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Tertiary lymphoid structures (TLS) are observed in several cancers and are associated with favorable prognosis. This study aimed to examine the clinicopathological, genetic, and gene expression profiles of lung adenocarcinoma patients with TLS.A total of 112 patients with pathological stage IB lung adenocarcinoma who underwent complete resection between 2011 and 2015 were enrolled in this study. We investigated whether TLS correlated with prognosis and programmed death-ligand 1 (PD-L1) expression. Furthermore, the correlation of TLS with tumor mutation burden (TMB) and genetic mutations was evaluated in patients for whom whole-exon sequencing data were available. In addition, using the Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) dataset, gene expression analysis according to the TLS status was performed.Among the 112 patients, 49 were TLS-positive (TLS+). TLS+ correlated with longer recurrence-free survival (RFS) than TLS-negative cases (TLS-) (hazard ratio [HR], 0.47; 95 % confidence interval [CI]: 0.23-0.88, p = 0.02). In the multivariate analysis, TLS was a better independent prognostic factor for RFS (HR 0.37, 95 %CI 0.18-0.72, p 0.01). PD-L1 expression was not significantly different between TLS+ and TLS- patients (p = 0.54). TMB in TLS+ was similar to that in TLS- patients (p = 0.39); however, it tended to be lower than that in TLS- especially among smokers (p = 0.07). In gene expression analysis, RNA expression of chemokines related to lymph node formation, such as CXCL13, CCL19 and CCL21, was significantly higher, and biological processes such as positive regulation of humoral immune response and regulation of antigen receptor-mediated signaling pathway were enhanced in TLS+.TLS was a favorable prognostic factor and was not associated with PD-L1 expression in patients with lung adenocarcainoma. Moreover, gene expression analysis indicated that TLS is a site for the generation and regulation of antitumor immune responses.

Purpose: We evaluated plasma cell-free DNA (cfDNA) and tissue-based sequencing concordance for comprehensive oncogenic driver detection in non–small cell lung cancer (NSCLC) using a large-scale prospective screening cohort (LC-SCRUM-Liquid). Experimental Design: Blood samples were prospectively collected within 4 weeks of corresponding tumor tissue sampling from patients with advanced NSCLC to investigate plasma cfDNA sequencing concordance for alterations in 8 oncogenes (EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1) compared with tissue-based next-generation targeted sequencing. Results: Paired blood and tissue samples were obtained in 1,062/1,112 enrolled patients with NSCLC. Oncogenic alteration was detected by plasma cfDNA sequencing and tissue assay in 455 (42.8%) and 537 (50.5%) patients, respectively. The positive percent agreement of plasma cfDNA sequencing compared with tissue DNA and RNA assays were 77% (EGFR, 78%; KRAS, 75%; BRAF, 85%; HER2, 72%) and 47% (ALK, 46%; RET, 57%; ROS1, 18%; MET, 66%), respectively. Oncogenic drivers were positive for plasma cfDNA and negative for tissue due to unsuccessful genomic analysis from poor-quality tissue samples (70%), and were negative for plasma cfDNA and positive for tissue due to low sensitivity of cfDNA analysis (61%). In patients with positive oncogenic drivers by plasma cfDNA sequencing but negative by tissue assay, the response rate of genotype-matched therapy was 85% and median progression-free survival was 12.7 months. Conclusions: Plasma cfDNA sequencing in patients with advanced NSCLC showed relatively high sensitivity for detecting gene mutations but low sensitivity for gene fusions and MET exon 14 skipping. This may be an alternative only when tissue assay is unavailable due to insufficient DNA and RNA. See related commentary by Jacobsen Skanderup et al., p. 1381

Purpose:We evaluated plasma cell-free DNA (cfDNA) and tissue-based sequencing concordance for comprehensive oncogenic driver detection in non–small cell lung cancer (NSCLC) using a large-scale prospective screening cohort (LC-SCRUM-Liquid).Experimental Design:Blood samples were prospectively collected within 4 weeks of corresponding tumor tissue sampling from patients with advanced NSCLC to investigate plasma cfDNA sequencing concordance for alterations in 8 oncogenes (EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1) compared with tissue-based next-generation targeted sequencing.Results:Paired blood and tissue samples were obtained in 1,062/1,112 enrolled patients with NSCLC. Oncogenic alteration was detected by plasma cfDNA sequencing and tissue assay in 455 (42.8%) and 537 (50.5%) patients, respectively. The positive percent agreement of plasma cfDNA sequencing compared with tissue DNA and RNA assays were 77% (EGFR, 78%; KRAS, 75%; BRAF, 85%; HER2, 72%) and 47% (ALK, 46%; RET, 57%; ROS1, 18%; MET, 66%), respectively. Oncogenic drivers were positive for plasma cfDNA and negative for tissue due to unsuccessful genomic analysis from poor-quality tissue samples (70%), and were negative for plasma cfDNA and positive for tissue due to low sensitivity of cfDNA analysis (61%). In patients with positive oncogenic drivers by plasma cfDNA sequencing but negative by tissue assay, the response rate of genotype-matched therapy was 85% and median progression-free survival was 12.7 months.Conclusions:Plasma cfDNA sequencing in patients with advanced NSCLC showed relatively high sensitivity for detecting gene mutations but low sensitivity for gene fusions and MET exon 14 skipping. This may be an alternative only when tissue assay is unavailable due to insufficient DNA and RNA.See related commentary by Jacobsen Skanderup et al., p. 1381

Supplementary Figure S1. Consort diagram. Supplementary Figure S2. Frequency of the targetable gene alterations detected by plasma cfDNA sequencing (A) and tissue assay (B) in squamous cell carcinoma Supplementary Figure S3. Positive percent agreement of plasma cfDNA sequencing compared to tissue assay according to patient characteristics. PPA, positive percent agreement. Supplementary Figure S4. Positive percent agreement of plasma cfDNA sequencing compared to tissue assay according to metastatic site. PPA, positive percent agreement.

Supplementary Table S1 Patient characteristics in patients with 8 oncogene drivers and squamous cell carcinoma Supplementary Table S2 Detectability of eight oncogenic alterations by plasma cfDNA sequencing compared to tissue assay Supplementary Table S3 Detectability of eight oncogenic alterations by plasma cfDNA sequencing compared to tissue assay in patients only with brain metastasis Supplementary Table S4 Clinical outcomes of patients treated with a genotype-matched therapy who had oncogenic alterations detected by only plasma cfDNA sequencing.

Supplementary Figure from A Large-Scale Prospective Concordance Study of Plasma- and Tissue-Based Next-Generation Targeted Sequencing for Advanced Non–Small Cell Lung Cancer (LC-SCRUM-Liquid)

Supplementary Data from A Large-Scale Prospective Concordance Study of Plasma- and Tissue-Based Next-Generation Targeted Sequencing for Advanced Non–Small Cell Lung Cancer (LC-SCRUM-Liquid)

Introduction: This study aimed to clarify the correlation between the number of AMs and prognosis and to examine the gene expression of AMs in lung squamous cell carcinoma (SqCC). Methods: We reviewed 124 stage I lung SqCC cases in our hospital and 139 stage I lung SqCC cases in The Cancer Genome Atlas (TCGA) cohort in this study. We counted the number of AMs in the peritumoral lung field (P-AMs), and in the lung field distant from the tumor (D-AMs). Moreover, we performed a novel ex vivo bronchoalveolar lavage fluid (BALF) analysis to select AMs from surgically resected lung SqCC cases and examined the expression of IL10, CCL2, IL6, TGFβ, and TNFα (n=3). Results: Patients with high P-AMs had significantly shorter overall survival (OS) (pEx vivoBALF analysis revealed that AMs collected from the tumor vicinity showed higher expression of IL10 and CCL2 than AMs from distant lung fields in all 3 cases (IL-10: 2.2, 3.0, and 10.0-fold; CCL-2: 3.0, 3.1, and 3.2-fold). Moreover, addition of recombinant CCL2 significantly increased the proliferation of RERF-LC-AI, a lung SqCC cell line. Conclusion: The current results indicated the prognostic impact of the number of peritumoral AMs and suggested the importance of peritumoral tumor microenvironment in lung SqCC progression.

Background Superior sulcus tumours (SSTs) are relatively uncommon and one of the most intractable lung cancers among non-small cell lung cancer (NSCLC). We planned a multicenter, single-arm confirmatory trial of new multidisciplinary treatment using immune-checkpoint inhibitor. The aim is to evaluate the safety and efficacy of new multidisciplinary treatment with perioperative durvalumab after chemoradiotherapy (CRT). Methods The primary endpoint is 3-year overall survival. Patients receive induction CRT with sequential two courses of durvalumab, followed by surgical resection for resectable SST. The regimen for CRT is two courses of cisplatin and S-1, and concurrent radiotherapy (66 Gy/33 Fr). After surgery, 22 courses of post-operative durvalumab therapy are administered. For unresectable SST, an additional 22 courses of durvalumab are administered after induction durvalumab. Results In two cases as a safety cohort, the safety of intervention treatment up to 30 days after surgery was examined, and there were no special safety signals. Patient enrollment has now resumed in the main cohort. Conclusions The results of this study may contribute to the establishment of a new standard of care for SST, which is an intractable NSCLC.

Background: The efficacy of osimertinib as a first-line treatment for patients with poor performance status (PS) remains unclear. Patients & methods: This multicenter retrospective study evaluated patients treated with osimertinib between 2018 and 2020, with PS 2–4. Results: Among 36 patients with PS 2, the median progression-free survival (PFS), 1-year PFS, median overall survival (OS) and 1-year OS were 14.5 months, 65.4%, 18.1 months and 72.7%, respectively. Among 20 patients with PS 3–4, the median PFS, 1-year PFS, median OS and 1-year OS were 3.0 months, 27.1%, 5.0 months and 46.1%, respectively. Conclusion: Osimertinib was not as efficacious as other EGFR-tyrosine kinase inhibitors.

Objectives Several preclinical data proposed a potential efficacy of osimertinib, a third-generation EGFR tyrosine kinase inhibitor, for EGFR exon 20 insertion (EGFR ex20ins)-positive non-small cell lung cancer (NSCLC). However, reported case series and a retrospective study proposed controversial efficacy. The efficacy of osimertinib in EGFR ex20ins-positive NSCLC have not been well evaluated in prospective clinical trials. In this study, we performed a prospective, single-arm, multi-center, open-label, non-randomized phase I/II study to evaluate efficacy of osimertinib for EGFR ex20ins-positive NSCLC. Materials and methods From August 2018 to January 2020, 14 NSCLC patients with EGFR ex20ins were enrolled, of whom 2 were excluded because they did not meet the inclusion criteria. Efficacy and safety of 80 mg osimertinib were evaluated. In addition, we performed a translational exploratory study to clarify the association of mutation type-specific drug sensitivity, osimertinib pharmacokinetic data, and clinical efficacy. Results Of the evaluated patients, none experienced objective response, 7 experienced stable disease (58.3%), and 5 experienced disease progression (41.7%). The median progression free survival (PFS) was 3.8 months, and the median overall survival was 15.8 months. Interestingly, the exploratory study demonstrated statistically significant positive correlation between plasma osimertinib concentration/in vitro IC50 ratio and PFS (R = 0.9912, P = 0.0001), highlighting the mutation type-specific concentration-dependent efficacy of osimertinib for EGFR ex20ins-positive NSCLC. Conclusions Regular dose, 80 mg/day, of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. The translational study proposed the potential efficacy of higher dose osimertinib in a subgroup of EGFR ex20ins-positive NSCLC.

Lung cancer is one of the most aggressive tumour types. Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small-cell lung cancer (NSCLC)1. However, such oncogenic drivers are not found in 25–40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC2. Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome screening platform (LC-SCRUM-Asia, UMIN000036871). The CLIP1–LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive with other known oncogenic drivers. We show that kinase activity of the CLIP1–LTK fusion protein is constitutively activated and has transformation potential. Treatment of Ba/F3 cells expressing CLIP1–LTK with lorlatinib, an ALK inhibitor, inhibited CLIP1–LTK kinase activity, suppressed proliferation and induced apoptosis. One patient with NSCLC harbouring the CLIP1–LTK fusion showed a good clinical response to lorlatinib treatment. To our knowledge, this is the first description of LTK alterations with oncogenic activity in cancers. These results identify the CLIP1–LTK fusion as a target in NSCLC that could be treated with lorlatinib. Whole-transcriptome sequencing of a subset of 75 non-small-cell lung cancer specimens in a multi-institutional genome screening study identified a fusion of the CLIP1 and LTK genes with transformational potential due to constitutive LTK kinase activity.

Background It has recently been suggested that concomitant medication may affect the clinical outcome of patients treated with immune checkpoint inhibitors (ICIs). However, only a few studies on the impact of concomitant medication on immune‐related adverse events (irAEs) have previously been reported. Here, we aimed to determine the impact of concomitant medication on the efficacy and safety of ICIs. Methods We retrospectively analyzed the data of 300 patients treated with nivolumab or pembrolizumab for advanced non‐small cell lung cancer (NSCLC) between January 2016 and July 2018. Multivariate logistic regression analysis was used to assess the effect of concomitant medication on treatment response or irAEs. A multivariate Cox proportional hazards model was used to evaluate concomitant medication‐related factors associated with time‐to‐treatment failure or overall survival (OS). Results A total of 70 patients responded to treatment and 137 experienced irAEs. The response rate and incidence of irAEs in patients treated with ICIs were not significantly associated with concomitant medication. Multivariate analysis showed that the use of opioids was an independent factor (time‐to‐treatment failure: hazard ratio 1.39, p = 0.021, OS: hazard ratio 1.54, p = 0.007). Conclusions The efficacy and safety of nivolumab or pembrolizumab in the treatment of patients with advanced NSCLC were not significantly influenced by concomitant medication. However, opioid usage might be associated with shorter OS in patients treated with these ICIs. Further mechanistic investigations should explore whether these associations are purely prognostic or contribute to ICI resistance., Concomitant medication had no significant effect on the efficacy and safety of immune checkpoint inhibitors. Opioid use was associated with shorter overall survival and further study of this possible effect is required. This study is the first to demonstrate the impact of angiotensin receptor blockers or vitamin D on ICI treatment in patients with non‐small cell lung cancer.

BACKGROUND: PD-L1 in pathological tissue samples is known as a biomarker for immune checkpoint inhibitors (ICI) to unresectable non-small cell lung cancer (NSCLC) patients. However, collecting pathological tissue is highly invasive, and lower invasive test is needed. As an alternative diagnostic target, circulating cancer cells (CTCs) that are known to exist in the peripheral blood of cancer patients are garnering attention. PURPOSE: The goal of this study is to verify the utility of CTC analysis isolated by a novel system (Sysmex, Hyogo) against pathological testing of tumor samples. The primary objective is to determine whether CTCs can be detected in unresectable NSCLC patients, and the secondary objective is to evaluate the relationship between CTCs and clinicopathological features or clinical outcome. METHODS: Blood samples were collected from 45 patients with unresectable NSCLC and 17 healthy controls. CTCs were size-dependently enriched from whole blood, immunofluorescent stained with pan-CK (AE1/AE3), PD-L1, CD45/34/16, and Hoechst, and analyzed by Molecular Imaging Flow Cytometry (MI-1000). Fluorescence intensity and cell images of each marker were obtained by MI-1000. RESULTS: Cells positive for Hoechst but negative for blood cell markers were defined as non-blood cells (NBCs). Pan-CK positive NBCs were defined as CTCs. A similar number of NBCs were detected in both patients and healthy controls. When using a threshold set at two standard deviations above the mean fluorescence intensity of pan-CK and PD-LI of NBCs in healthy controls, 28.9% of patients had two or more CTCs. On the other hands, PD-L1 positive NBCs were only detected in patients, and the sensitivity of detecting CTCs or PD-L1 positive NBCs was 86.7%. Concordance with PD-L1 expression of tumor tissue was evaluated for three parameters: the number of PD-L1 positive NBCs, the median and the mean fluorescence intensities. The AUC in each case was low, indicating no concordance between PD-L1 expression of tumor tissue and CTCs. Additionally, no relation was found with the overall survivals and progression-free survival when comparing patients divided into two groups: those with two or more PD-L1 positive cells and those with less than two. CONCLUSION: The detected rate of pan-CK positive cells was low ( Citation Format: Mami Onishi, Eri Morita, Tetsuya Sakai, Yoshitaka Zenke, Masatoshi Yanagida, Koichi Goto. Development of a CTC-based novel diagnostic technology for unresectable non-small cell lung cancer [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 3321.

Objective The aim of this study was to assess long-term outcomes after lobectomy in patients with clinical T1 N0 lung cancer based on thin-section computed tomography. Methods We collected the data of patients with pathological adenocarcinoma who had undergone lobectomy. The patients were categorized into 4 groups according to a consolidation tumor ratio and tumor size. Groups A and B included tumors with consolidation tumor ratio ≤0.5 and size ≤3 cm. Group A consisted of tumors ≤2 cm. Group B consisted of the remaining tumors. Groups C and D consisted of tumors with consolidation tumor ratio >0.5. Group C consisted of those with tumors ≤2 cm and Group D consisted of tumors of size 2 to 3 cm. The 10-year overall survival and recurrence-free survival rates were examined. Results Among the 543 patients, the 10-year overall survival was 80.4% and the 10-year recurrence-free survival rate was 77.1%. The 10-year overall survival for group A was 94.0%, 92.7% for group B, 84.1% for group C, and 68.8% for group D, and the 10-year recurrence-free survival rate for each group was 94.0%, 89.0%, 79.7%, and 66.1%, respectively. Group A + B showed better overall survival than group C + D (hazard ratio, 2.78; 95% confidence interval, 1.45-5.06) and better 10-year recurrence-free survival (hazard ratio, 2.74; 95% confidence interval, 1.55-4.88). No patient in group A had recurrence. Conclusions Those patients with total tumor size ≤3 cm and consolidation tumor ratio ≤0.5 showed excellent prognosis and might be suitable candidates for sublobar resection. If noninferior survival of segmentectomy compared with lobectomy is confirmed in an ongoing Japan Clinical Oncology Group trial, segmentectomy will be included in the standard of care.

Lung cancer is the most common cause of cancer-related death globally. In addition, its incidence increases with age, with approximately half of all cases diagnosed in patients aged ≥70. Molecular targeted therapies and immunotherapies for advanced non-small-cell lung cancer have markedly improved outcomes over the past two decades. Despite the high incidence of lung cancer in older people, most trials excluded such patients from enrollment. Therefore, the optimal treatment strategies for older patients remain unclear. The present review summarizes the published literature and provides guidance on the treatment of older patients with lung cancer within three broad stages: (i) early-stage lung cancer, (ii) locally advanced lung cancer and (iii) metastatic lung cancer. We also discuss the use of the latest evidence for older patients.

The usefulness of the histopathology of biopsy samples for predicting the efficacy of immunotherapy in non-squamous, non-small cell lung cancer (NSq NSCLC) patients remains unclear. We retrospectively investigated the associations between the histopathological features in biopsy samples and survival outcomes in advanced NSq NSCLC patients receiving pembrolizumab. NSq NSCLC was classified histopathologically as morphological adenocarcinoma or non-small cell carcinoma (NSCC: absence of definitive features of either adenocarcinoma or a squamous morphology). We investigated the association between the tumor morphological features and immune/genetic features by examining the tumor PD-L1 expression and tumor mutation burden (TMB). Among 33 advanced NSq NSCLC patients with tumor PD-L1 scores ≥ 50% receiving pembrolizumab as first-line therapy, a biopsy diagnosis of NSCC was associated with a significantly longer progression-free survival [median 16.8 vs. 2.3 months; hazard ratio (HR) 0.26; 95% CI 0.10–0.62, P = 0.01] and overall survival (median NR vs. 10.1 months; HR 0.35; 0.12–0.97, P = 0.04) as compared to that of morphological adenocarcinoma. In an analysis of 367 biopsy samples, the NSCC group showed a higher percentage of samples with PD-L1 scores ≥ 50% than the morphological adenocarcinoma group (35% vs. 10%). The NSCC group (n = 8) also showed a significantly higher TMB than the morphological adenocarcinoma group (n = 7) (median 236 vs. 25 mutations/whole exome, P = 0.01). Absence of definitive morphological features in a biopsy sample could be a useful predictor of the efficacy of pembrolizumab in NSq NSCLC patients with tumor PD-L1 scores ≥ 50%, as these tumors are likely to show high tumor PD-L1 expression and high TMB.

Loss of the chromatin remodeling SWItch/Sucrose Non-fermentable (SWI/SNF) complex is implicated in the pathogenesis of several types of neoplasms. The aim of this study was to examine the clinicopathological features of non-small cell lung cancer (NSCLC) with loss of expression of the SWI/SNF complex.Specimens from a total 1013 NSCLC cases used for tissue microarrays (TMAs) were immunohistochemically examined for expression of SWI/SNF complex (BAF) subunits, namely SMARCA4, SMARCA2, ARID1A, and ARID1B. We examined the clinicopathological features and PD-L1 expression status in NSCLC cases with loss of expression of one or more subunits of the SWI/SNF complex (BAF-Loss). Moreover, we compared the tumor mutation burden (TMB) between NSCLC cases with BAF-Loss and those with intact expression of the four subunits (BAF-Intact).Using TMA, BAF-Loss was observed in 5.4% of cases (SMARCA4: 2.4%, SMARCA2: 2.4%, ARID1A: 1.3%, and ARID1B: 0.3%). Concurrent loss of expression of two or more subunits of the SWI/SNF complex was detected in 0.7% of cases. BAF-Loss was significantly associated with smoking history, young age, male sex, pulmonary emphysema/bullae, large invasive tumor size, pleural invasion, vascular invasion, solid-predominant morphology, and absence of a lepidic growth component. A higher proportion of PD-L1-positive cases was observed among NSCLC patients with BAF-Loss than BAF-Intact (42% vs 26%, P 0.01). In stage I NSCLC, SWI/SNF-Loss (n = 23) was associated with shorter overall survival (HR: 2.43; 95% CI: 1.18-5.01; P = 0.01) and recurrence-free survival (HR: 2.22; 95% CI: 1.17-4.24; P 0.01) compared to BAF-Intact (n = 563). The degree of TMB was significantly higher among NSCLC patients with BAF-Loss (n = 3) than BAF-Intact (n = 7) (median 437 vs 113 mutations/whole-exome, P = 0.02).The current results suggest that loss of SWI/SNF expression in NSCLC is associated with aggressive clinicopathological features, PD-L1-positive status and high TMB.

Human epidermal growth factor receptor 2 (HER2) mutations are present in ∼3% of patients with non-small cell lung cancer (NSCLC), with exon-20 insertions accounting for ∼90% of such HER2 mutations and having been identified as driver oncogenic alterations. Antibody-cytotoxic drug conjugates including trastuzumab deruxtecan have shown an excellent efficacy for NSCLC with HER2 mutations. We have now performed a phase II study to evaluate the efficacy of ado-trastuzumab emtansine (T-DM1) for NSCLC positive for HER2 exon-20 insertion mutations.Eligible patients with HER2 exon-20 insertion mutations confirmed by next-generation sequencing or multiplex polymerase chain reaction platforms and a history of one or two lines of chemotherapy received T-DM1 (3.6 mg/kg) intravenously every 21 days. The primary end-point of the study was the objective response rate (ORR).Between February 2019 and July 2020, 22 patients were enrolled in the study. A775_G776insYVMA was the most frequent HER2 exon-20 insertion mutation, accounting for 19 (86.4%) of the 22 patients. The ORR was 38.1% (90% confidence interval, 23.0-55.9%), and the disease control rate was 52.4%. The median duration of response was 3.5 months, and the median progression-free survival and median overall survival were 2.8 and 8.1 months, respectively. Toxicity was mild, with the frequency of adverse events of grade ≥3 being low.T-DM1 is a potential treatment option for patients with NSCLC with HER2 exon-20 insertion mutations. Further investigation of biomarkers for T-DM1 is warranted to improve its efficacy for NSCLC with such mutations.JapicCTI-194620.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is generally performed for the diagnosis of hilar/mediastinal lymph node metastasis in patients with lung cancer. Recently, a 25-gauge (G) needle became available, but robust evidence of its usefulness in routine clinical practice is still lacking. METHODS: A prospective randomized crossover trial was performed, in which patients with suspected hilar/mediastinal lymph node metastasis of lung cancer underwent EBUS-TBNA. The primary endpoint was the rate of yield histology specimens containing malignant cells. RESULTS: From December 2018 to February 2020, 102 patients were randomly assigned to EBUS-TBNA using a 22G needle first, followed by a 25G needle (n=50) or EBUS-TBNA using a 25G needle first, followed by a 22G needle (n=52). There was no difference in the diagnostic yield of malignancy between the histology specimens obtained by using the 22G and 25G needles (75% vs. 75%, respectively, P=0.37). The sizes of the tissue samples (16.4 vs. 4.9 mm(2), respectively) and number of malignant cells in the tissue samples (626 vs. 400, respectively) were both significantly higher when using the 22G needle than when using the 25G needle. CONCLUSIONS: No significant difference in the diagnostic yield between the 22G and 25G needles was observed for the diagnosis of lymph node metastasis of lung cancer, suggesting that needles of either gauge could be used for the biopsy. However, we would recommend use of the 22G needle, because it provided larger specimens and specimens containing larger numbers of malignant cells. TRIAL REGISTRATION: University hospital Medical Information Network Clinical Trial Registry (ID: UMIN000036680).

Background The aim of this study was to identify patients with pathological stage I lung adenocarcinoma at high risk of recurrence. Methods We retrieved data from 536 patients with pathological stage I lung adenocarcinoma who underwent lobectomy and were enrolled in a prospective multiinstitutional study (the JCOG0201 study). Invasive component size, excluding lepidic component, was used as the tumor size. Recurrence-free survival (RFS) was estimated by the Kaplan-Meier method, and a multivariable Cox proportional hazards model identified independent prognostic factors associated with worse RFS. Results The all-patient 10-year RFS was 83.9% (median follow-up 10.2 years). Multivariable Cox analysis revealed that age greater than 65 years (hazard ratio [HR], 2.60; 95% confidence interval (CI), 1.66-4.07), invasive component size greater than 2 cm (HR, 2.70; 95% CI, 1.40-5.23), visceral pleural invasion (HR, 2.17; 95% CI, 1.23-3.81), and vascular invasion (HR, 2.59; 95% CI, 1.47-4.55) were potential independent prognostic factors for RFS. When patients were divided into a high-risk group for recurrence (invasive component size >2 cm or positive for visceral pleural invasion or for vascular invasion; n = 124) and a low-risk group (invasive component size ≤2 cm and negative for visceral pleural invasion and vascular invasion; n = 408), there was a significant difference in RFS between the high-risk and low-risk groups (high-risk group: HR, 3.61; 95% CI, 2.35-5.55). Conclusions Pathological stage I lung adenocarcinoma patients with an invasive component size greater than 2 cm, visceral pleural invasion, or vascular invasion were at high risk for recurrence.

SMARCA4 is a subunit of the switch/sucrose non‐fermentable (SWI/SNF) chromatin‐remodeling complex. An effective treatment for SMARCA4‐deficient non‐small cell lung carcinoma (NSCLC) has not yet been established. Correlations between a response to immune checkpoint inhibitors and the SWI/SNF complex have been suggested, but little is known about the efficacy of immune checkpoint inhibitors against SMARCA4‐deficient NSCLC. A 43‐year‐old man underwent left upper lobe lung resection and was diagnosed with SMARCA4‐deficient lung adenocarcinoma. Two months after surgery, multiple lung metastases appeared. Immunohistochemical analysis showed no PD‐L1 expression. Whole‐exon sequencing revealed a relatively high tumor mutation burden at 396. After the failure of three standard chemotherapy regimens, the patient was treated with nivolumab as fourth‐line treatment. An obvious reduction in the lung metastases was obtained for more than 14 months. We report the first case of SMARCA4‐deficient NSCLC with a high tumor mutation burden successfully treated with nivolumab. Anti‐PD‐1 antibodies might be a promising treatment strategy for patients with SMARCA4‐deficient NSCLC.

9103 Background: Osimertinib is a standard drug for first-line treatment of patients with advanced non–small cell lung cancer (NSCLC) harboring EGFR mutations (mt). While tumor mutational burden (TMB)-high and co-occurring genetic alterations (alt) have been reported to be negatively associated with the efficacy of other EGFR-TKIs, the impact of co-occurring genetic alt with EGFR major mt on the efficacy of osimertinib remains unclear. Methods: In a multi-institutional genomic screening project (LC-SCRUM-Asia), we have analyzed lung cancer patients for genomic alt by a targeted next-generation sequencing (NGS) system, Oncomine Comprehensive Assay and Genexus/OPA. We retrospectively evaluated the association between the genomic profile and efficacy of first-line osimertinib for EGFR-mutated NSCLC based on the LC-SCRUM-Asia database. Results: Between March 2015 and January 2022, 12,705 NSCLC patients were enrolled in the LC-SCRUM-Asia database, and EGFR mt was detected in 2,232 patients. Of these, 324 patients, including 171 with ex19del (53%) and 153 with L858R (47%), received first-line treatment with osimertinib. The patient characteristics were as follows: median age, 69 years (range 31-97); females, 64%; never-smokers, 57%; adenocarcinoma, 97%; and performance status 0-1, 99%. The frequency of compound EGFR mt and TMB were higher in the L858R (LR) group than in the ex19del (Ex19) group (compound mt (%), 12 vs. 4; mean TMB (mt/Mb), 3.4 vs. 2.5). There were no differences in the frequencies of other co-occurring genetic alt between the two groups. Higher TMB, alt of genes encoding receptor tyrosine kinase (RTK), including FGFR1, RET, MET etc., and amp of cell-cycle related genes were significantly associated with shorter progression-free survival (PFS) in the entire group (median PFS: TMB > 3 vs. ≤3 mt/Mb = 11.4 vs. 17.1 months; p = 0.023; RTK gene alt+ vs. alt- = 9.7 vs. 15.2 months; p = 0.014; cell-cycle gene amp+ vs. amp- = 10.6 vs. 15.6 months, p = 0.001). EGFR subgroup analysis showed that a higher TMB was significantly associated with a shorter PFS in the LR group (> 3 vs. ≤3 mt/Mb = 10.0 vs. 17.1 months, p < 0.001), but not in the Ex19 group. On the other hand, alt of genes encoding RTK and amp of cell-cycle related genes were significantly associated with a shorter PFS in the Ex19 group (RTK gene alt+ vs. alt- = 8.4 vs. 17.8 months, p = 0.008; cell-cycle gene amp+ vs. amp- = 10.6 vs. 17.5 months, p = 0.003), but not in the LR group. Multivariate analysis identified RTK gene alt in the Ex19 group and higher TMB in the LR group as being independently associated with a shorter PFS. Conclusions: First-line osimertinib treatment was less effective in NSCLC patients harboring Ex19 with other RTK gene alt or LR with a higher TMB, indicating that co-occurring genetic alt affecting the efficacy of osimertinib differ between NSCLC patients harboring Ex19 and LR.

Identification of targetable fusions as oncogenic drivers in non-small cell lung cancer has transformed its diagnostic and therapeutic paradigm. In a recent article in Nature, Izumi et al. report the discovery of CLIP1-LTK fusion as a novel oncogenic driver in lung cancer, targetable using the ALK tyrosine kinase inhibitor lorlatinib.

Background Nivolumab has shown promising results against non‐small‐cell lung cancer (NSCLC). However, its efficacy to treat central nervous system (CNS) metastases, specifically among programmed cell death 1 ligand 1 (PD‐L1)‐negative patients, remains unclear. Case A 66‐year‐old woman was diagnosed with adenocarcinoma stage II and underwent a left lower lobectomy. The histopathological evaluation revealed stage IVA with pleural dissemination. The patient did not harbor an epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement, and PD‐L1 expression of the surgical specimen using 22C3 assay was 0%. Single brain metastasis was detected, and carboplatin and nab‐paclitaxel were administered. After three cycles, asymptomatic multiple brain metastases were identified, and the patient was treated with nivolumab as second‐line chemotherapy. Six months later, MRI revealed an intracranial complete response (CR). Nivolumab was discontinued after 23 cycles due to immune‐related adverse events (irAEs) of grade 2 rash. However, its effects were sustained for 13 months after discontinuation. We were unable to evaluate the PD‐L1 expression of brain metastases, which may show heterogeneity. Conclusion This case demonstrates that nivolumab effectively treated a patient with negative PD‐L1 expression of the lung harboring CNS metastases.

Tumor necrosis is a negative prognostic factor in various cancers. High-grade neuroendocrine carcinomas (HGNEC) of the lung, such as small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), commonly have histopathological features of tumor necrosis. However, the prognostic value of tumor necrosis remains unknown.A total of 81 patients with HGNEC (SCLC, n = 42; LCNEC, n = 39) who underwent complete resection were enrolled. The proportion of necrosis in the tumor tissues was quantified using digital image analysis. We analyzed the relationship between the proportion of necrosis, clinicopathological factors, and prognosis. Moreover, we examined the correlation between genomic alterations and proportion of necrosis.The median proportion of necrosis was 10.6 % (range, 0-62.8 %). The proportion of necrosis was not significantly different between SCLC (median, 5.1 %; range, 0-62.8 %) and LCNEC (median: 14.2 %; range, 0-59.3 %) (p = 0.14). The cumulative incidence of recurrence (CIR) and lung cancer-specific cumulative incidence of death (LC-CID) were significantly higher in patients with 10 % or higher necrosis (necrosis ≥ 10 %) than in those with less than 10 % (necrosis10 %) (hazard ratio [HR], 2.94; 95 % confidence interval [CI], 1.30-6.64, and HR, 2.87; 95 % CI, 1.13-7.29, respectively). In the bivariate analysis, necrosis ≥ 10 % was independently associated with higher CIR and tended to be associated with higher LC-CID. The frequency of genomic alterations in the PI3K/AKT/mTOR pathway, MYC family, MAPK/ERK pathway, and major RTK signaling pathways were not different between the necrosis ≥ 10 % and necrosis10 % groups for both SCLC and LCNEC.High proportion of tumor necrosis (≥ 10 %) had a negative prognostic value in surgically resected HGNEC.

Importance Insufficient data are available regarding the long-term outcomes and cumulative incidences of toxic effects that are associated with chemoradiotherapy (CRT) for patients with stage III non–small-cell lung cancer. Objective To evaluate survival and late toxic effects 10 years after patients were treated with curative CRT. Design, Setting, and Participants This multicenter, phase 3 West Japan Thoracic Oncology Group (WJTOG) 0105 randomized clinical trial was conducted between September 2001 and September 2005 in Japan. Patients with histologically or cytologically confirmed non–small-cell lung cancer with unresectable stage III disease were assessed for eligibility. Additional data were analyzed from January 2018 to December 2019. Interventions A total of 440 eligible patients were randomly assigned to groups as follows: A (control), 4 cycles of mitomycin/vindesine/cisplatin plus thoracic radiotherapy (TRT) of 60 Gy; B, weekly irinotecan/carboplatin for 6 weeks plus TRT of 60 Gy followed by 2 courses of irinotecan/carboplatin consolidation; or C, weekly paclitaxel/carboplatin for 6 weeks plus TRT of 60 Gy followed by 2 courses of paclitaxel/carboplatin consolidation. Main Outcomes and Measures The primary outcome was 10-year survival probability after CRT. The secondary outcome was late toxic effects that occurred more than 90 days after initiating CRT. Results From September 2001 to September 2005, 440 patients (group A, n = 146 [33.2%; median (range) age, 63 (31-74) years; 18 women (12.3%)]; group B, n = 147 [33.4%; median (range) age, 63 (30-75) years; 22 women (15.0%)]; group C, n = 147 [33.4%; median (range) age, 63 (38-74) years; 19 women (12.9%)]) were enrolled. The median (range) follow-up was 11.9 (7.6-13.3) years. In groups A, B, and C, median (range) overall survival times were 20.5 (17.5-26.0), 19.8 (16.7-23.5), and 22.0 (18.7-26.2) months, respectively, and 10-year survival probabilities were 13.6%, 7.5%, and 15.2%, respectively. There were no significant differences in overall survival among treatment groups. The 10-year progression-free survival probabilities were 8.5%, 6.5%, and 11.1% in groups A, B, and C, respectively. Grade 3 or 4 late toxic effect rates were 3.4% (heart, 0.7%; lung, 2.7%) in group A, and those only affecting the lung represented 3.4% and 4.1% in groups B and C, respectively. No other cases of late toxic effects (grades 3/4) were observed since the initial report. Conclusion and Relevance In this 10-year follow-up of a phase 3 randomized clinical trial, group C achieved similar efficacy and toxic effect profiles as group A 10 years after initiating treatment. These results serve as a historical control for the long-term comparisons of outcomes of future clinical trials of CRT. Trial Registration UMIN Clinical Trial Registry:UMIN000030811

Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients' reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients.

Background Cases of exacerbation of pre-existing neuromuscular diseases induced by immune checkpoint inhibitors (ICIs) have rarely been reported because patients with autoimmune diseases have generally been excluded from ICI therapy due to the increased risk of exacerbation. We describe the first case of an elderly patient who experienced exacerbation of a previously undiagnosed sporadic inclusion body myositis (sIBM), the most common myopathy in the geriatric population, which was triggered by anti-programmed cell death-1 therapy. Case presentation A 75-year-old man who was receiving pembrolizumab presented with limb weakness. Three years prior, he had noticed slowly progressive limb weakness, but he received no diagnosis. After the first infusion of pembrolizumab, his creatine kinase (CK) levels had increased. The neurological examination and muscle biopsy findings confirmed the diagnosis of sIBM and suggested exacerbation of sIBM induced by pembrolizumab. After the patient’s CK levels decreased, pembrolizumab was restarted. The tumor progressed after its treatment with pembrolizumab. The patient died after 15 months of follow-up. Conclusions In patients with slowly progressive limb weakness, sIBM should be explored before ICI therapy. In addition, if patients show high CK levels after ICI introduction, it is necessary to confirm whether they have sIBM in order to avoid unnecessary immunosuppressive therapies and assess whether they can tolerate ICI reintroduction.

We analyzed 135 patients (including 27 EGFR-mutant and 29 EGFR-wild) with T1-3N0M0 non-squamous NSCLC treated by PBT. Considering the 3-year cumulative incidence, the EGFR-mutant group showed a significantly lower infield failure rate (9% vs 27%, p = 0.02) and higher out-of-field failure rate (67% vs 40%, p = 0.02) than the EGFR-wild group.

Background EGFR exon 20 insertion gene mutation (ex20ins) accounts for about 4-12% of the total EGFR gene mutations in non-small cell lung cancer (NSCLC) patients. NSCLC patients with EGFR ex20ins is known to be less sensitive to 1st- or 2nd-generation EGFR-TKIs. Although 3rd-generation EGFR-TKI, osimertinib is active against in vitro models of EGFR ex20ins, its efficacy has not yet been fully elucidated. This phase I/II study is conducted to evaluate the clinical efficacy of osimertinib in NSCLC patients with EGFR ex20ins. Method This is a single-arm, multi-center, open-label, non-randomized phase I/II study (UMIN000031929) consisting of stage 1 and stage 2 (Simon's two-stage design). In stage 1, 12 patients receive osimertinib 80mg once daily until they meet the termination criteria, such as, disease progression, severe toxicities, withdrawal etc. In stage 2, 9 patients receive the same dose of osimertinib if more than 1 patient achieve PR or CR in stage 1. At the transition from stage 1 to 2, Independent Data Monitoring Committee (IDMC) will provide recommendation regarding the need for study continuation, termination or dose modification of osimertinib. Patients with advanced or metastatic NSCLC with EGFR ex20ins who have a history of chemotherapy within 0 to 3 regimens are enrolled. Patients with history of EGFR-TKI treatment (gefitinib, erlotinib, afatinib, dacomitinib) can be included if the EGFR-TKI treatment did not show any clinical benefit. Patients with EGFR gene mutations, such as exon 19 deletion, L858R, T790M, G719X, L861Q are excluded. Primary end point is objective response rate (ORR) assessed via Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points are progression-free survival, overall survival, and safety profiles. Blood sampling is obtained at 4-weeks after starting osimertinib to analyze pharmacokinetic parameters. We also perform liquid biopsy for next generation sequencing at before and after acquiring resistance to osimertinib to clarify resistant mechanisms of osimertinib in EGFR ex20ins. We explore the relationship among clinical outcome, side effect, pharmacokinetic parameters and subtype of EGFR ex20ins. Result Recruitment began in June 2018 and by February 2020, 12 patients were enrolled in stage 1 at 6 institutions. Backgrounds of the patients were as follows, the median age was 63 years (range 22-84), female/male 6/6, ECOG PS 0/1 8/4, cStage IIIA/IIIb/IVA/IVB 1/1/2/8. The ORR was 0% (CR/PR 0, SD 8, PD 4), and the DCR was 66.7%. From the result of stage 1, one of the IDMC's recommendations was protocol revision since it is presumed that increasing the dose of osimertinib could be clinically promising. At the conference, the influence of subtype of EGFR ex20ins and blood levels of osimertinib on survival will be evaluated and the results of interim analysis for stage 1 will be presented. Conclusion Regular dose of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. Funding AstraZeneca. Citation Format: Eiki Ichihara, Hiroyuki Yasuda, Yuta Takashima, Yoshitaka Zenke, Shinji Takeuchi, Masahiro Morise, Katsuyuki Hotta, Mineyoshi Sato, Shingo Matsumoto, Azusa Tanimoto, Reiko Matsuzawa, Katsuyuki Kiura, Hideki Terai, Shinnosuke Ikemura, Koichi Goto, Kenzo Soejima. Phase I/II study of osimertinib in EGFR exon 20 insertion mutations in non-small cell lung cancer patients: AEX20 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT106.

Programmed death ligand 1 (PD-L1) expression is a predictive biomarker for patient response to nivolumab in nonsquamous NSCLC. However, the number of biopsy samples and tumor cells (TCs) required to assess PD-L1 expression remains unclear.A total of 222 biopsy samples from 80 patients with nonsquamous NSCLC treated with nivolumab were collected. Number of TCs and PD-L1 score were compared among the sample containing the largest number of TCs (Max-TC), the sample containing the smallest number of TCs (Min-TC), and the total samples from each patient. The impact of the number of samples and TCs on the prediction of patient response to nivolumab with use of PD-L1 scores was evaluated.There was a mismatch in PD-L1 scores less than 1% and those of at least 1% between Max-TC and the total samples in one patient (1%) and between Max-TC and Min-TC in six patients (8%). The optimal number of TCs to match PD-L1 expression less than 1% versus at least 1% between Max-TC and Min-TC was 100 (sensitivity = 0.676 and 1 - specificity = 0.333). PD-L1 expression of at least 1% in Min-TCs containing at least 100 TCs was associated with longer progression-free survival (median 7.6 versus 1.8 months [p0.01]) and overall survival (median not reached versus 9.9 months [p = 0.04]) compared with PD-L1 expression less than 1%. However, there were no differences in progression-free survival (median 3.9 versus 2.3 months [p = 0.37]) or overall survival (median 9.7 versus 7.6 months [p = 0.60]) between PD-L1 expression of at least 1% and PD-L1expression less than 1% in Min-TCs containing fewer than 100 TCs.Single biopsy samples containing at least 100 TCs are required to evaluate PD-L1 expression for predicting patient response to nivolumab.

9097 Background: TMB estimation using targeted NGS panels is widely performed in clinical practice. The objective of this study was to determine the optimal NGS panel for estimating TMB and to evaluate its clinical implications for NSCLC. Methods: Two NGS panels, Oncomine Tumor Mutation Load Assay (OMLA) and FoundationOne (F1), were compared to select the most accurate TMB prediction panel. From February 2017 to May 2018, 350 lung cancer patients were analyzed by whole-exome sequencing (WES), and the concordance rate of OMLA and F1 to WES was examined. In addition, its clinical utility as a biomarker for immune checkpoint inhibitors (ICIs) was evaluated in our international genome screening network (LC-SCRUM-Asia). From June 2019 to December 2020, 3141 patients with NSCLC from 185 institutions were enrolled, and genomic analysis was successful. The clinico-genomic database of LC-SCRUM-Asia was used for this analysis. Results: The linear correlation with WES was 0.80 for OMLA and 0.78 for F1. This indicated that OMLA was more strongly correlated with WES. The cutoff value of F1 was 10 mut/Mb, which corresponded to 9 mut/Mb (OMLA) and 194 mutations (WES). The sensitivity of the OMLA for WES was 79%, and the specificity was 85%. Meanwhile, the sensitivity of the F1 was 74%, and the specificity was 80%. OMLA more accurately predicted TMB, and its clinical utility was evaluated. 3141 NSCLC patients, consisting of 2282 adenocarcinomas, 593 squamous cell carcinomas, and 266 others, were analyzed for TMB, estimated using OMLA. The median number of mutations was 4.2 mut/Mb (range, 0-718.4/Mb). High TMB (≥9 mut/Mb) was observed in 17.2% (393/2282) of adenocarcinoma cases and 25.8% (153/593) in squamous cell carcinoma cases. 778 patients were treated with ICI or ICI plus chemotherapy as the first-line treatment. Patients’ characteristics were as follows: male/female; 595/183, median age (range); 67 (25-90), stage II/III/VI/recurrence; 11/90/649/28, TMB high/low; 177/601, ICI/ICI plus chemotherapy; 114/664. The progression-free survival (PFS) was significantly longer in patients with high TMB than in those with low TMB (median PFS, 7.5 vs. 5.9 months, p = 0.0314). The overall survival (OS) was significantly longer in patients with high TMB than in those with low TMB (median OS, 27.4 vs. 20.4 months, p = 0.006). Conclusions: The TMB estimated by OMLA correlated more strongly with the WES-derived TMB comparing with F1. TMB estimated by OMLA was correlated with PFS and OS in NSCLC patients treated with ICIs. Prospective clinical trials are needed to determine whether TMB estimated by OMLA is a biomarker for ICI.

9054 Background: RAS ( KRAS, NRAS and HRAS) is a targetable oncogene family in several cancers, including NSCLC, and the clinical development of various RAS-targeted therapies are ongoing. However, the clinical relevance of uncommon RAS mutations, such as NRAS and HRAS mutations, in NSCLC patients (pts) remains unclear. Methods: In a large-scale genomic screening project (LC-SCRUM-Asia), we have prospectively analyzed lung cancer pts for genomic alterations by a targeted next-generation sequencing (NGS) system, Oncomine Comprehensive Assay. We evaluated clinico-pathological and genomic characteristics in NRAS- or HRAS-mutated NSCLC pts comparing with those in KRAS-mutated pts based on the LC-SCRUM-Asia database. Results: Since March 2015 to December 2020, 9131 NSCLC pts were enrolled in the LC-SCRUM-Asia, and 8374 of them (92%) were successfully analyzed by NGS. The RAS mutation frequencies were 1134 KRAS (14%), 50 NRAS (0.6%), and 15 HRAS (0.2%). The most frequent variant of NRAS and HRAS mutations was Q61X (78%) and G13X (80%), respectively, whereas that of KRAS was G12X (84%). Patient characteristics were summarized in Table. Male was significantly frequent in NRAS- than in KRAS-group (p=0.03), and smokers were frequent in all the three groups (overall, 79%). The majority of NRAS (70%) and KRAS mutations (89%) were detected in adenocarcinoma (Ad), whereas 60% of HRAS mutations were in squamous cell carcinoma (Sq). Tumor mutation burden (TMB) was significantly higher in NRAS-mutated tumors than in KRAS-mutated tumors (p=0.03). Concomitant TP53 mutations were significantly frequent in HRAS-mutated pts than in KRAS-mutated pts (53% vs. 30%, p=0.05), and STK11 mutations were also tended to be frequent in HRAS-mutated pts than in KRAS-mutated pts (20 vs. 7%, p=0.10). Therapeutic efficacy of PD-1/PD-L1 inhibitors was not different among the three groups in the current follow-up data, but HRAS-mutated tumors did not respond to PD-1/PD-L1 inhibitors (response rate, 0%; median PFS, 1.6 months). Conclusions: NRAS- or HRAS-mutated NSCLCs were different from KRAS-mutated NSCLCs in clinico-pathological and genomic profiles. In particular, the immunotherapies were not effective for HRAS-mutated NSCLCs.[Table: see text]

9094 Background: A variety of oncogene drivers have been identified in NSCLC and molecularly-stratified precision medicine has led to improved survival in advanced NSCLC. Next-generation sequencing (NGS)-based testing is utilized to detect actionable gene alterations; however, the TAT of NGS is often too long to translate into clinical decision making. Thus, rapid multi-gene testing alternatives are needed. Methods: A lung cancer genomic screening project (LC-SCRUM-Asia) capturing clinical outcome was established in 2013 to identify patients with oncogene drivers and to support the development of novel targeted therapies. Since February 2013 to May 2019 (LC-SCRUM-Asia 1st-phase), single gene testing and/or a targeted NGS assay, Oncomine Comprehensive Assay (OCA), were used for the genomic screening. Since June 2019 to December 2020 (2nd-phase), a multi-gene PCR assay (Amoy 9-in-1 test) and a rapid NGS assay (Genexus/Oncomine Precision Assay [OPA]) were also implemented as rapid multi-gene testing. Results: A total of 10667 Japanese NSCLC patients, including 6826 in the 1st-phase and 3841 in the 2nd-phase, were enrolled in the LC-SCRUM-Asia. Success rate for OCA: 93%, for 9-in-1 test: 98%, for Genexus/OPA: 96%. Median TAT for OCA: 21 days, for 9-in-1 test: 3 days, for Genexus/OPA: 4 days. The frequencies of genetic alterations detected in the 1st-/2nd-phase were EGFR: 17/24%, KRAS: 15/16%, HER2 ex20ins: 4/3%, ALK fusions: 3/3%, RET fusions: 3/2%, ROS1 fusions: 3/2%, MET ex14skip: 2/2%, BRAF V600E: 1/1%, NRG1 fusions: 0/0.2% and NTRK3 fusions: 0.05/0.04%. Overall percent agreement of 9-in-1 test compared with OCA for EGFR/KRAS/HER2/BRAF/MET/ALK/ROS1/RET/NTRK3 alterations was 98%, and that of OPA compared with OCA was 95%. The rate of patients who received targeted therapies as 1st-line treatment was significantly elevated in the 2nd-phase compared with the 1st-phase (510/3841 [13%] vs. 567/6826 [8%], p < 0.001). Through the genomic screening, 1410 (37%) and 1269 (18%) candidate patients for clinical trials of KRAS, HER2, BRAF, MET, ALK, ROS1, RET or TRK-targeted drugs were identified in the 2nd-phase and in the 1st-phase, respectively. The rate of patients who were actually enrolled into the genotype-matched clinical trials were also significantly higher in the 2nd-phase than in the 1st-phase (222 [6%] vs. 186 [3%], p < 0.001). In 1st-line treatments for advanced NSCLC patients, the median progression-free survival was 8.5 months (95% CI, 7.7−9.4) in the 2nd-phase (n = 1839) versus 6.1 months (95% CI, 5.9−6.3) in the 1st-phase (n = 4262) (p < 0.001). Conclusions: Both the 9-in-1 test and Genexus/OPA had short TATs (3−4 days), high success rates (96−98%) and good concordance (95−98%) compared with another NGS assay (OCA). These rapid multi-gene assays highly contributed to enabling precision medicine and the development of targeted therapies for advanced NSCLC.

Background Gastric acid-suppressing medications (AS), namely, proton pump inhibitors and histamine-2 receptor antagonists, increase gastric pH, which may reduce the absorption of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors—erlotinib and gefitinib. Patients and Methods From 2008 to 2011, 130 consecutive patients with advanced non–small-cell lung cancer (NSCLC) harboring EGFR mutations were treated with either erlotinib or gefitinib at our institution. The clinical characteristics of the patients were reviewed, and the efficacy and toxicity of erlotinib and gefitinib were compared for patients receiving and not receiving AS. Results Among the 130 patients, 47 received AS (AS users group), while the remaining 83 patients did not (AS non-users group). The overall response rate (ORR) and median progression-free survival (PFS) in the subject population was 60% and 10 months, respectively. In the AS users and non-users groups, the ORR was 64% and 63% ( P = .92), while the median PFS was 8.7 and 10.7 months ( P = .13), respectively. No significant difference in either ORR or PFS was observed between the 2 groups. With regard to the toxicity, the frequencies of rash (83% vs. 86%; P = .60) and diarrhea (34% vs. 29%; P = .55) were similar for both groups. A multivariate analysis identified that AS use was not a significant factor for either PFS or OS. Conclusion Concurrent use of AS did not affect the efficacy or toxicity of erlotinib and gefitinib in patients with advanced NSCLC harboring EGFR mutations.