and erlotinib (HR: 0.79, CrI: 0.44-1.42), and had comparable OS to osimertinib (HR: 0.94, CrI: 0.69-1.29). In addition, dacomitinib had the highest probability of being ranked first in the network (50.1%) followed by osimertinib (24.6%). Dacomitinib trended towards improved OS compared to other EGFR-TKIs and had the highest probability of being ranked first in the network. Therefore, dacomitinib should be considered as one of the standard first-line treatment options for patients diagnosed with advanced EGFR+ NSCLC.

Relationship between the efficacy of immunotherapy and characteristics of specific tumor mutation genes in non-small cell lung cancer patients.

BackgroundImmune checkpoint inhibitors (ICIs) have greatly improved the prognosis and overall management of non‐small cell lung cancer (NSCLC) patients, but in the long term less than 20% of patients benefit from treatment with ICIs. Therefore, it is necessary to guide the choice of immunotherapy population through biomarkers in order to maximize the benefit for NSCLC patients. This article mainly explores the relationship between the efficacy of immunotherapy and specific tumor mutation gene characteristics in an NSCLC population.MethodsThis was a prospective analysis of patients with advanced NSCLC who visited the Department of Respiratory Medicine of Peking Union Medical College Hospital from March 2018 to June 2019 and were instructed to use PD‐1 inhibitors. The follow‐up deadline was 31 December 2019. The tumor pathological tissues were tested for tumor mutation genes, and the patients were evaluated for efficacy according to RECIST 1.1. The patients were divided into the durable benefit group (DCB) and the nonsustainable benefit group (NDB). DCB/NDB was used as the outcome variable. Various statistics methods were used to explore the independent predictors of long‐term benefits associated with immunotherapy and to draw a progression‐free survival curve for the relevant predictors.ResultsA total of 44 patients were examined for tumor mutation genes in pathological tissues; 20 in the DCB group and 24 in the NDB group. Specific gene mutations occurred in TP53 38.64%, KRAS 31.82%, EGFR 20.45%, BRCA 20.45%, ERBB (excluding EGFR) 18.18%, PTEN 15.91%, CDK4/6 13.64%, POLE 11.36%, MET 11.36%, PIK3CA 9.10%, FGFR 9.10%, BRAF 9.10%, JAK 9.10%, ALK 6.82%, POLD1 4.55%, BLM 4.55%. Chi‐square test results showed that there were statistically significant differences between DCB and NDB groups with eight mutations such as KRAS. Logistic regression showed that the KRAS mutation was statistically significant (P < 0.001). Two accuracy indicators, Random Forest Classification of Mean Decrease Gini and Mean Decrease Accuracy, evaluated the importance of the impact of different gene mutations on the outcome. Under two different measures, the variables were all KRAS mutations. It is suggested that the mutation of the KRAS gene is an independent predictor of the long‐term benefit of immunotherapy.ConclusionsThe mutation of KRAS gene in tumor tissues is an independent predictor of the long‐term benefit of immunotherapy, and the predictive ability is better.

Non-small cell lung cancer PDL1 &gt;50%—should we go single or combo?

Recent years have witnessed a revolution in the era of immune checkpoint inhibitors (ICIs). It has greatly impacted the oncological field and especially advanced non-small cell lung cancer (NSCLC) treatment. Here, we summarized the 3 main treatment protocols for a specific population of NSCLC with strong PD-L1 staining (PD-L1 ≥50%); which include ICI (e.g., pembrolizumab) monotherapy, ICI in combination with chemotherapy or combination ICIs. To date, it is uncertain whether there is a therapeutic difference amongst the PD-L1 TPS ≥50% group in comparison to other PD-L1 subdivisions. The findings reviewed here show that the combination ICI with chemotherapy yields the best response rate in comparison to other treatment protocols. Crucially, this treatment protocol is highly suggested for patients with high disease burden, especially for those with liver or brain involvement.

Real-world clinical outcomes of first-generation and second-generation epidermal growth factor receptor tyrosine kinase inhibitors in a large cohort of European non-small-cell lung cancer patients

BackgroundFirst-generation or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are commonly used in EGFR-mutation-positive advanced non-small-cell lung cancer (NSCLC) with no relevant differences in efficacy in randomised clinical trials (RCTs). Patients enrolled to RCTs may differ from NSCLC population in everyday practice. Limited real-world experience (RWE) exists on efficacy of EGFR TKIs in European patient cohorts.Patients and methodsIn this retrospective study, real-world data of all patients who started first-line EGFR TKIs between 2012 and 2016 in Poland were analysed. The main endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints were an objective response rate and toxicity.ResultsA total of 620 treatment-naive EGFR mutated patients with stage III/IV NSCLC were analysed with follow-up time of 24.5 months. A significantly longer median PFS (p=0.005) and higher 1-year OS rate (p=0.004) for afatinib (16.4 months and 78.2%) vs gefitinib (10.3 months and 69.1%) and erlotinib (12.1 months and 71.6%) were observed. In multivariate analysis toxicity was predictive for PFS and OS. In patients with adverse events (AEs) versus those without AEs, improved median PFS (13.6 months vs 8.8 months) and median OS (23.6 vs 15.5 months) were observed. Median OS in the group with AE of grades 3–4 and those with AE of grades 1–2 were 42.1 months and 23.4 months, respectively.ConclusionThis study represents the largest RWE of first-line TKI therapy in a European country with longer survival of patients receiving second-generation TKI. We confirmed in everyday practice the role of toxicity as a marker of clinical benefit.