Chinese Non-small Cell Lung Cancer Research Articles

Abstract 1403: Comprehensive characterization of 1038 Chinese non-small cell lung cancer patients of different PD-L1 expression levels

Abstract Background: Programmed death ligand 1 (PD-L1) is currently one of the most well-characterized markers for predicting response to immunotherapy in non-small cell lung cancer (NSCLC). Multiple clinicohistologic and genetic characteristics have been proposed as correlates of PD-L1 expression. However, few studies have examined the associations between PD-L1 expression and immune infiltration or chromosomal arm-level alterations. In this comprehensive characterization, we identified clinical features, oncogenic drivers and other genomic abnormalities, impaired biological pathways, arm-level amplifications and losses, and infiltration of immune cell populations that were associated with PD-L1 expression. Methods: We retrospectively included 1038 NSCLC patients who had both PD-L1 Tumor Proportion Score (TPS) by the 22C3 assay and genomic profiles acquired with targeted sequencing using 8-, 168-, and 520-gene panels (Burning Rock Biotech, Guangzhou, China). Multiplex immunohistochemistry (mIHC) was used to analyze immune infiltration. Association analysis was performed to identify patient characteristics associated with PD-L1 expression. Results: The negative (TPS <1%), low (1-49%), and high (≥50%) PD-L1 expression classes accounted for 25.2% (n = 262), 43.2% (n = 449), and 31.5% (n = 327) patients, respectively. PD-L1 expression was positively associated with advanced tumor stage, the male sex, squamous carcinoma, ALK fusions, KRAS G12/13X mutations, BRAF V600E, ROS1 fusion, MET exon 14 skipping, altered TP53, LPR1B, FAT1, PTPRD, KDR, and CD274, and altered pathways such as MAPK, RAS, DNA damage response, p53 signaling, and checkpoint factors. The negative correlates included driver-positive status, EGFR L858R, EGFR exon 19 deletions, ERBB2 exon 20 insertions, altered RMB10, STK11, RICTOR, GNAS, and PIK3C2G, and aberrant receptor tyrosine kinase, ERBB2 signaling, and non-homologous end joining. In terms of arm-level aberrations, PD-L1 positivity was associated with 3p, 3q, 7p or 7q amplification and 18p, 20p, or 20q deletion. We also found that 9p, 9q, 10p, 12p, 12q, and 19p amplifications were most frequent in high PD-L1-high patients, who were also more likely to harbor 18p, 29p, or 20q deletion when compared with compared with PD-L1-negative patients. mIHC analysis revealed that PD-L1 expression was associated with proportions of CD3+, CD3+CD8+, CD3+PD-1+, CD8+PD-1+, and PD-1+ cells in the tumor and CD3+PD-1+, CD8+PD-1+, and PD-1+ cells in the stroma, suggesting increased tumor infiltration of cytotoxic T cells associated with PD-L1 expression. Conclusions: This study provides a comprehensive analysis of the associations between PD-L1 expression and a multitude of histopathologic, genomic, and immunologic features. Further research is warranted for validation and association of these factors with clinical outcomes. Citation Format: Weiqiang Yin, Jinghao Liang, Zhihua Guo, Zixian Xie, Haonan Zhao, Fayuan Wu. Comprehensive characterization of 1038 Chinese non-small cell lung cancer patients of different PD-L1 expression levels [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 1403.

Abstract 3312: Comparison of risk factors to molecular risk stratification in Chinese early-stage non-squamous non-small cell lung cancer patients

Abstract Background: Improved risk stratification for non-small cell lung cancer (NSCLC) represents a critical unmet need. A Clinical Laboratory Improvement Amendments (CLIA)-certified, 14-gene, quantitative PCR (qPCR)-based expression assay was found to better stratify mortality risk. The association of molecular risk stratification with other clinicopathological, radiomic, and genetic risk factors have not been fully identified, especially in Chinese NSCLC patients (pts). Methods: We newly recruited 102 early-stage non-squamous NSCLC pts who had undergone complete surgical resection. RNA was extracted from tumor tissue specimens and prospective molecular risk stratification by the 14-gene prognostic assay was performed. Gene mutation status and tumor mutational burden (TMB) were evaluated. Histological sections and clinical records were reviewed for canonical prognostic indicators that have been reported to be associated with lung cancer risk. Results: Of the 102 pts, the mean age was 55 years, 66 (64.7%) were female, and 18 (17.7%) had a smoking history. The majority of pts (84, 82.4%) were stage I, with 1 atypical adenomatous hyperplasia (AAH), 6 adenocarcinomas in situ (AIS), 1 stage II, and 2 stage III. 64 pts were deemed low-risk by molecular testing, 24 were intermediate-risk, and 14 were high-risk. The pts of AAH and AIS were all in the low-risk group. The maximum tumor diameter (MTD) in the high-risk group was the highest. There were no significant differences in age, sex, smoking status, pathologic stage, NCCN risk criteria, micropapillary or solid (MP/S) pattern, or the number of lesions between the three groups. The most common driver mutations were EGFR (65%), TP53 (28%), and RBM10 (13%). The molecular risk stratification had a significant association with TP53 (p = 0.013), TP53 loss of function (LOF, p = 0.01), KRAS (p = 0.011), and APC mutation (p = 0.05), but not with EGFR mutation and co-mutational status. TMB in the low-risk pts was significantly lower than in other pts (p = 0.007). The low-risk pts had lower SUVmax (p = 0.076), significantly lower mean CT value (p = 0.023), and mean enhanced CT value (p = 0.005) compared with others. In the NCCN low-risk pts, 25 were molecular low-risk, 12 were intermediate-risk, and 9 were high-risk. The risk stratification showed a significant association with SUVmax, TP53 mutation, and TMB in the NCCN low-risk pts. Pearson correlation showed the molecular risk score was significantly associated with MTD, TMB, SUVmax, mean CT value, mean enhanced CT value, and max CT value. SUVmax showed the strongest correlation with the risk score. Conclusion: The molecular risk stratification by the 14-gene assay was associated with canonical prognostic indicators, like TP53 LOF, TP53, KRAS, APC mutation, TMB, mean CT value, and mean enhanced CT value. Our study provides more evidence of the clinical utility of the qPCR-based prognostic assay. Citation Format: Naixin Liang, Jianchao Xue, Ming Zhao, Bowen Li, Yadong Wang, Zhicheng Huang, Yankai Xia, Ruirui Li, Zhongxing Bing, Zhibo Zheng, Jianpeng Zhang, Bin Wang, Zhe Feng, Xinyu Liu, Haochen Li, Xiaoqing Yu, Yang Song. Comparison of risk factors to molecular risk stratification in Chinese early-stage non-squamous non-small cell lung cancer patients [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 3312.

Ultra-rapid Idylla™ EGFR mutation screening followed by next-generation sequencing: An integrated solution to molecular diagnosis of non-small cell lung cancer.

Rapid profiling of the EGFR mutations is crucial to help clinicians choose the optimal treatment for patients with advanced/metastatic Non-Small Cell Lung Cancer (NSCLC). Unfortunately, current diagnostic techniques, including ARMS-PCR and NGS, generally require several days to deliver final results. This diagnostic delay may lead to treatment delays for patients who are worsening rapidly. This study introduced the ultra-rapid Idylla™ system for rapid, sensitive and specific identification of the EGFR mutations among Chinese NSCLC patients. Idylla™ EGFR Assay, an integrated cartridge running on the Idylla™ system, which can detect 51 EGFR mutations directly from Formalin-Fixed, Paraffin-Embedded (FFPE) samples within 2.5 hours, was used in this study. The sensitivity and specificity of the Idylla™ system were evaluated in comparison with ARMS-PCR or NGS using 95 clinical samples. The Idylla™ system achieved a sensitivity of 97.6%, a specificity of 100%, and an overall concordance of 97.9% for 95 retrospective samples. When compared to ARMS-PCR, the Idylla™ system demonstrated high accuracy with an overall agreement of 97.1% (34/35), a sensitivity of 95.2% (20/21) (95% CI, 76.2% - 99.9%), and an estimated specificity of 100% (12/12) (95% CI, 76.8% - 100%) for 35 prospective samples. This Idylla system provides a rapid, accurate and simple approach for screening EGFR mutations, which can guide Tyrosine Kinase Inhibitors (TKI) treatment for NSCLC patients in a timely manner.

Interpretation of expert consensus on treatment for stage III non‐small cell lung cancer

Interpretation of expert consensus on treatment for stage III non‐small cell lung cancer

Landscape and Predictive Significance of the Structural Classification of EGFR Mutations in Chinese NSCLCs: A Real-World Study

Background: Non-classical EGFR mutations demonstrate heterogeneous and attenuated responsiveness to EGFR TKIs. Non-small cell lung cancer (NSCLC) patients with atypical EGFR mutations have limited therapeutic options. A recent study established a novel structural-based classification of EGFR mutations and showed its value in predicting the response to TKI. We sought to interrogate the distribution of different structural types and to validate the predictive value in Chinese NSCLCs. Methods: A total of 837 tumor samples were retrospectively recruited from 522 patients with unresectable EGFR-mutant NSCLC. EGFR mutations were classified into four groups: classical-like, T790M-like, Ex20ins-L, and PACC. Treatment information and clinical outcomes were obtained from 436 patients. The time to treatment failure (TTF) was determined on a per-sample basis. Results: Of the 837 EGFR-mutant samples, 67.9%, 18.5%, 9.0%, and 3.1% harbored classical-like, T790M-like, PACC, and Ex20ins-L mutations, respectively. Thirteen (1.6%) samples carried mutations beyond the four types. Among the 204 samples with atypical mutations, 33.8%, 36.7%, 12.7%, and 10.3% were classical-like, PACC, Ex20ins-L, and T790M-like, respectively. In patients with PACC mutations, second-generation TKIs demonstrated a significantly longer TTF than first-generation TKIs (first-line: 15.3 vs. 6.2 months, p = 0.009; all-line: 14.7 vs. 7.1 months, p = 0.003), and a trend of longer TTF than third-generation TKIs (all-line: 14.7 vs. 5.1 months, p = 0.135). Conclusions: Our study depicted the landscape of structural types of EGFR mutations in Chinese NSCLC patients. Our results also suggest that the structural classification can serve as a predictive marker for the efficacy of various EGFR TKIs, which would guide therapeutic decision making.

Efficacy of Osimertinib Combined with Bevacizumab in Advanced Non-small Cell Lung Cancer Patients with Acquired EGFR T790M Mutation

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) capable of overcoming non-small cell lung cancer (NSCLC) with EGFR T790M mutation. Although the addition of bevacizumab to 1st generation EGFR-TKIs confers a significant improvement in progression-free survival (PFS) in treatment-naive EGFR mutant NSCLC patients, osimertinib plus bevacizumab combination failed to show prolongation in the phase 2 study WJOG8715L. Data of such combination in Chinese patients are still lacking. This study aimed to explore the efficacy of the addition of bevacizumab to osimertinib as second-line therapy in real-world data, and to evaluate the role of anti-angiogenesis plus osimertinib combination therapeutic strategies in pretreated Chinese NSCLC patients with acquired EGFR T790M mutation. A total of 42 advanced NSCLC patients with acquired EGFR T790M mutation after prior EGFR-TKIs treatment were collected between January 2020 to August 2021, with 16 cases treated with osimertinib plus bevacizumab and 26 cases treated with osimertinib. The treatment effect of patients were analyzed. The objective response rate (ORR) in combination group and osimertinib group were 43.8% and 50.0% respectively (P=0.694). No statistically significant difference in median PFS (14.0 mon vs 13.0 mon, P=0.797) and overall survival (OS) (29.0 mon vs 26.0 mon, P=0.544) between the combination group and osimertinib group were observed. Prior history of bevacizumab was identified as an independent predictor of PFS (P=0.045) and OS (P=0.023). Our study demonstrated that adding bevacizumab to osimertinib could not show advantages in PFS and OS in pretreated NSCLC patients harboring EGFR T790M-mutation.

Landscape of Savolitinib Development for the Treatment of Non-Small Cell Lung Cancer with MET Alteration-A Narrative Review.

Non-small cell lung cancer (NSCLC) is increasingly being treated with targeted therapies. Savolitinib (Orpathys®) is highly selective mesenchymal epithelial transition (MET)-tyrosine kinase inhibitor (TKI), which is conditionally approved in China for advanced NSCLC with MET exon 14 skipping mutations (METex14). This article summarizes the clinical development of savolitinib, as a monotherapy in NSCLC with METex14 mutation and in combination with epidermal growth factor receptor (EGFR) inhibitor in post EGFR-TKI resistance NSCLC due to MET-based acquired resistance. Preclinical models demonstrated anti-tumor activities in MET-driven cancer cell line and xenograft tumor models. The Phase Ia/Ib study established an optimized, recommended phase II dose in Chinese NSCLC patients, while TATTON study of savolitinib plus osimertinib in patients with EGFR mutant, MET-amplified and TKI-progressed NSCLC showed beneficial efficacy with acceptable safety profile. In a pivotal phase II study, Chinese patients with pulmonary sarcomatoid carcinoma, brain metastasis and other NSCLC subtype positive for METex14 mutation showed notable responses and acceptable safety profile with savolitinib. Currently, results from ongoing clinical trials are eagerly anticipated to confirm the efficacious and safety benefits of savolitinib as monotherapy and in combination with EGFR-TKI in acquired resistance setting in advanced NSCLC and its subtypes with MET alterations.

Characterization of driver mutations in Chinese non-small cell lung cancer patients using a novel targeted sequencing panel.

The identification of driver mutations has greatly promoted the precise diagnosis and treatment of non-small cell lung cancer (NSCLC), but there is lack of targeted sequencing panels specifically designed and applied to Chinese NSCLC patients. This study aimed to design and validate of a novel sequencing panel for comprehensive characterization of driver mutations in Chinese NSCLC patients, facilitating further exploration of downstream pathway alterations and therapeutic utility. A novel target sequencing panel including 21 driver genes was designed and examined in a cohort of 260 Chinese NSCLC patients who underwent surgery in Peking Union Medical College Hospital (PUMCH). Genetic alterations were identified and further analyzed for driver mutations, downstream pathways and therapeutic utilities. The most frequently identified driver mutations in PUMCH NSCLC cohort were on genes TP53 (28%), EGFR (27%) and PIK3CA (19%) for lung adenocarcinoma (LUAD), and TP53 (41%), PIK3CA (14%) and CDKN2A (13%) for lung squamous cell carcinoma (LUSC), respectively. Downstream pathway analysis revealed common pathways like G1_AND_S1_PHASES pathway were shared not only between LUAD and LUSC patients, but also among three different NSCLC cohorts, while other pathways were subtype-specific, like the unique enrichment of SHC1_EVENT_IN_EGFR_SIGNALING pathway in LUAD patients, and P38_ALPHA_BETA_DOWNSTREAM pathway in LUSC patients, respectively. About 60% of both LUAD and LUSC patients harbored driver mutations as sensitive biomarkers for different targeted therapies, covering not only frequent mutations like EGFR L858R mutation, but also rare mutations like BRAF D594N mutation. Our study provides a novel target sequencing panel suitable for Chinese NSCLC patients, which can effectively identify driver mutations, analyze downstream pathway alterations and predict therapeutic utility. Overall it is promising to further optimize and apply this panel in clinic with convenience and effectiveness.

Prognostic biomarkers correlated with immune infiltration in non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related mortality in men and women globally. Non-small cell lung cancer (NSCLC) is the most prevalent subtype, accounting for 85-90% of all cancers. Although there have been dramatic advances in therapeutic approaches in recent decades, the recurrence and metastasis rates of NSCLC are as high as 30-40% with the 5-year overall survival rate being less than 15%. Therefore, it is necessary to explore the pathogenesis of NSCLC at the genetic level and identify prognostic biomarkers and novel therapeutic targets. Here, we aimed to identify mutated genes with high frequencies in Chinese NSCLC patients using next-generation sequencing and to investigate their relationships with the tumor mutation burden (TMB) and tumor immune microenvironment. A total of 110 NSCLC patients were enrolled to profile the genetic variations. Mutations in EGFR (62.37%), TP53 (61.29%), LRP1B (13.98%), FAT1 (12.90%), KMT2D (11.83%), CREBBP (10.75%), and RB1 (9.68%) were most prevalent. TP53, LRP1B, KMT2D, and CREBBP mutations were all significantly associated with high TMB (P < 0.05 or P < 0.01). The infiltrating levels of immune cells and immune molecules were enriched significantly in the LRP1B mutation group. LRP1B mutations significantly correlated with stimulating and inhibitory immunoregulators. Gene set enrichment analysis revealed that cell cycle, the Notch signaling pathway, the insulin signaling pathway, and the mTOR signaling pathway are related to LRP1B mutations in the immune system. LRP1B mutations may be of clinical importance in enhancing the anti-tumor immune response and may be a promising biomarker for predicting immunotherapy responsiveness.

An EGFR L858R mutation identified in 1862 Chinese NSCLC patients can be a promising neoantigen vaccine therapeutic strategy.

This study aimed to develop a vaccine that targets mutation-derived neoantigen in Chinese non-small-cell lung cancer (NSCLC). A cohort of 1862 Chinese NSCLC patients who underwent targeted sequencing with a 1021-gene panel was investigated. HLA typing was done using OptiType v1.0 and neoantigens were predicted by netMHCpan v4.0. HLA LOH was inferred using the lohhla algorithm and TMB were quantified by counting the total number of non-synonymous ones based on our panel data. CIBERSORT was utilized to estimate the TME in different EGFR mutant subtype by using TCGA data. HLA-A*11:01(42.59%) was the top one allele and HLA-A*33:03(12.94%) ranked 12th. EGFR L858R (22.61%) was the most prevalent gene variant. The binding affinity (IC50 MT = 22.9 nM) and shared frequency (2.93%) of EGFR L858R in combination with HLA-A*33:03 were optimal. Inasubsequentfurther analysis on immunological features of EGFR mutant subtypes, 63.1% HLA loss of heterozygosity LOH (HLA LOH) and 0.37% (7 of 1862) B2M aberrations were found in our population, both had no significant association with EGFR mutant subtypes suggesting that theprocessof antigen presentation involved HLA LOH and B2M mechanisms in EGFR L858R is working. Tumor mutation burden (TMB) was investigated by utilizing our panel and showed that EGFR L858R had the lowest TMB compared with other EGFR mutant subtypes. In addition, analysis of 22 immune cell types from The Cancer Genome Atlas (TCGA) data showed EGFR L858R was correlated with low level of CD8 T cells, activated CD4 memory T cells and elevated level of macrophage M2 suggesting an inhibited tumor microenvironment (TME). Our study identified that EGFR L858R neoantigen had the potential to generate cancer vaccines in NSCLC patients with HLA A*33:03. The neoantigen-based vaccines may become an effective salvage regimen for EGFR L858R subgroup after targeted therapy or immune checkpoint inhibitors (ICIs) failure.

A Novel TP53 Gene Mutation Sustains Non-Small Cell Lung Cancer through Mitophagy.

Lung cancer is the leading cause of cancer death in the world. In particular, non-small-cell lung cancer (NSCLC) represents the majority of the lung cancer population. Advances in DNA sequencing technologies have significantly contributed to revealing the roles, functions and mechanisms of gene mutations. However, the driver mutations that cause cancers and their pathologies remain to be explored. Here, we performed next-generation sequencing (NGS) on tumor tissues isolated from 314 Chinese NSCLC patients and established the mutational landscape in NSCLC. Among 656 mutations, we identified TP53-p.Glu358Val as a driver mutation in lung cancer and found that it activates mitophagy to sustain cancer cell growth. In support of this finding, mice subcutaneously implanted with NSCLC cells expressing TP53-p.Glu358Val developed larger tumors compared to wild-type cells. The pharmaceutical inhibition of autophagy/mitophagy selectively suppresses the cell proliferation of TP53-null or TP53-p.Glu358Val-expressing lung cancer cells. Together, our study characterizes a new TP53 mutation identified from Chinese lung cancer patients and uncovers its roles in regulating mitophagy, providing a new insight into NSCLC treatment.

Peripheral absolute eosinophil count identifies the risk of serious immune-related adverse events in non-small cell lung cancer.

BackgroundImmune-related adverse events (irAEs) have drawn a lot of attention lately as a result of the predominance of immunotherapy in advanced non-small cell lung cancer (NSCLC). However, the clinical evidence for irAEs in real life is limited. In this paper, the occurrence of irAEs in Chinese NSCLC patients was examined, and possible risk factors for the emergence of severe irAEs were discovered.MethodsOur retrospective investigation assessed the occurrence of adverse events (AEs) and prognosis of 213 patients who received immunotherapy for NSCLC. Using univariate and multivariate logistic regression models, the association between clinicopathological traits and the incidence of severe irAEs was investigated. To assess the prognostic impact of irAEs, survival data was analyzed.ResultsAmong the 213 NSCLC patients, 122 (57.3%) had irAEs of any grade, and 38 (17.8%) had high-grade (grade 3-5) AEs. Baseline peripheral absolute eosinophil count (AEC) (HR 6.58, 95% CI: 1.5-28.8, P=0.012) was found to be an independent predictor of high-grade irAEs by multivariate analysis. The survival analysis revealed that patients with severe irAEs had worse OS (15.7 vs. 20.8 months, 95% CI: 11.6-19.8 vs. 16.0-25.5, P=0.026).ConclusionAccording to our findings, the peripheral absolute eosinophil count (AEC) is a reliable indicator of severe irAEs in NSCLC. Serious irAEs that occur in patients often reflect poor prognoses. In the future, high-grade irAEs should receive more attention.

Bifidobacterium breve predicts the efficacy of anti-PD-1 immunotherapy combined with chemotherapy in Chinese NSCLC patients.

Gut microbes play an important role in the occurrence of lung cancer, immunotherapy, and chemotherapy. In this study, we analyzed the characteristics of gut microbes in patients with lung cancer and investigated the effect of gut microbes on anti-PD-1 therapy combined with chemotherapy. Fecal samples from 21 non-small cell lung cancer (NSCLC) patients and 22 healthy volunteers who were treated in the Fourth Hospital of Hebei Medical University from 2019 to 2021 were collected. DNA was extracted from all samples, and the V3-V4 region of the bacterial 16S rRNA gene was PCR-amplified using the Illumina sequencing platform, and R language was used for data analysis. There were significant differences in the Beta diversity and metabolic pathways of gut microbes between NSCLC patients and healthy individuals (p < 0.05). Bifidobacterium, Escherichia, and Sarterella were significantly enriched in patients with clinical benefit response (p < 0.05), and these three bacteria had certain predictive value for clinical benefit. Patients with Bifidobacterium breve had significantly longer median progression-free survival (mPFS) compared with patients with no detectable Bifidobacterium breve feces at baseline (106 days vs. NR, p < 0.001). Multivariate COX analysis showed that the presence of B.breve was an independent good prognostic factor affecting the PFS of patients receiving combination therapy (p < 0.05). The clinical efficacy of anti-PD-1 therapy combined with chemotherapy in Chinese advanced NSCLC patients is closely related to the gut microbiota, and Bifidobacterium breve may be a potential biomarker to predict the efficacy of immune-combined chemotherapy.

Real-world clinical treatment outcomes in Chinese non-small cell lung cancer with EGFR exon 20 insertion mutations.

Background EGFR exon 20 insertions (EGFR ex20ins) constitute a heterogeneous subset of EGFR-activating alterations. However, the effectiveness of standard therapy in patients with EGFR ex20ins remains poor.MethodsIn our study, we retrospectively collected next-generation sequencing (NGS) data from 7,831 Chinese NSCLC patients and analyzed the relationship between EGFR ex20ins variations and medical records.ResultsOur data showed that EGFR ex20ins account for up to 3.5% of all EGFR mutation non-small-cell lung cancer (NSCLC) patients and 1.6% of all NSCLC patients in China. Thirty-eight different variants of EGFR ex20ins were identified in 129 NSCLC patients. We observed that the patients with EGFR ex20ins may benefit from the anti-angiogenesis agents significantly (P = 0.027). In the EGFR ex20ins near-loop group, patients who received second-/third-generation EGFR-TKI therapy treatment as first-line treatment had a longer median progression-free survival (PFS) than those who initiated treatment with first-generation EGFR-TKI or chemotherapy. Patients with co-mutations of EGFR ex20ins near-loop and TP53 tended to have a shorter OS in second-/third-generation EGFR-TKI therapy (P = 0.039). Additionally, median PFS was significantly longer in patients harboring EGFR ex20ins far-loop variants who received chemotherapy as a first-line setting (P = 0.037).ConclusionsOverall survival was significantly longer in EGFR ex20ins patients with anti-angiogenesis agents. For the choice of first-line strategy, NSCLC with EGFR ex20ins near-loop variants may benefit from second-/third-generation EGFR-TKI, while patients harboring EGFR ex20ins far-loop variants might have better outcomes from chemotherapy. TP53 could serve as a potential predictive marker in poor prognosis for EGFR ex20ins near-loop patients.

EP16.03-006 Genetic Characteristics of EGFR Concurrent Variants with RB1 and TP53 in NCSLC Patients

EGFR-TKIs (tyrosine kinase inhibitor) can effectively improve the survival rate of NSCLC patients with EGFR sensitive mutations. However, concomitant alterations along with EGFR mutations often affect the effect of EGFR-TKIs. The genome characteristic of EGFR co-mutation is of great significance for guiding clinical treatment. In this study, we first reported the genetic characteristics of EGFR/RB1/TP53 co-variation in the Chinese non-small cell lung cancer (NSCLC) cohort.

1125P Real-world molecular testing and treatment patterns in epidermal growth factor receptor (EGFR) mutation-positive, locally advanced or metastatic Chinese non-small cell lung cancer patients failing first-line EGFR-tyrosine kinase inhibitors

Epidermal Growth Factor Receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) patients failing first-line (1L) EGFR- tyrosine kinase inhibitors (TKI) can benefit from subsequent targeted therapies. However, the real world data on the testing patterns and subsequent treatment patterns among patients failing 1L EGFR-TKI are lacking.

1102P Genomic alterations correlated with the expression of PD-L1 based on the next-generation sequencing in Chinese non-small cell lung cancer

Blockade of programmed cell death protein-1 (PD1)/programmed cell death ligand-1 (PD-L1) interaction is one of important immunotherapies in lung cancers. Current research also focused on the relationship between genomic alterations and the expression of PD-L1. Therefore, we analyzed the molecular characteristics and its correlation with the expression of PD-L1, which may help to establish a reasonable tumor classification strategy to improve immunotherapy. Tissue specimens were obtained from 391 cases suffered from lung cancer. Frequencies of gene alterations were detected and analyzed using next-generation sequencing(152 or 603 genes). All specimens were also performed for PD-L1 (22C3) by immunohistochemistry (IHC) with PD-L1 tumor proportion score (TPS) reported for further analysis. In 391 lung cancer samples, 113 (28.9%) cases had comutations in both TP53 and EGFR, 110 (28.1%) cases had alterations in EGFR only, 94 (24.0%) cases had alterations in TP53 only, and 74(18.9%) cases were wild-type of TP53 and EGFR. Two major alterated genes were TP53 (57.0%) and EGFR (52.9%), both of whose frequencies were significantly higher than the other tested genes (P < 0.05). Groups with alterations in EGFR, APC (3.3%) or RBM10 (4.1%) were significantly associated with the decreased expression of PD-L1 (P < 0.05), while alterations in TP53 were significantly associated with the increased expression of PD-L1 (P < 0.05). Comparative analysis revealed that alterations (single or compound mutation) occured in either EGFR or TP53 affect the PD-L1 expression in this Chinese cohort. Although alterations in either EGFR or TP53 has independent and synergistic effects on the PD-L1 expression, there is limited evidence for those alterations serving as predictive biomarkers for the PD-L1 status. Furthermore, whether patients with both high PD-L1 expression and alterations in EGFR or TP53 can benefit from immunotherapies is still in question, and this subgroup is still worthy of clinical molecular recognition by further study.

EP08.01-009 TRBV Haplotype Profile Was Related to Immune-Induced Adverse Events in Chinese Patients With Advanced NSCLC

Immune-related adverse events (irAE) are inevitable following immunotherapy, which significantly impact the quality of life and possibly cause therapy discontinuation or interruption in cancer patients. Previous studies reported that T-cell receptor beta variable (TRBV) gene was related to irAE in Caucasian patients with non-small cell lung cancer (NSCLC). However, the relationship between TRBV gene and irAE remains to be revealed in Chinese NSCLC patients.

Analysis of the Effcacy and Safety of Amivantamab in Non-small Cell Lung Cancer Patients with EGFR/MET Gene Abnormalities: A Single Center's Experience

背景与目的表皮生长因子受体（epidermal growth factor receptor, EGFR）和细胞间质上皮转换因子（cellular-mesenchymal to epithelial transition factor, c-Met）是非小细胞肺癌（non-small cell lung cancer, NSCLC）中常见的变异基因，都是受体酪氨酸激酶，在下游信号转导方面具有协同作用。针对EGFR和c-Met通路的靶向药物联合应用后，能够阻断PI3K/AKT/mTOR途径和Ras/Raf/Mek途径，限制补偿通路激活，发挥抗肿瘤作用。以Amivantamab为代表的EGFR和c-Met双特异性抗体新型药物能同时阻断两条信号通路，在肺癌临床研究中展现出良好前景。然而目前国内应用较少，相关经验缺乏。本研究将介绍我中心Amivantamab疗效数据和不良反应处理经验，探讨此类药物对我国EGFR/MET基因异常NSCLC的应用价值。方法收集2020年8月-2021年12月于我院接受Amivantamab治疗的晚期NSCLC病例的临床数据，分析其治疗反应率、生存和不良反应。结果本研究共纳入15例患者，其中Amivantamab单药治疗6例，Amivantamab联合Lazertinib治疗9例。治疗后7例（46.7%）达部分缓解（partial response, PR），7例（46.7%）达疾病稳定（stable disease, SD），1例（6.7%）达疾病进展（progressive disease, PD），总体客观缓解率（objective response rate, ORR）为46.7%，总体疾病控制率（disease control rate, DCR）为93.3%。7例EGFR外显子20插入突变患者中，2例（28.6%）达PR，5例（71.4%）达SD，DCR为100.0%，中位缓解持续时间（duration of response, DOR）未成熟，2例PR者仍持续缓解。5例奥希替尼耐药的患者中，2例（40.0%）达PR，3例（60.0%）达SD，DCR为100.0%，中位DOR未成熟，1例PR者仍持续缓解。中位随访时间为8.7个月（0.9个月-18.6个月），截至最后一次随访，共有6例患者发生疾病进展，3例患者死亡，中位无进展生存期和中位总生存期未成熟。常见的不良事件为皮疹（86.7%），甲沟炎（80.0%）和输液反应（60.0%），多为1级-2级。3级及以上不良反应包括皮疹（33.3%），转氨酶升高（13.3%）、水肿（6.7%）、血栓栓塞（6.7%）、间质性肺炎（6.7%）和血小板减低（6.7%）。结论Amivantamab对EGFR外显子20插入突变和奥希替尼耐药的中国晚期NSCLC治疗有效，与国外疗效数据相仿。整体安全性可耐受，需重点关注皮疹、甲沟炎、输液反应等不良反应。

Abstract 5396: DNA damage repair gene mutations predict the efficacy of immunization combined with platinum chemotherapy in advanced non-small cell lung cancer: A retrospective cohort study

Abstract Purpose: DNA damage repair (DDR) mutations are known to predict response to platinum-based chemotherapy in multiple solid tumors, as well as immunotherapy in non-small cell lung cancer (NSCLC). However, the predictive value of DDR in immunization combined with platinum chemotherapy remains unclear. Methods: We retrospectively collected information from 495 patients with advanced NSCLC whose tumors were analyzed using next-generation sequencing (NGS) and analyzed the characteristics of DDR mutations. Among them, 64 patients with NSCLC who received platinum chemotherapy and 37 patients who received immunotherapy combined with platinum chemotherapy were included in the prognostic analysis. Results: The DDR genes was commonly mutated in Chinese NSCLC population (242/495, 48.89%). In Chinese NSCLC cohort, DDR mutations showed a strong association with high tumor mutational burden (TMB-H) (DDR mutant vs DDR wild-type: 7.26 muts/Mb vs 5.15 muts/Mb, P=0.001) and higher rates of strong PD-L1 (TPS≥50%) positivity (DDR mutant vs DDR wild-type: 28.74% vs 20.69). Sixty-four advanced NSCLC patients treated with platinum-based chemotherapy were analyzed, the ORRs were 16% for the patients with DDR mutations (DDRmut) and 2.70% for the DDR wild-type (DDRwt) subgroup (P&amp;lt;0.05), and the DCRs were 88% for the DDRmut group and 48.64% for the DDRwt group (P&amp;lt;0.05). The DDRmut patients had significantly improved median PFS than the DDRwt group (7.07 months vs 4.27 months, hazard ratio (HR) =0.57, 95%CI 0.33−0.97, P= 0.0303). Median OS was also significantly better among the DDRmut patients than in the DDRwt group (29.93 vs 20.7 months, HR=0.49, 95%CI 0.25−0.97, P= 0.0359). Moreover, in thirty-Seven advanced NSCLC patients treated with immunization combined with platinum chemotherapy, the ORRs were 45% for the patients with DDR mutations (DDRmut) and 11.76% for the DDR wild-type (DDRwt) subgroup (P&amp;lt;0.05), and the DCRs were 95% for the DDRmut group and 70.59% for the DDRwt group (P&amp;lt;0.05). The DDRmut patients had significantly improved median PFS than the DDRwt group (16.83 months vs 5.83 months, hazard ratio (HR) =0.34, 95%CI 0.12−0.973, P= 0.0079). For patients in the DDRmut group, PFS receiving immunization combined with platinum chemotherapy was significantly better than those receiving platinum-based chemotherapy (16.83 months vs 7.07 months, hazard ratio (HR) =0.48, 95%CI 0.24−0.97, P= 0.046). However, for patients in the DDRwt group, there was no significant difference in PFS between those who received immunization combined with platinum chemotherapy and those who received platinum-based chemotherapy (5.8 months vs 4.2 months, hazard ratio (HR) =0.76, 95%CI 0.394−1.495, P= 0.491). Conclusions: DDR mutations may serve as a positive predictor of immunization combined with platinum chemotherapy in patients with advanced NSCLC. Citation Format: Zhiwe Xiao, Lingling Sun, Yating Zheng, Hanrui Chen, Xinting Zheng, Jiamin Luo, Chuying Gu, Ruiting Lin, Xue Hu, Mengli Huang, Lizhu Lin. DNA damage repair gene mutations predict the efficacy of immunization combined with platinum chemotherapy in advanced non-small cell lung cancer: A retrospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5396.