Treatment Of Advanced Non-small Cell Lung Cancer Patients Research Articles

Revolutionizing NSCLC Treatment: Immunotherapy Strategies for EGFR-TKIs Resistance.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment choice for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. EGFR-TKIs have made significant progress in the treatment of advanced NSCLC patients, but drug resistance issues still inevitably arise. The mechanism of drug resistance and subsequent treatment has been current research challenge and priority. Immune checkpoint inhibitors (ICIs) are a new choice for late-stage NSCLC patients without druggable molecular alterations. Currently, several studies have applied ICIs therapy for NSCLC patients with EGFR-TKIs resistance and explored the potential efficacy of ICIs. This review elaborates on the current status of immunotherapy after EGFR-TKIs resistance, including ICIs monotherapy, combined with EGFR-TKIs, chemotherapy, antiangiogenic drugs, and other therapies.

Strategies and influencing factors for the treatment of advanced non-small cell lung cancer based on epidermal growth factor receptor tyrosine kinase inhibitors: a narrative review.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the primary treatment for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations, significantly enhancing patient prognosis. Despite the efficacy of EGFR-TKIs, monotherapy faces challenges such as variability among individuals and early drug resistance. This article aims to explore the treatment strategies and influencing factors for advanced NSCLC patients treated with EGFR-TKIs, optimize treatment plans, and improve the prognosis of patients with advanced NSCLC. We undertook a comprehensive, narrative review of the latest literature to define the current application and progress of EGFR-TKIs in treating patients with advanced NSCLC. The efficacy and promise of EGFR-TKIs, both as monotherapy and combined with other agents, for treating patients with advanced NSCLC are outlined. The study delves into the mechanisms of resistance and the ongoing development of EGFR-TKIs. Various factors influencing the treatment of advanced NSCLC patients with EGFR-TKIs are also examined. EGFR-TKIs alone improve survival in patients with advanced NSCLC. Combined with other agents, some regimens have shown improved benefits in overcoming drug resistance and prolonging patient survival. It is imperative to focus on developing novel EGFR-TKIs and investigate innovative combination therapies to maximize patient benefit.

Chinese expert consensus on iruplinalkib for the treatment of locally advanced or metastatic ALK-positive non-small cell lung cancer (2024 edition)

Anaplastic lymphoma kinase (ALK) fusion gene is one of the most common driver gene in non-small cell lung cancer (NSCLC). Epidemiological data showed that ALK gene fusion is detected in 9.06% of Chinese advanced NSCLC patients. ALK-tyrosine kinase inhibitors (TKIs) have become the standard treatment for advanced NSCLC patients with ALK gene fusion. Seven different ALK-TKIs have been approved by the National Medical Products Administration (NMPA) of China, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, and iruplinalkib. Iruplinalkib is a novel new-generation ALK-TKI independently developed in China. On June 27, 2023, the NMPA approved iruplinalkib for the treatment of locally advanced or metastatic ALK-positive NSCLC patients whose disease has progressed after previous treatment with crizotinib or who are intolerant to crizotinib. On January 16, 2024, the NMPA approved iruplinalkib for the first-line treatment of locally advanced or metastatic ALK-positive NSCLC patients. In order to better understand the efficacy and safety of iruplinalkib, and facilitate more rationally clinical application of iruplinalkib, the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care and the Chinese Association for Clinical Oncologists co-organized experts to compile the "Chinese expert consensus on iruplinalkib for the treatment of locally advanced or metastatic ALK-positive non-small cell lung cancer (2024 edition)".

Abstract 6401: Predictive models for first-line immunotherapy based on spatial tumor immune microenvironment in patients with advanced non-small cell lung cancer (NSCLC)

Abstract Background: Anti-programmed cell death protein 1/programmed cell death ligand 1 (anti-PD1/PDL1) based immunotherapy is the standard first-line treatment for advanced NSCLC patients without targetable driver mutations, but PDL1 immunohistochemistry (IHC) shows limited predictive value as companion diagnostics. Recent studies have elucidated a strong relationship between immunotherapy efficacy and tumor immune microenvironment (TIME) using single-cell multi-omics technology. In this study, we aim to develop predictive models for both objective response rate (ORR) and progression-free survival (PFS) using TIME features with machine learning in advanced NSCLC patients treated with first-line immunotherapy. Methods: A total of 210 patients with advanced NSCLC who received anti-PD-1/PDL-1 therapy at Shanghai Chest Hospital from Jan. 2020 to Jan. 2023 were included in this study. Among them, 110 cases who received pembrolizumab were randomly split into training set and validation set with a 2:1 ratio. The remaining patients were designated as independent validation cohort. Five multiplex immunohistochemistry (mIHC) panels were developed based on literature review and in-house dataset mining. mIHC tests were performed using baseline tumor samples. Immunotherapy efficacy was evaluated by ORR and PFS (RECIST v1.1). ORR and PFS models were developed using machine learning methods in training set with 5-fold cross-validation and further validated in validation set and independent validation cohort. Results: After data cleaning, 68 cases in training set and 34 cases in validation set were further analyzed. In terms of single immune- or spatial- based biomarker, positive rate of PD1+ cells in stroma and spatial relationship of PD1+/PDL1+ cell pairs exhibited the highest correlation with ORR. In addition, positive rate of PDL1+ tumor cells and nearest distance between FOXP3+ cells and tumor cells were highly correlated with PFS. Our ORR model achieved an AUC of 0.82 in the training set and 0.82 in the validation set. When applying optimal cutoff in our PFS model to stratify patients into low- and high- risk groups, low-risk group showed prolonged PFS in both training set (p < 0.0001; HR: 0.25, 95% CI [0.13 - 0.51]) and validation set (p = 0.00046; HR: 0.22, 95% CI [0.09 - 0.55]). Moreover, our ORR model outperformed PDL1 IHC (AUC: 0.81 vs 0.60; DeLong’s test p = 0.005) in these 102 patients. Independent validation of the models is still awaited. Conclusion: Using machine learning methods, we developed and validated ORR and PFS predictive models for first-line immunotherapy in advanced NSCLC patients based on mIHC technology. Our models displayed superior diagnostic performance compared to PDL1 IHC results. Citation Format: Chan Xiang, Jianjian Zheng, Sidong Chen, Zhanxian Shang, Shi Yang, Lianying Guo, Lei Jiao, Yang Wang, Yuchen Han. Predictive models for first-line immunotherapy based on spatial tumor immune microenvironment in patients with advanced non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6401.

Furmonertinib for EGFR-mutant advanced non-small cell lung cancer: a glittering diamond in the rough of EGFR-TKI.

The third-generation EGFR-TKIs, such as osimertinib, aumolertinib, and furmonertinib, have been recommended as the preferred treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC). Among them, furmonertinib shows several advantages in terms of clinical efficacy. Firstly, compared to osimertinib and aumolertinib, furmonertinib was the first EGFR-TKI with median progression-free survival (mPFS) of over 20.0m (20.8m) for advanced NSCLC with classical EGFR-mutations. Furthermore, furmonertinib achieved a mPFS of 18.1m in advanced NSCLC with unfavorable prognostic factors, such as the 21 L858R mutation and central nervous system (CNS) metastasis, which is unrivalled by osimertinib. Secondly, furmonertinib is the only FDA-approved EGFR-TKI for breakthrough therapy in newly-diagnosed advanced NSCLC with EGFR ex20ins mutation. Thirdly, the relatively longer mPFS of 20.8m was observed in furmonertinib compared to osimertinib and aumolertinib (15.2m and 15.3m) in EGFR-mutant advanced NSCLC with CNS metastases. More importantly, the efficacy of furmonertinib increases within the dose range of 80-240mg per day. Finally, furmonertinib can be an optional treatment for advanced NSCLC patients who develop resistance to osimertinib or aumolertinib. In conclusion, furmonertinib may be a glittering star in the field of EGFR-TKI, which requires further exploration and expansion.

Cost-effectiveness of tumor-treating fields plus standard therapy for advanced non-small cell lung cancer progressed after platinum-based therapy in the United States.

Background: Tumor treating fields (TTF) was first approved for treatment of glioblastoma. Recently, the LUNAR study demonstrated that TTF + standard therapy (ST) extended survival in patients with advanced non-small cell lung cancer (NSCLC). This primary objective of this study is to analyze the cost-effectiveness of this treatment from the United States healthcare payers' perspective. Methods: A 3-health-state Markov model was established to compare the cost-effectiveness of TTF + ST and that of ST alone. Clinical data were extracted from the LUNAR study, supplemented by additional cost and utility data obtained from publications or online sources. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analysis were conducted. The willingness-to-pay (WTP) threshold per quality-adjusted life-years (QALYs) gained was set to $150,000. The main results include total costs, QALYs, incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (INMB). Subgroup analyses were conducted for two types of ST, including immune checkpoint inhibitor, and docetaxel. Results: During a 10-year time horizon, the costs of TTF + ST and ST alone were $431,207.0 and $128,125.9, and the QALYs were 1.809 and 1.124, respectively. The ICER of TTF + ST compared to ST was $442,732.7 per QALY, and the INMB was -$200,395.7 at the WTP threshold. The cost of TTF per month was the most influential factor in cost-effectiveness, and TTF + ST had a 0% probability of being cost-effective at the WTP threshold compared with ST alone. Conclusion: TTF + ST is not a cost-effective treatment for advanced NSCLC patients who progressed after platinum-based therapy from the perspective of the United States healthcare payers.

Predictors of Response to Chemotherapy in Patients with Advanced Non-small Cell Lung Cancer: A Prospective Cohort Study

Introduction: Lung cancer carries the highest cancer-related mortality rates worldwide. Despite all recent advances, the mortality from lung cancer is still rising. A better understanding of the risk factors may help us predict responses to chemotherapy for better management. Aim: To evaluate predictors of response to chemotherapy in advanced Non-Small Cell Lung Cancer (NSCLC) patients. Materials and Methods: This was a prospective cohort study conducted in the Department of Pulmonary Medicine at Government Medical College and Hospital, Chandigarh, India. A total of 60 confirmed cases of advanced (stage IIIB and IV) NSCLC patients were enrolled consecutively for a duration of two years. Baseline clinical parameters, routine blood tests, spirometry, exercise capacity using the 6 Minute Walk Test Distance (6MWTD), and Computed Tomography (CT)-based tumour size were recorded. Certain pre-defined patient, disease, and therapy-related factors (age, gender, dyspnoea, baseline blood tests, tumour size, histology, etc.) were evaluated for their possible role as predictors of treatment response in advanced NSCLC patients. A positive response was defined if the response to chemotherapy was Complete Response (CR) or Partial Response (PR), and a negative response if the response was Progressive Disease (PD) or Stable Disease (SD) as per revised RECIST (Response evaluation criteria in solid tumors) 1.1 criteria. Variables between the two groups were compared using the Mann-Whitney U test and Chi-square test. To find out the factors that may predict response to treatment, univariate and multivariate logistic regression analysis were used. Results: Out of a total of 60 confirmed cases of NSCLC patients, only 40 patients were able to complete the four cycles of chemotherapy. The mean age of the patients was 58.5±9.6 years. There were a total of 35 males (87.5%) and five females (12.5%) in the study. Out of 40 patients, 27 (67.5%) had squamous cell carcinoma and 13 (32.5%) had adenocarcinoma. On univariate analysis, Neutrophil-Lymphocyte Ratio (NLR) had a statistically significant association with tumour response (p<0.001). On multivariate analysis, advanced age (p=0.05) and high (>3.81) NLR (p=0.002) were found as independent predictors of poor response to chemotherapy. Conclusion: Pre-treatment high NLR and advanced age are significant factors for a poor response to chemotherapy treatment in advanced NSCLC patients.

Characteristics, management, and healthcare resources of patients with advanced non–small-cell lung cancer surviving 5 years after nivolumab treatment initiation: A national database analysis

BackgroundData on long-term survivors with advanced non-small-cell lung cancer (NSCLC) treated with nivolumab are available from randomized trials. Characteristics, management, and healthcare resources of those patients need to be confirmed with real-world data. MethodsThe UNIVOC retrospective observational study included all patients with advanced NSCLC recorded in the French national hospital database starting nivolumab in 2015 and followed them until December 2020. The Kaplan-Meier method estimated the overall survival (OS). A machine learning approach identified patients with similar treatment sequences. ResultsWithin the 3,050 patients who had nivolumab initiation,5-year OS rate was 14.6 % (95 %CI 13.3 %–16.2 %). In total, data covering at least 5 years of follow-up were retrieved for 231 surviving patients. Survivors were younger, often female and had fewer comorbidities than non-survivors. Three clusters of patients with different nivolumab treatment durations were identified: 1/ Continuous nivolumab treatment; 2/ Long period of nivolumab treatment followed by chemotherapy or no treatment; 3/ Short period of nivolumab treatment then chemotherapy or no treatment. At 5 years, 61.0 % of survivors were no longer receiving systemic therapy, 26.4 % were treated with nivolumab, 8.7 % chemotherapy, and 3.9 % other immunotherapies. Among 5-y survivor patients, the average number of hospitalisations per patient decreased from 23.4 to 12.8 between the 1st and the 5th year. In the 5th year, 46 % of patients had no more hospitalization for lung cancer. ConclusionsThis large nationwide study confirms the long-term benefit of nivolumab treatment for advanced NSCLC patients in the real-world setting, with a 5-year survival rate similar to that reported in clinical trials.

Efficacy and safety of nintedanib in patients with non-small cell lung cancer, and novel insights in radiation-induced lung toxicity.

Nintedanib is a tyrosine kinase inhibitor of fibroblast growth factor-, vascular endothelial growth factor-, and platelet-derived growth factor receptors. These three receptors promote new blood vessel formation and maintenance, which is essential for tumor growth and spread. Several trials have shown that nintedanib plays a substantial role in treating patients with non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis. Recently, several clinical trials of nintedanib to treat NSCLC have been reported. In this review, we focus on our current understanding of nintedanib treatment for advanced NSCLC patients and summarize the literature on using nintedanib in radiation-induced lung toxicity and the efficacy and tolerability of nintedanib.

AK112, a novel PD-1/VEGF bispecific antibody, in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC): an open-label, multicenter, phase II trial

Inhibiting vascular endothelial growth factor (VEGF) function can improve the efficacy of immunotherapy by modulating the tumor immune microenvironment. AK112 is the first-in-class humanized IgG1 bispecific antibody targeting programmed death-1 (PD-1) and VEGF. This study aimed to evaluate the efficacy and safety of AK112 combined with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). This open-label, multicenter, phase II clinical trial was conducted in 11 hospitals in China. Eligible participants were adults aged 18-75 years with locally advanced or metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, at least one measurable lesion, and an estimated life expectancy of at least 3 months. The participants were categorized into three cohorts based on prior therapy and functional genomic alterations. Patients in cohort 1 were previously untreated advanced NSCLC, had no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene modifications, and received AK112 combined with pemetrexed (500mg/m2) for non-squamous (non-sq)-NSCLC or paclitaxel (175mg/m2) for sq-NSCLC plus carboplatin (area under the curve of 5mg/mL per min) for four cycles, followed by AK112 with pemetrexed for non-sq-NSCLC and AK112 alone for sq-NSCLC as maintenance therapy. The participants in cohort 2 had advanced NSCLC with EGFR-sensitive mutations, failed previous EGFR-tyrosine kinase inhibitor (TKI) therapy, and received pemetrexed plus AK112 and carboplatin for four cycles, followed by pemetrexed plus AK112 as maintenance therapy. The participants in cohort 3 had advanced NSCLC who failed systemic platinum-based chemotherapy and anti-PD-1/programmed death-ligand 1 (PD-L1) treatments and received AK112 plus docetaxel (75mg/m2). Two dosages of AK112 (10 or 20mg/kg) were examined in each cohort, and the drug was administered intravenously on day 1 of each 3-week treatment cycle. The primary endpoints were the investigator-assessed objective response rate (ORR) and safety. This study was registered with ClinicalTrials.gov (NCT04736823). Eighty-three patients were enrolled from February 2021 to August 2022 and received the study treatment. Cohorts 1, 2, and 3 had 44, 19, and 20 patients, respectively. The confirmed ORR was 53.5% (23/43) [95% CI, 36.9-67.1], 68.4% (13/19) [95% CI, 43.4-87.4], and 40.0% (8/20) [95% CI, 19.1-63.9] in cohorts 1, 2, and 3, respectively. In cohort 1, the median PFS was not reached, and the 12-month PFS rate was 59.1%. In cohorts 2 and 3, the median PFS were 8.5 [95% CI, 5.5-NE] and 7.5 [95% CI, 2.3-NE] months, and the 12-month PFS rates were 35.5% and 44.5%, respectively. The most common grade ≥3 treatment-related adverse events were decreased white blood cell count [7 (8.4%)], neutropenia [5 (6.0%)], thrombocytopenia [2 (2.4%)], anemia [4 (4.8%)], and myelosuppression [2 (2.4%)]. AK112 plus platinum-doublet showed promising antitumor activity and safety not only in first-line treatment of advanced NSCLC patients without driver mutation but also in patients with EGFR-functional mutation who failed previous EGFR-TKI therapy and advanced NSCLC patients who failed prior systemic platinum-based chemotherapy and PD-1/PD-L1 inhibitor treatments, suggesting a valuable potential new treatment option for this patient population. Akeso Biopharma, Inc., Zhongshan, China, and National Natural Science Foundation of China.

HTA4 Pembrolizumab Vs. Standard of Care Chemotherapy As First-Line Treatment for Advanced Non-Small Cell Lung Cancer with High Pd-L1 Expression Levels: A Cost-Utility Analysis from the Ontario, Canada Public Payer Perspective

Initial 1-year results from the pivotal KEYNOTE-024 (KN024) trial showed improved efficacy of pembrolizumab over chemotherapy in advanced non-small cell lung cancer (NSCLC). 5-year results from KN024 are now available. The cost-utility of pembrolizumab can be re-analysed, addressing the uncertainty regarding long-term outcomes highlighted in the previous 2017 pan-Canadian Oncology Drug Review assessment. The objective of this study was to assess the cost-utility of pembrolizumab monotherapy vs chemotherapy as first-line treatment in advanced NSCLC patients, with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥50% from the Ontario, Canada public payer perspective.

Molecular characterization of resistance to immune checkpoint inhibitor and chemotherapy treatment in advanced non-small cell lung cancer.

9034 Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and a leading cause of cancer death. Standard of care (SOC) treatment for advanced NSCLC patients include immune checkpoint inhibitors (ICI) and/or chemotherapy (CT). However, the majority of patients do not respond to SOC therapy. Mechanisms of resistance and how they differ across treatments are not fully understood. We characterized molecular markers of resistance for advanced NSCLC patients with ICI monotherapy, CT, or combination ICI-CT. Methods: Advanced stage III or IV NSCLC patients with adenocarcinoma histology who received at least 21 days of ICI monotherapy, CT, or combination ICI-CT were identified from a de-identified, multimodal real-world database from Tempus Labs, Inc. All patients had a tissue biopsy taken within 100 days prior to the specified therapy start and all samples underwent next generation sequencing with the Tempus xT assays (DNA-seq of 596-648 genes at 500x coverage and whole transcriptome RNA-seq). Resistance to therapy was defined as having time to next treatment < 90 days, or disease progression or death within 120 days of therapy initiation. We characterized the clinical and molecular characteristics of patients and compared differential expression of genes by resistance status for each cohort. Results: A total of 365 patients were included in the study (ICI = 121, CT = 122, ICI-CT = 122). Across cohorts, 30% of patients were identified as having resistance to treatment (ICI = 35%, CT = 23%, ICI-CT = 32%). 53% of patients were > 65 years (median [range] = 67 [25- 88]), and 53% were males. Most patients were white (63%) and had a history of tobacco use (85% current or former smoker). At the time of biopsy, most patients were diagnosed with metastatic NSCLC (Stage IV = 73%) and had received no previous lines of therapy (92%). The alteration frequencies of known NSCLC oncogenic driver mutations including TP53 (65%), KRAS (42%), STK11 (14%), KEAP1 (11%), and EGFR (9%) were broadly consistent with previous characterizations of NSCLC. Validated biomarkers of response to ICI treatment such as Tumor Mutation Burden, IFN-γ signaling, PD-1, and PD-L1 expression were negatively associated with resistance to ICI treatment. Across the ICI, ICI-CT, and CT cohorts, 253, 153, and 178 genes, respectively, were significantly upregulated (FDR < 0.05, LogFC > 1) in patients with resistance to treatment. Of the 550 distinct genes correlated to resistance across treatments, 95% were unique to each cohort, and only 32 genes (5%) were shared across more than one treatment cohort. Conclusions: Distinct molecular characteristics were associated with resistance to ICI and/or CT treatment. This suggests that mechanisms of resistance to ICI monotherapy, ICI-CT, or CT could be separate and unique. Further research can provide valuable insights for novel therapies or combinations.

Predictive Value of Total Metabolic Tumor Burden Prior to Treatment in NSCLC Patients Treated with Immune Checkpoint Inhibition.

We aimed to assess the predictive value of the total metabolic tumor burden prior to treatment in patients with advanced non-small-cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs). Pre-treatment 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (PET/CT) scans performed in two consecutive years for staging in adult patients with confirmed NSCLC were considered. Volume, maximum/mean standardized uptake value (SUVmax/SUVmean), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were assessed per delineated malignant lesion (including primary tumor, regional lymph nodes and distant metastases) in addition to the morphology of the primary tumor and clinical data. Total metabolic tumor burden was captured by totalMTV and totalTLG. Overall survival (OS), progression-free survival (PFS) and clinical benefit (CB) were used as endpoints for response to treatment. A total of 125 NSCLC patients were included. Osseous metastases were the most frequent distant metastases (n = 17), followed by thoracal distant metastases (pulmonal = 14 and pleural = 13). Total metabolic tumor burden prior to treatment was significantly higher in patients treated with ICIs (mean totalMTV ± standard deviation (SD) 72.2 ± 78.7; mean totalTLG ± SD 462.2 ± 538.9) compared to those without ICI treatment (mean totalMTV ± SD 58.1 ± 233.8; mean totalTLG ± SD 290.0 ± 784.2). Among the patients who received ICIs, a solid morphology of the primary tumor on imaging prior to treatment was the strongest outcome predictor for OS (Hazard ratio HR 28.04, p < 0.01), PFS (HR 30.89, p < 0.01) and CB (parameter estimation PE 3.46, p < 0.01), followed by the metabolic features of the primary tumor. Interestingly, total metabolic tumor burden prior to immunotherapy showed a negligible impact on OS (p = 0.04) and PFS (p = 0.01) after treatment given the hazard ratios of 1.00, but also on CB (p = 0.01) given the PE < 0.01. Overall, biomarkers on pre-treatment PET/CT scans showed greater predictive power in patients receiving ICIs, compared to patients without ICI treatment. Morphological and metabolic properties of the primary tumors prior to treatment in advanced NSCLC patients treated with ICI showed great outcome prediction performances, as opposed to the pre-treatment total metabolic tumor burdens, captured by totalMTV and totalTLG, both with negligible impact on OS, PFS and CB. However, the outcome prediction performance of the total metabolic tumor burden might be influenced by the value itself (e.g., poorer prediction performance at very high or very low values of total metabolic tumor burden). Further studies including subgroup analysis with regards to different values of total metabolic tumor burden and their respective outcome prediction performances might be needed.

Efficacy of ICI-based treatment in advanced NSCLC patients with PD-L1≥50% who developed EGFR-TKI resistance.

Platinum-based chemotherapy is still the standard of care for Epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) patients after developing EGFR-TKI resistance. However, no study focusing on the role of immuno checkpoint inhibitor (ICI) based treatments for EGFR mutated NSCLC patients who carried programmed death ligand 1 (PD-L1) tumor proportion score (TPS) greater than 50% progressed after EGFR-TKI therapy. In this study, we retrospectively investigated the outcomes of ICI-based treatments for EGFR mutated NSCLC patients carried PD-L1 TPS≥50% after developing EGFR-TKI resistance and to explore the population that may benefited from ICI-based treatment. We retrospectively collected data of advanced NSCLC patients with EGFR mutations and PD-L1 TPS≥50% who have failed prior EGFR-TKI therapies without T790M mutation at Shanghai Chest Hospital between January 2018 and June 2021. Progression-free survival (PFS) and overall survival (OS) were utilized to evaluate the outcomes of this study. A total of 146 patients were included. Up to June 20th, 2022, median follow-up was 36.7 months (IQR, 12.5-44.2 months). Among the population, 66 patients (45.2%) received chemotherapy, the remaning (54.8%) received ICI-based treatment, including 56 patients(70.0%) received ICI combined with chemotherapy (IC) and 24 patients (30.0%) received ICI monotherapy (IM). In IC group,31 patients received ICI combined with chemotherapy,19 patients received ICI combined with antiangiogenic therapy and remaing received ICI combined with chemotherapy and antiangiogenic therapy. Survival analysis shown that patients who received ICI-based treatment had better progress-free survival (PFS) and overall survival (OS) compared with those treated with other therapy (median PFS, 10.0 vs. 4.0 months, P<0.001; median OS, 39.5 vs. 24.2 months, P<0.001). What's more, patients who treated with IC treatment had a superior survival time than those received IM treatment (median PFS, 10.3 vs. 7.0 months, P<0.001; median OS, 41.6 vs. 32.4 months, P<0.001). Subgroup analysis found that the PFS and OS benefit of IC was evident in all subgroups. For advanced NSCLC patients with EGFR mutations and PD-L1 TPS≥50% who have failed prior EGFR-TKI therapies without T790M mutation, ICI-based treatment could provide a more favorable survival than classical chemotherapy. What' s more, compared with ICI monotherapy, ICI combined with chemotherapy seems to be the preferred treatment.

Efficacy and safety analyses of epidermal growth factor receptor tyrosine kinase inhibitors combined with chemotherapy in the treatment of advanced non–small-cell lung cancer with an EGFR/TP53 co-mutation

PurposeEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) combined with cytotoxic chemotherapy are highly effective in the treatment of advanced non–small-cell lung cancer (NSCLC) with EGFR mutations. The purpose of this study is to evaluate the efficacy and safety of this combination in advanced NSCLC patients with an EGFR/TP53 co-mutation.MethodsNinety-five advanced NSCLC patients with an EGFR/TP53 co-mutation were enrolled in this study. Treatments with either EGFR-TKI monotherapy (T group, n = 61) or EGFR-TKI combined with chemotherapy (TC group, n = 34) were evaluated in relation to objective response rate (ORR), disease control rate (DCR), median time to progression (TTP), and median overall survival (OS).ResultsThere were no statistically significant differences in DCR between the treatment groups. The ORR was significantly improved in the TC group versus the T group (55.9% vs. 34.4%, P = 0.042). A higher median TTP was noted in TC group compared with T group (16.1 vs. 11.1 months, P = 0.002). Patients without brain metastases in TC group had a longer median OS than in T group (48.4 vs. 28.8 months, P = 0.003). However, there was a non-significant trend towards longer OS in TC group in the entire cohort (36.9 vs. 28.2 months, P = 0.078). Cox multivariate regression analysis showed that clinical stage, brain metastases, EGFR21 L858R mutation, and T790M status at first progression were independent risk factors for OS. However, the incidence of grade 3 or higher adverse events were higher in the TC group than in the T group (32.4% vs. 13.1%, P = 0.025).ConclusionOur study indicates that EGFR-TKIs combined with chemotherapy could significantly improve the ORR and TTP of advanced NSCLC patients with an EGFR/TP53 co-mutation. Combination therapy may be a promising treatment for advanced NSCLC patients with an EGFR/TP53 co-mutation without brain metastases.

Predictors of survival to immunotherapy and chemoimmunotherapy in non-small cell lung cancer: A meta-analysis.

Many patients with non-small cell lung cancer (NSCLC) derive poor benefit from immunotherapy (IO). For some of them, adding chemotherapy (CT) can improve the outcomes, but the reliability of programmed death-ligand 1 (PD-L1) expression as the only biomarker to distinguish these patients is unsatisfactory. We sought to detect clinicopathological and molecular predictive factors of survival that might be added to PD-L1 expression in the selection of patients who should receive IO alone or chemoimmunotherapy (CIT). We conducted a systematic search of randomized controlled clinical trials investigating IO, alone or with CT, vs CT alone in treatment-naïve advanced NSCLC patients. Meta-analyses and meta-regression analyses were performed to investigate IO alone vs CT, CIT vs CT, and IO alone vs CIT. A total of 14 367 patients with advanced NSCLC across 25 randomized controlled clinical trials were included. Squamous histology, male sex, current and former smoker status, PD-L1 expression of 50% or more, and high tumor mutational burden (TMB) correlated with improved survival with IO alone compared with CT. Conversely, female sex, no smoking history, negative PD-L1 expression, and low TMB correlated with unsatisfactory outcomes with IO alone vs CT but not with CIT vs CT. CIT improved survival vs IO alone in female patients, never smokers, those having a PD-L1 expression of 1% or more (but not with a PD-L1 of ≥ 50%) or a low TMB and in patients with central nervous system metastasis. These findings suggest some clinicopathological and molecular features that, added to PD-L1 expression, could help in the selection of the most appropriate first-line IO-based treatment for advanced NSCLC patients.

The efficacy and tolerability of combining pemetrexed-based chemotherapy with gefitinib in the first-line treatment of non-small cell lung cancer with mutated EGFR: A pooled analysis of randomized clinical trials.

BackgroundEpidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) monotherapy is the standard of care in treating advanced non-small cell lung cancer (NSCLC). Nevertheless, whether adding pemetrexed-based chemotherapy to EGFR-TKI targeted therapy furtherly prolongs survival outcomes and improves responses remains controversial. Therefore, we conducted this pooled analysis to compare the efficacy and tolerability between gefitinib plus pemetrexed-based chemotherapy and gefitinib alone in the first-line treatment of advanced NSCLC patients with mutated EGFR.MethodsWe systematically searched PubMed, Web of Science, Embase, and Cochrane CENTRAL on June 23, 2022. Eligible studies were registered randomized clinical trials comparing gefitinib plus pemetrexed-based chemotherapy with gefitinib alone. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Objective response rate (ORR), disease control rate (DCR), and discontinuation rate (DR) were explored as secondary outcomes.ResultsEight studies within five randomized clinical trials were eligible. Gefitinib combined with pemetrexed-based chemotherapy significantly prolonged OS (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.37–0.89, p = 0.0125) and PFS (HR 0.52, 95% CI 0.39–0.70, p < 0.0001) versus gefitinib alone. In subgroup analysis, patients with EGFR exon 19 deletion and exon 21 L858R could benefit from the addition of pemetrexed-based chemotherapy to gefitinib in terms of PFS (EGFR exon 19 deletion: HR 0.50, 95% CI 0.34–0.75, p = 0.0008; EGFR exon 21 L858R: HR 0.46, 95% CI 0.26–0.82, p = 0.0079) but not OS. In addition, ORR was improved after the administration of gefitinib plus pemetrexed-based chemotherapy against gefitinib (odds ratio [OR] 1.91, 95% CI 1.44–2.55, p < 0.0001). Both strategies showed comparable DCRs (OR 1.46, 95% CI 0.94–2.26, p = 0.0952) and DRs (risk ratio [RR] 2.80, 95% CI 0.69–11.44, p = 0.1509).ConclusionCompared with gefitinib alone, combining pemetrexed-based chemotherapy with gefitinib significantly improved OS and PFS in advanced EGFR-mutant NSCLC patients with acceptable tolerability. However, the accurate sub-population who could have OS benefits requires further validation.

Efficacy, safety, and prognostic factors of anlotinib treatment in advanced non-small cell lung cancer patients.

This study aimed to evaluate the treatment response, survival profiles, prognostic factors and adverse events of anlotinib in treating advanced non-small cell lung cancer (NSCLC) patients. Totally, 158 advanced NSCLC patients were included in this retrospective study. All patients received anlotinib treatment until disease progression or intolerance: Administrated orally 12 mg/d for 2 weeks then discontinued for 1 week (3 weeks as a treatment cycle). Furthermore, treatment response, adverse events, and survivals were evaluated. After 2 treatment cycles, no (0%) patients achieved complete response (CR), 7 (5.0%) patients achieved partial response (PR), 112 (80.0%) patients achieved standard deviation (SD), and 21 (15.0%) patients achieved progressive disease (PD), resulting in objective response rate (ORR) of 5.0% and disease control rate (DCR) of 85.0%. After 4 treatment cycles, no (0%) patients achieved CR, 3 (4.3%) patients achieved PR, 51 (74.0%) patients achieved SD, and 15 (21.7%) patients achieved PD, resulting in ORR of 4.3% and DCR of 78.3%. For survivals, the median progression-free (PFS) was 3.7 months (95% confidence interval [CI]: 2.7-4.7 months), and the median overall survival (OS) was 12.4 months (95% CI: 9.4-15.3 months). Subsequently, multivariate Cox's regression analyses illuminate that histological type (adenosquamous carcinoma vs. adenocarcinoma) and other mutation apart from epidermal growth factor receptor independently predicted shorter PFS; meanwhile, history of smoke and brain metastases independently predicted decreased OS. Regarding safety, most of the adverse events were at mild grade. Anlotinib displays good efficacy and well-tolerant safety profiles in the treatment of advanced NSCLC patients.

1070P Previous viral infections assessed by pan-virus phage immunoprecipitation sequencing (PhIP-Seq) predict response to immune checkpoint blockers (ICBs) in non-small cell lung cancer (NSCLC)

ICBs revolutionized the treatment of advanced NSCLC patients but only a fraction of them obtain a response and clinical benefit from ICBs is often difficult to predict. Viral infections, whether acute, chronic or latent, have an impact on the immune system but their effect on ICBs efficacy is unknown. The aim of our study is to unveil the potential implications of antibody response to previous viral infections in predicting the response to ICBs in NSCLC patients.

Abstract LB538: Characterization of GB263T, a tri-specific antibody against EGFR/cMET/cMET for NSCLC

Abstract Background: The EGFR tyrosine kinase inhibitors (TKIs) have been effectively used for non-small cell lung cancer (NSCLC) driven by EGFR mutations. However, patients eventually develop drug resistance via various mechanisms such as secondary EGFR mutations and activation of alternative pathways. The cMET amplification is one of the resistant mechanisms. Amivantamab, a bispecific antibody to EGFR/c-Met has shown that concurrent inhibition of EGFR and c-Met can overcome resistance of EGFR-TKIs and improve patient outcomes. Thus, amivantamab has been approved for the treatment of advanced NSCLC patients with EGFR exon20ins mutations in the US. GB263T is a novel EGFR/cMET/cMET tri-specific antibody with enhanced ADCC function. The current study has demonstrated GB263T exhibited robust anti-tumor activity by in vitro and in vivo studies. Methods: GB263T has been extensively characterized. The binding/blocking activities were analyzed by SPR and ELISA. The protein levels and phosphorylation of EGFR/cMET were detected by Western Blot. Internalization ability was evaluated by confocal microscope. ADCC function was tested by Jurkat-CD16A-NFAT-Luc reporter system. Various CDX and PDX models were used to evaluate the in vivo efficacy in tumor inhibition. Results: GB263T showed high affinity binding to EGFR and cMET, with robust blocking activity. Moreover, GB263T induced receptor internalization and EGFR/cMET phosphorylation in NSCLC cell lines. GB263T dose-dependently inhibited the proliferation of cells containing EGFR exon 20 insertion mutations and C797S mutations. In addition, potent ADCC function against NSCLC cell lines was observed. Significant in vivo anti-tumor efficacy was demonstrated by multiple tumor models of EGFR exon 20 insertion, EGFR C797S mutation, cMET amplification, and cMET exon 14 skipping mutation. Conclusions: GB263T is a novel tri-specific antibody that exhibited robust anti-tumor activity. The preclinical data indicate that GB263T has great potential to become an effective therapeutics in the treatment of NSCLC. Citation Format: Qinglin Du, Wengang Zeng, Xueyan Yang, Liwen Liang, Xueqin Li, Yan Li, Yiqi Cao, Zongjun Xia, Jing Zhang, Qian Ding, Shuhua Han. Characterization of GB263T, a tri-specific antibody against EGFR/cMET/cMET for NSCLC [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 LB538.