PD-L1 recruits phospholipase C and enhances tumorigenicity of lung tumors harboring mutant forms of EGFR.
Ghosh Soma,Nataraj Nishanth Belugali,Noronha Ashish,Patkar Sushant,Sekar Arunachalam,Mukherjee Saptaparna,Winograd-Katz Sabina,Kramarski Lior,Verma Aakanksha,Lindzen Moshit,Garcia Diana Drago,Green Joseph,Eisenberg Galit,Gil-Henn Hava,Basu Arkaprabha,Lender Yan,Weiss Shimon,Oren Moshe,Lotem Michal,Geiger Benjamin,Ruppin Eytan,Yarden Yosef
Cell reports
Cancer immunotherapy focuses on inhibitors of checkpoint proteins, such as programmed death ligand 1 (PD-L1). Unlike RAS-mutated lung cancers, EGFR mutant tumors have a generally low response to immunotherapy. Because treatment outcomes vary by EGFR allele, intrinsic and microenvironmental factors may be involved. Among all non-immunological signaling pathways surveyed in patients' datasets, EGFR signaling is best associated with high PD-L1. Correspondingly, active EGFRs stabilize PD-L1 transcripts and depletion of PD-L1 severely inhibits EGFR-driven tumorigenicity and metastasis in mice. The underlying mechanisms involve the recruitment of phospholipase C-γ1 (PLC-γ1) to a cytoplasmic motif of PD-L1, which enhances PLC-γ1 activation by EGFR. Once stimulated, PLC-γ1 activates calcium flux, Rho GTPases, and protein kinase C, collectively promoting an aggressive phenotype. Anti-PD-L1 antibodies can inhibit these intrinsic functions of PD-L1. Our results portray PD-L1 as a molecular amplifier of EGFR signaling and improve the understanding of the resistance of EGFR tumors to immunotherapy.
10.1016/j.celrep.2021.109181
Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer.
Nature genetics
Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts.
10.1038/s41588-023-01355-5
Efficacy of ICI-based treatment in advanced NSCLC patients with PD-L1≥50% who developed EGFR-TKI resistance.
Frontiers in immunology
Introduction: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. Methods: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. Results: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. Conclusions: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.
10.3389/fimmu.2023.1161718
Association with PD-L1 Expression and Clinicopathological Features in 1000 Lung Cancers: A Large Single-Institution Study of Surgically Resected Lung Cancers with a High Prevalence of EGFR Mutation.
Lee Seung Eun,Kim Yu Jin,Sung Minjung,Lee Mi-Sook,Han Joungho,Kim Hong Kwan,Choi Yoon-La
International journal of molecular sciences
Programmed cell death ligand 1 (PD-L1) expression is an important biomarker for predicting response to immunotherapy in clinical practice. Hence, identification and characterization of factors that predict high expression of PD-L1 in patients is critical. Various studies have reported the association of PD-L1 expression with driver genetic status in non-small cell cancer; however, the results have been conflicting and inconclusive. We analyzed the relationship between PD-L1 expression and clinicopathological factors including driver genetic alterations in 1000 resected lung cancers using a clinically validated PD-L1 immunohistochemical assay. PD-L1 expression was significantly higher in squamous cell carcinoma (SCC) compared to adenocarcinomas. PD-L1 expression in adenocarcinoma was associated with higher N-stage, solid histologic pattern, wild type, and positive, but no significant association with the clinicopathological factors in SCC. mutant adenocarcinomas with distinctive clinicopathologic features, especially solid histologic pattern and higher stage showed higher PD-L1 expression. To the best of our knowledge, this study is the largest to evaluate the association between PD-L1 expression and clinicopathological and molecular features in lung cancer with a highly prevalent mutation. Therefore, our results are useful to guide the selection of lung cancer, even -mutated adenocarcinoma patients with PD-L1 expression, for further immunotherapy.
10.3390/ijms20194794
Pembrolizumab in Combination With Erlotinib or Gefitinib as First-Line Therapy for Advanced NSCLC With Sensitizing EGFR Mutation.
Yang James Chih-Hsin,Gadgeel Shirish M,Sequist Lecia VanDam,Wu Chien-Liang,Papadimitrakopoulou Vassiliki A,Su Wu-Chou,Fiore Joseph,Saraf Sanatan,Raftopoulos Harry,Patnaik Amita
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
INTRODUCTION:Anti-EGFR agents are standard treatments for patients with EGFR-mutant advanced NSCLC. The feasibility of combining erlotinib or gefitinib with the anti-programmed death 1 immunotherapy pembrolizumab was evaluated in the phase 1/2 KEYNOTE-021 study (NCT02039674). METHODS:Adults with previously untreated stage IIIB/IV EGFR-mutant NSCLC were treated with pembrolizumab 2 mg/kg intravenously every 3 weeks plus oral erlotinib 150 mg daily in cohort E or oral gefitinib 250 mg daily in cohort F, using a 3 + 3 design with cohort expansion. rTumor response was evaluated per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review. The primary objective was determination of a recommended phase 2 dose. RESULTS:Twelve patients enrolled to receive pembrolizumab plus erlotinib and seven to receive pembrolizumab plus gefitinib. No dose-limiting toxicities or grade 5 events occurred. Pembrolizumab plus erlotinib was feasible, with adverse events similar to those expected for monotherapy. However, pembrolizumab plus gefitinib was not feasible due to grade 3/4 liver toxicity in five of seven patients (71.4%), leading to permanent treatment discontinuation in four patients. The most frequently occurring treatment-related adverse events with pembrolizumab plus erlotinib were rash (50.0%), dermatitis acneiform, diarrhea, hypothyroidism, and pruritus (33.3% each). The objective response rate was 41.7%, including response in all four patients with programmed death ligand 1 expression 50% or greater. CONCLUSIONS:Although pembrolizumab plus gefitinib was not feasible, the toxicity profile observed with pembrolizumab plus erlotinib suggests combining immunotherapy with anti-EGFR therapy is feasible. Pembrolizumab plus erlotinib did not improve objective response rate compared with previous monotherapy studies; further evaluation would be necessary to evaluate potential effects on other efficacy outcomes.
10.1016/j.jtho.2018.11.028
Deciphering the immunosuppressive tumor microenvironment in ALK- and EGFR-positive lung adenocarcinoma.
Cancer immunology, immunotherapy : CII
INTRODUCTION:The advent of immune checkpoint blockade (ICB) has led to significantly improved disease outcome in lung adenocarcinoma (ADC), but response of ALK/EGFR-positive tumors to immune therapy is limited. The underlying immune biology is incompletely understood. METHODS:We performed comparative mRNA expression profiling of 31 ALK-positive, 40 EGFR-positive and 43 ALK/EGFR-negative lung ADC focused on immune gene expression. The presence and levels of tumor infiltration lymphocytes (TILs) as well as fourteen specific immune cell populations were estimated from the gene expression profiles. RESULTS:While total TILs were not lower in ALK-positive and EGFR-positive tumors compared to ALK/EGFR-negative tumors, specific immunosuppressive characteristics were detected in both subgroups: In ALK-positive tumors, regulatory T cells were significantly higher compared to EGFR-positive (fold change: FC = 1.9, p = 0.0013) and ALK/EGFR-negative tumors (FC = 2.1, p = 0.00047). In EGFR-positive tumors, cytotoxic cells were significantly lower compared to ALK-positive (FC = - 1.7, p = 0.016) and to ALK/EGFR-negative tumors (FC = - 2.1, p = 2.0E-05). A total number of 289 genes, 40 part of cytokine-cytokine receptor signaling, were differentially expressed between the three subgroups. Among the latter, five genes were differently expressed in both ALK-positive and EGFR-positive tumors, while twelve genes showed differential expression solely in ALK-positive tumors and eleven genes solely in EGFR-positive tumors. CONCLUSION:Targeted gene expression profiling is a promising tool to read out tumor microenvironment characteristics from routine diagnostic lung cancer biopsies. Significant immune reactivity including specific immunosuppressive characteristics in ALK- and EGFR-positive lung ADC, but not a total absence of immune infiltration supports further clinical evaluation of immune-modulators as partners of ICB in such tumors.
10.1007/s00262-021-02981-w
Immunogenicity of Del19 EGFR mutations in Chinese patients affected by lung adenocarcinoma.
Pan Deng,Zhou Dapeng,Cai Weijing,Wu Weibo,Tan Wen Ling,Zhou Caicun,Lou Yanyan
BMC immunology
BACKGROUND:Mutant peptides presented by cancer cells are superior vaccine candidates than self peptides. The efficacy of mutant K-Ras, P53 and EGFR (Epidermal Growth Factor Receptor) peptides have been tested as cancer vaccines in pancreatic, colorectal, and lung cancers. The immunogenicity of EGFR Del19 mutations, frequent in Chinese lung adenocarcinoma patients, remains unclear. RESULTS:We predicted the HLA binding epitopes of Del19 mutations of EGFR in Chinese lung adenocarcinoma patients with NetMHC software. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the EGFR-reactive IgG in lung cancer patients. Del19 mutations may be presented by multiple HLA Class I molecules, with delE746_A750 presented by 37.5% of Chinese population. For HLA Class II molecules, Del19 mutations of EGFR may be presented by multiple HLA-DRB1 molecules, with delE746_A750 presented by 58.1% of Chinese population. Serum reactivity to wild type EGFR protein was significantly higher in patients with Del19 EGFR mutations than those with EGFR L858R point mutation or with EGFR wild type genotype. CONCLUSIONS:These findings suggest that Del19 mutations of EGFR, with an estimated frequency of 40% in Chinese lung adenocarcinoma patients, may serve as unique targets for immunotherapy in Chinese lung cancer patients.
10.1186/s12865-019-0320-1
A phase I/IB trial of binimetinib in combination with erlotinib in NSCLC harboring activating KRAS or EGFR mutations.
Lung cancer (Amsterdam, Netherlands)
BACKGROUND:Activating mutations in EGFR or KRAS are highly prevalent in NSCLC, share activation of the MAPK pathway and may be amenable to combination therapy to prevent negative feedback activation. METHODS:In this phase 1/1B trial, we tested the combination of binimetinib and erlotinib in patients with advanced NSCLC with at least 1 prior line of treatment (unless with activating EGFR mutation which could be treatment-naïve). A subsequent phase 1B expansion accrued patients with either EGFR- or KRAS-mutation using the recommended phase 2 dose (RP2D) from Phase 1. The primary objective was to evaluate the safety of binimetinib plus erlotinib and establish the RP2D. RESULTS:43 patients enrolled (dose-escalation = 23; expansion = 20). 17 harbored EGFR mutation and 22 had KRAS mutation. The RP2D was erlotinib 100 mg daily and binimetinib 15 mg BID × 5 days/week. Common AEs across all doses included diarrhea (69.8%), rash (44.2%), fatigue (32.6%), and nausea (32.6%), and were primarily grade 1/2. Among KRAS mutant patients, 1 (5%) had confirmed partial response and 8 (36%) achieved stable disease as best overall response. Among EGFR mutant patients, 9 were TKI-naïve with 8 (89%) having partial response, and 8 were TKI-pretreated with no partial responses and 1 (13%) stable disease as best overall response. CONCLUSIONS:Binimetinib plus erlotinib demonstrated a manageable safety profile and modest efficacy including one confirmed objective response in a KRAS mutant patient. While clinical utility of this specific combination was limited, these results support development of combinations using novel small molecule inhibitors of RAS, selective EGFR- and other MAPK pathway inhibitors, many of which have improved therapeutic indices. CLINICAL TRIAL REGISTRATION:NCT01859026.
10.1016/j.lungcan.2023.107313
[Research Progress in Immune Checkpoint Inhibitors Combination Therapy Applied to
Non-small Cell Lung Cancer after EGFR Mutation-targeted Therapy Resistance].
Zhongguo fei ai za zhi = Chinese journal of lung cancer
With the development of precision medicine for lung cancer, targeted therapy has greatly improved the survival and prognosis of patients with advanced non-small cell lung cancer (NSCLC), but the occurrence of acquired drug resistance ultimately leads to patients with no targeted drugs available and no standard treatment options for this group of patients afterwards. The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced NSCLC. However, due to the unique features of NSCLC with epidermal growth factor receptor (EGFR) mutation, such as immunosuppressive tumor microenvironment (TME), single ICIs treatment has limited clinical benefits in NSCLC patients with EGFR mutation, and the combination of ICIs with chemotherapy and/or targeted therapies is the trend. This review further discusses potential subpopulations with EGFR mutations that may benefit from ICIs treatment, and analyzes how decisions can be made in the era of combined immunotherapy to maximize the efficacy of ICIs treatment in EGFR mutation targeted therapy for NSCLC patients with drug resistance, with the aim of achieving individualized treatment.
10.3779/j.issn.1009-3419.2023.101.17
The value of innovation: association between improvements in survival of advanced and metastatic non-small cell lung cancer and targeted and immunotherapy.
BMC medicine
BACKGROUND:Significant improvements in mortality among patients with non-small cell lung cancer (NSCLC) in the USA over the past two decades have been reported based on Surveillance, Epidemiology, and End Results (SEER) data. The timing of these improvements led to suggestions that they result from the introduction of new treatments; however, few studies have directly investigated this. The aim of this study was to investigate the extent to which population level improvements in survival of advanced and/or metastatic NSCLC (admNSCLC) patients were associated with changes in treatment patterns. METHODS:We utilized a de-identified database to select three cohorts of patients with admNSCLC: (1) patients with non-oncogene (EGFR/ALK/ROS1/BRAF) positive tumors, (2) patients with ALK-positive (ALK+) tumors, and (3) patients with EGFR-positive (EGFR+) tumors. All patients were diagnosed with admNSCLC between 2012 and 2019. Multivariable Cox models adjusting for baseline characteristics and receipt of targeted and immunotherapy were utilized to explore the relationship between these variables and changes in the hazard of death by calendar year in each cohort. RESULTS:We included 28,154 admNSCLC patients with non-oncogene positive tumors, 598 with ALK+ tumors, and 2464 with EGFR+ tumors eligible for analysis. After adjustment for differences in baseline characteristics, the hazard of death in patients who had non-oncogene positive tumors diagnosed in 2015, 2016, 2017, 2018 ,and 2019 was observed to be 12%, 11%, 17%, 20%, and 21% lower respectively than that for those diagnosed in 2012. Upon additionally adjusting for receipt of first line or second line immunotherapy, the decrease in the hazard of death by calendar year was no longer observed, suggesting improvements in survival observed over time may be explained by the introduction of these treatments. Similarly, decreases in the hazard of death were only observed in patients with ALK+ tumors diagnosed between 2017 and 2019 relative to 2012 but were no longer observed following adjustment for the use of 1st and later generation ALK inhibitors. Among patients with EGFR+ tumors, the hazard of death did not improve significantly over time. CONCLUSION:Our findings expand on the SEER data and provide additional evidence suggesting improvements in survival of patients with advanced and metastatic NSCLC over the past decade could be explained by the change in treatment patterns over this period.
10.1186/s12916-021-02070-w
EGFR Mutations and PD-L1 Expression in Early-Stage Non-Small Cell Lung Cancer: A Real-World Data From a Single Center in Brazil.
The oncologist
BACKGROUND:Targeted and immunotherapies are currently moving toward early-stage settings for patients with non-small cell lung cancer (NSCLC). Predictive biomarkers data are scarce in this scenario. We aimed to describe the frequency of EGFR mutations and PD-L1 expression levels in early-stage non-squamous patients with NSCLC from a large, single Brazilian oncology center. METHODS:We retrospectively evaluated patients with NSCLC diagnosed at an early-stage (IB to IIIA-AJCC seventh edition) at Barretos Cancer Hospital (n = 302). EGFR mutational status was assessed in FFPE tumor tissues using distinct methodologies (NGS, Cobas, or Sanger sequencing). PD-L1 expression was evaluated by immunohistochemistry (clone 22C3) and reported as Tumor Proportion Score (TPS), categorized as <1%, 1-49%, and ≥50%. We evaluated the association between EGFR mutational status and PD-L1 expression with sociodemographic and clinicopathological parameters by Fisher's test, qui-square test, and logistic regression. Survival analysis was assessed by the Kaplan-Meier method and Cox regression model. RESULTS:EGFR mutations were detected in 17.3% (n = 48) of cases and were associated with female sex, never smokers, and longer overall and event-free survival. PD-L1 positivity was observed in 36.7% (n = 69) of cases [TPS 1-49% n = 44(23.4%); TPS ≥50% n = 25(13.3%)]. PD-L1 positivity was associated with smoking, weight loss, and higher disease stages (IIB/IIIA). CONCLUSION:The frequencies of EGFR mutations and PD-L1 positivity were described for early-stage non-squamous patients with NSCLC. These results will be essential for guiding treatment strategies with the recent approvals of osimertinib and immunotherapy in the adjuvant setting.
10.1093/oncolo/oyac167
Nivolumab as maintenance therapy following platinum-based chemotherapy in EGFR-mutant lung cancer patients after tyrosine kinase inhibitor failure: A single-arm, open-label, phase 2 trial.
Thoracic cancer
BACKGROUND:As the outcome of immunotherapy can be improved when concurrently or sequentially combined with cytotoxic chemotherapy or radiotherapy, we investigated the efficacy of immunotherapy maintenance following platinum-based chemotherapy in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) after EGFR-tyrosine kinase inhibitor (EGFR-TKI) failure. METHODS:In this prospective, open-label, single arm phase 2 trial, we enrolled patients aged 18 years or older with EGFR-mutant NSCLC, which progressed after first- or second-line EGFR-TKI. Patients received platinum-based chemotherapy followed by nivolumab maintenance therapy. They were intravenously administered 240 mg of nivolumab every 2 weeks for 3 months followed by 480 mg every 4 weeks until disease progression or unacceptable toxic effects occurred. The primary endpoint was progression-free survival (PFS). Secondary outcomes were overall survival (OS) and incidence of grade 3-4 treatment-related adverse events (AEs). RESULTS:We enrolled 26 patients between May 2020 and July 2021. The median PFS was 1.7 months (95% CI: 0.401-2.999 months). The median OS was 21.4 months (95% CI: 18.790-24.010 months) with 6- and 12-month OS rates of 96.2% and 76.9%, respectively. The objective response rate was 7.7% (2/26) and disease control rate, 11.5% (3/26). The tumor mutational burden by next-generation sequencing in blood was not related to the treatment outcomes. Grade 3-4 treatment-related AEs occurred in four (15.4%) patients; the most frequent AE was increased alanine aminotransferase (7.7%). CONCLUSION:Nivolumab maintenance following platinum-based chemotherapy did not show clinical benefits after EGFR-TKI failure in patients with EGFR-mutant NSCLC.
10.1111/1759-7714.15083
Artesunate promoted anti-tumor immunity and overcame EGFR-TKI resistance in non-small-cell lung cancer by enhancing oncogenic TAZ degradation.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Lung cancer is the leading cause of cancer-related death worldwide. The development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) has brought favorable survival benefits to patients with non-small-cell lung cancer (NSCLC); unfortunately, acquired drug resistance remains a major barrier to the treatment of NSCLC. Recent studies have demonstrated that the transcriptional co-activator with a PDZ-binding motif (TAZ, also called WWTR1) induces tumor immune evasion by directly modulating the expression of programmed death ligand 1 (PD-L1), a key therapeutic target for checkpoint immunotherapy. Moreover, aberrant activation of TAZ is also a major mechanism of acquired resistance to EGFR-TKIs in NSCLC. Therefore, TAZ signaling blockade might be an effective strategy to overcome resistance to ICIs and EGFR-TKIs in NSCLC. In this study, we showed for the first time that artesunate effectively reduced TAZ and PD-L1 expression in NSCLC. We further demonstrated that artesunate suppressed TAZ/PD-L1-induced T-cell growth inhibition in vitro and enhanced anti-tumor immunity by recruiting infiltrating CD8 + T-cells in syngeneic mouse models. Artesunate also inhibited the stem cell-like properties of NSCLC cells and suppressed tumor growth in xenografts bearing gefitinib-resistant tumors. In addition, our results of molecular docking and cellular thermal shift assay analysis suggested that artesunate might directly target the TAZ-TEAD complex and induce proteasome-dependent TAZ degradation in NSCLC cells. These results suggest that artesunate enhanced anti-tumor immunity and overcame EGFR-TKI resistance in NSCLC at least in part by suppressing TAZ/PD-L1 signaling.
10.1016/j.biopha.2022.113705
PD-L1 expression and T cells infiltration in patients with uncommon EGFR-mutant non-small cell lung cancer and the response to immunotherapy.
Chen Kaiyan,Cheng Guoping,Zhang Fanrong,Zhu Guanxia,Xu Yanjun,Yu Xiaoqing,Huang Zhiyu,Fan Yun
Lung cancer (Amsterdam, Netherlands)
OBJECTIVES:The efficacy of immunotherapy in epidermal growth factor receptor (EGFR)-activating non-small cell lung cancer (NSCLC) is limited. However, a series of patients with uncommon EGFR alterations was reported to derive clinical benefit from PD-1 blockade. To characterize the tumor immune microenvironment, we retrospectively evaluated tumor PD-L1 expression and T cells infiltration among NSCLC patients with uncommon EGFR mutations. MATERIALS AND METHODS:Immunohistochemistry was used to analyze the expression of PD-L1 and the abundance of CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs). Chi-square test and Cox proportional hazards regression were conducted to investigate the correlations between the immune microenvironment features and clinicopathological variables and survival, as well as to explore the potential of immunotherapy in this patient population. RESULTS:Among 600 NSCLC patients with EGFR alterations, we identified 49 (8.2 %) bearing uncommon mutations, including G719X, L861Q, S768I, and Ex20 ins. In total, 49.0 % (24/49) of these patients showed positive PD-L1 expression in tumor cells, markedly higher than the proportion in patients with classic sensitive mutations (19del and L858R, 12.2 % [67/551], P < 0.05). Furthermore, PD-L1 expression was associated with relatively short overall survival (OS; 15.2 vs 29.3 months, P = 0.006) and was identified as an independent predictor of OS (hazard ratio=2.57, 95 % confidence interval: 1.03-7.12, P = 0.045). Additionally, PD-L1 positivity was predominantly observed among tumors with CD8+ TILs infiltration (P = 0.001). Uncommon EGFR-mutant tumors had a high frequency (36.7 %) of concurrent PD-L1 expression and abundant CD8 + TILs infiltration. Moreover, this dual-positive group exhibited the most unfavorable prognosis (P = 0.023). Notably, patients with PD-L1 and CD8 dual positivity showed a favorable response to PD-1 inhibitors. CONCLUSIONS:High rates of concomitant PD-L1 expression and CD8 + TILs within the tumor microenvironment were observed in NSCLC patients with uncommon EGFR mutations. Further investigations are needed to confirm the therapeutic sensitivity to PD-1 blockade in this subgroup.
10.1016/j.lungcan.2020.02.010
The efficacy and possible mechanisms of immune checkpoint inhibitors in treating non-small cell lung cancer patients with epidermal growth factor receptor mutation.
Ma Lin,Diao Bowen,Huang Zhaoqin,Wang Bin,Yu Jinming,Meng Xiangjiao
Cancer communications (London, England)
Over the past few years, immune checkpoint inhibitors (ICIs) have greatly improved the survival for patients with non-small cell lung cancer (NSCLC) without driver mutations. Compared with wild-type tumors, tumors with epidermal growth factor receptor (EGFR) mutations show more heterogeneity in the expression level of programmed cell death-ligand 1 (PD-L1), tumor mutational burden (TMB), and other immune microenvironment characteristics. Whether ICIs are suitable for NSCLC patients with EGFR mutations is still worth exploring. In previous studies, no significantly improved benefits were observed with immunotherapy monotherapy in NSCLC patients with EGFR mutation. Here, we summarized and analyzed data from the clinical trials of ICIs or combined therapy in NSCLC patients with EGFR mutations. We also focused on the mechanisms affecting the efficacy of ICIs in NSCLC patients with EGFR mutations, the characteristics of potential responders, and provided insights into areas worth further investigations in future studies.
10.1002/cac2.12229
Safety and Patient-Reported outcomes of atezolizumab plus chemotherapy with or without bevacizumab in stage IIIB/IV non-squamous non-small cell lung cancer with EGFR mutation, ALK rearrangement or ROS1 fusion progressing after targeted therapies (GFPC 06-2018 study).
Lung cancer (Amsterdam, Netherlands)
BACKGROUND:In an open-label multicenter non-randomized non-comparative phase II study in patients with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC), oncogenic addiction (EGFR mutation or ALK/ROS1 fusion), with disease progression after tyrosine-kinase inhibitor and no prior chemotherapy (NCT04042558), atezolizumab, carboplatin, pemetrexed with or without bevacizumab showed some promising result. Beyond the clinical evaluation, we assessed safety and patient-reported outcomes (PROs) to provide additional information on the relative impact of adding atezolizumab to chemotherapy with and without bevacizumab in this population. MATERIALS:Patients received platinum-pemetrexed-atezolizumab-bevacizumab (PPAB cohort) or, if not eligible, platinum-pemetrexed-atezolizumab (PPA cohort). The incidence, nature, and severity of adverse events (AEs) were assessed. PROs were evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-Core 30 and EORTC QLQ-Lung Cancer 13). RESULT:Overall, 68 (PPAB) and 72 (PPA) patients were evaluable for safety. Grade 3-4 AEs occurred in 83.8% (PPAB) and 63.9% (PPA). Grade 3-4 atezolizumab-related AEs occurred in 29.4% and 19.4%, respectively. Grade 3-4 bevacizumab-related AEs occurred in 36.8% (PPAB). Most frequent grade 3-4 AEs were neutropenia (19.1% in PPAB; 23.6% in PPA) and asthenia (16.2% in PPAB; 9.7% in PPA). In PPAB, we observed a global stability in global health security (GHS) score, fatigue and dyspnea with a constant tendency of improvement, and a significant improvement in cough. In PPA, we observed a significant improvement in GHS score with a significant improvement in fatigue, dyspnea and cough. At week 54, we observed an improvement from baseline in GHS score for 49.2% of patients. In both cohorts, patients reported on average no clinically significant worsening in their overall health or physical functioning scores. CONCLUSION:PPAB and PPA combinations seem tolerable and manageable in patients with stage IIIB/IV non-squamous NSCLC with oncogenic addiction (EGFR mutation or ALK/ROS1 fusion) after targeted therapies.
10.1016/j.lungcan.2024.107843
Immunotherapy for oncogenic-driven advanced non-small cell lung cancers: Is the time ripe for a change?
Remon J,Hendriks L E,Cabrera C,Reguart N,Besse B
Cancer treatment reviews
Immune checkpoint inhibitors (ICIs) have been incorporated in the treatment strategy of advanced non-small cell lung cancer (NSCLC) in first- and second-line setting improving the prognosis of these patients. However, the treatment landscape has been also drastically overturned with the advent of targeted therapies in oncogenic-addicted advanced NSCLC patients. Despite ICIs represent an active and new treatment option for a wide range of advanced NSCLC patients, the efficacy and the optimal place of ICI in the treatment strategy algorithm of oncogenic-addicted tumors remains still controversial, as only a minority of trials with ICI enrol oncogenic-addicted NSCLC patients previously treated with standard therapy. Therefore, there are still several open questions about ICI in oncogenic-driven NSCLC, such as the efficacy and toxicities, which need to be addressed before considering treatment with ICI as a standard approach in this population. It is in this framework, we provide a thorough overview on this currently controversial topic.
10.1016/j.ctrv.2018.10.006
Clinical characteristics of patients treated with immune checkpoint inhibitors in EGFR-mutant non-small cell lung cancer: CS-Lung-003 prospective observational registry study.
Journal of cancer research and clinical oncology
PURPOSE:Immune checkpoint inhibitors (ICIs) are ineffective against epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). This study aimed to investigate the clinical characteristics of patients who were treated or not treated with ICIs, and of those who benefit from immunotherapy in EGFR-mutant NSCLC. METHODS:We analyzed patients with unresectable stage III/IV or recurrent NSCLC harboring EGFR mutations using a prospective umbrella-type lung cancer registry (CS-Lung-003). RESULTS:A total of 303 patients who met the eligibility criteria were analyzed. The median age was 69 years; 116 patients were male, 289 had adenocarcinoma, 273 had major mutations, and 67 were treated with ICIs. The duration of EGFR-TKI treatment was longer in the Non-ICI group than in the ICI group (17.1 vs. 12.7 months, p < 0.001). Patients who received ICIs for more than 6 months were categorized into the durable clinical benefit (DCB) group (24 patients), and those who received ICIs for less than 6 months into the Non-DCB group (43 patients). The overall survival in the DCB group exhibited longer than the Non-DCB group (69.3 vs. 47.1 months), and an equivalent compared to that in the Non-ICI group (69.3 vs. 68.9 months). Multivariate analysis for time to next treatment (TTNT) of ICIs showed that a poor PS was associated with a shorter TTNT [hazard ratio (HR) 3.309; p < 0.001]. Patients who were treated with ICIs and chemotherapy combination were associated with a longer TTNT (HR 0.389; p = 0.003). In addition, minor EGFR mutation was associated with a long TTNT (HR 0.450; p = 0.046). CONCLUSION:ICIs were administered to only 22% of patients with EGFR-mutated lung cancer, and they had shorter TTNT of EGFR-TKI compared to other patients. ICI treatment should be avoided in EGFR mutated lung cancer with poor PS but can be considered for lung cancer with EGFR minor mutations. Pathological biomarker to predict long-term responders to ICI are needed.
10.1007/s00432-024-05618-4
PD-1/PD-L1 expression in non-small-cell lung cancer and its correlation with EGFR/KRAS mutations.
Ji Mei,Liu Yan,Li Qing,Li Xiaodong,Ning Zhonghua,Zhao Weiqing,Shi Hongbing,Jiang Jingting,Wu Changping
Cancer biology & therapy
This study was aimed to detect the correlation among EGFR/KRAS status and PD-1/PD-L1 expression in non-small-cell lung cancer (NSCLC) patients. PD-1 and PD-L1 expressions were detected by immunohistochemistry in 100 surgically resected lung adenocarcinoma tissues and were statistically correlated with clinicopathological characteristics including EGFR and KRAS statuses. Besides, the overall survival (OS) times were analyzed. There was a statistical significances between PD-1 expression in tumor and KRAS status (P = 0.043), with a higher mutation rate in with lower PD-1 expression patients. There was a statistical significance between PD-L1 expression in tumor and EGFR status (P = 0.012), with a higher mutation rate in patients with lower PD-L1 expression. The OS of patients with EGFR mutation was significantly longer than those without EGFR mutation. The OS of patients with lower PD-L1 in tumor was significantly longer than those with higher PD-L1 expression. We found negative associations between PD-L1 expression in tumor and mutated EGFR status, as well as between PD-1 expression in tumor and mutated KRAS status.
10.1080/15384047.2016.1156256
The immune microenvironment in EGFR- and ERBB2-mutated lung adenocarcinoma.
ESMO open
BACKGROUND:Targeted therapies have improved survival and quality of life for patients with non-small-cell lung cancer with actionable driver mutations. However, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 gene (HER2, also known as ERBB2) exon 20 insertions (Ex20mut) are characterized by a poor response to currently approved tyrosine kinase inhibitors and immunotherapies. The underlying immune biology is not well understood. MATERIALS AND METHODS:We carried out messenger RNA expression profiling of lung adenocarcinomas (ADCs) with ERBB2 (n = 19) and EGFR exon 20-insertion mutations (n = 13) and compared these to tumors with classical EGFR mutations (n = 40, affecting EGFR exons 18, 19 or 21) and EGFR/ERBB2 mutation-negative lung ADC (EGFR/ERBB2wt, n = 26) focusing on immunologically relevant transcripts. Tumor-infiltrating immune cells were estimated from gene expression profiles. RESULTS:Cytotoxic cells were significantly lower in EGFR-mutated tumors regardless of the affected exon, while Th1 cells were significantly lower in EGFR-Ex20mut compared to EGFR/ERBB2wt tumors. We assessed the differentially expressed genes of ERBB2-Ex20mut and EGFR-Ex20mut tumors compared to EGFR-Ex18/19/21mut and EGFR/ERBB2wt tumors. Of these, the genes GUSB, HDAC11, IFNGR2, PUM1, RASGRF1 and RBL2 were up-regulated, while a lower expression of CBLC, GBP1, GBP2, GBP4 and MYC was observed in all three comparison groups. The omnibus test revealed 185 significantly (FDR = 5%) differentially expressed genes and we found these four most significant gene expression changes in the study cohort: VHL and JAK1 were overexpressed in ERBB2-Ex20mut and EGFR-Ex20mut tumors compared to both EGFR-Ex18/19/21mut and EGFR/ERBB2wt tumors. RIPK1 and STK11IP showed the highest expression in ERBB2-Ex20mut tumors. CONCLUSIONS:Targeted gene expression profiling is a promising tool to read out the characteristics of the tumor microenvironment from routine diagnostic lung cancer biopsies. Significant immune reactivity and specific immunosuppressive characteristics in ERBB2-Ex20mut and EGFR-Ex20mut lung ADC with at least some degree of immune infiltration support further clinical evaluation of immune-modulators as partners of immune checkpoint inhibitors in such tumors.
10.1016/j.esmoop.2021.100253
Comprehensive analyses reveal TKI-induced remodeling of the tumor immune microenvironment in EGFR/ALK-positive non-small-cell lung cancer.
Fang Yisheng,Wang Yuanyuan,Zeng Dongqiang,Zhi Shimeng,Shu Tingting,Huang Na,Zheng Siting,Wu Jianhua,Liu Yantan,Huang Genjie,Xue Yichen,Bin Jianping,Liao Yulin,Shi Min,Liao Wangjun
Oncoimmunology
Tyrosine kinase inhibitors (TKI) play a pivotal role in the treatment of non-small-cell lung cancer (NSCLC) with mutations in epidermal growth factor receptor (EGFR) and rearrangements in anaplastic lymphoma kinase (ALK). However, the influences of TKIs on the tumor immune microenvironment (TIM), especially dynamic changes of responders, have not yet been fully elucidated. Therefore, RNA sequencing and whole-exome sequencing were performed on EGFR/ALK-positive NSCLC samples before and after TKI treatment. In combination with neoantigen and mutational-load estimations, xCell and single-sample gene set enrichment analysis (ssGSEA) were used to assess tumor immune-cell infiltration and activity. Furthermore, weighted-gene correlation network analysis and the bottleneck method were used to identify the hub genes that affected treatment-related immune responses. We found that TKI treatment remodeled the TIM in treatment-responsive samples. Profound increases in the rate of anti-tumor cell infiltration and cytotoxicity was observed following TKI treatment, while antigen presentation was limited in ALK-rearranged samples. However, no significant change in anti-tumor cell infiltration or cytotoxicity was found between pre-treatment and post-progression samples. Subsequently, we found that neurofilament heavy (NEFH) mutations were enriched in samples after TKI treatment and were associated with reduced neutrophil infiltration. The cytotoxicity of EGFR-mutant NSCLCs with co-driver TP53 mutation and ALK-rearranged samples with wild-type TP53 seems to be more easily induced by TKI. Finally, the immune-associated score generated by hub genes was positively correlated with immune infiltration, immune activation, and a favorable prognosis. In conclusion, the dynamic changes in the TIM provide clues to drug selection and timing for TKI-immunotherapy combinations.
10.1080/2162402X.2021.1951019
The association of genomic alterations with PD-L1 expression in Chinese patients with EGFR/ALK wild-type lung adenocarcinoma and potential predictive value of Hippo pathway mutations to immunotherapy.
Cancer medicine
BACKGROUND:The study focuses on PD-L1 expression as an essential biomarker for gauging the response of EGFR/ALK wild-type NSCLC patients to FDA-approved immune checkpoint inhibitors (ICIs). It aims to explore clinical, molecular, and immune microenvironment characteristics associated with PD-L1 expression in EGFR/ALK wild-type lung adenocarcinoma patients eligible for ICI therapy. METHODS:In this retrospective study, tumor samples from 359 Chinese EGFR/ALK wild-type lung adenocarcinoma patients underwent comprehensive evaluations for PD-L1 expression and NGS-targeted sequencing. The investigation encompassed the analysis and comparison of clinical traits, gene mutations, pathways, and immune signatures between two groups categorized by PD-L1 status: negative (TPS < 1%) and positive (TPS ≥ 1%). Additionally, the study explored the link between genomic changes and outcomes following immunotherapy. RESULTS:High tumor mutational burden correlated significantly with PD-L1 positivity in patients with EGFR/ALK wild-type lung adenocarcinoma. Gene alterations, including TP53, KRAS, and others, were more pronounced in the PD-L1 positive group. Pathway analysis highlighted higher frequencies of alterations in pathways like RTK/RAS, p53, and Hippo in PD-L1-positive patients. The Hippo pathway's relevance was confirmed in separate immunotherapy cohorts, associated with better outcomes. In terms of immune cell infiltration, Hippo mutants exhibited higher levels of CD68 PD-L1 macrophages, CD8 T cells, and CD8 PD-1 T cells. CONCLUSIONS:This study offers insights into genomic features of Chinese EGFR/ALK wild-type lung adenocarcinoma patients based on PD-L1 expression. Notably, Hippo pathway alterations were linked to improved immunotherapy outcomes. These findings suggest connections between the Hippo pathway and PD-L1 expression, warranting further clinical and functional investigations. The research advances our understanding of PD-L1 expression's genomic context and immunotherapy response in EGFR/ALK wild-type lung adenocarcinoma.
10.1002/cam4.7038
PD-1 blockade augments CD8 T cell dependent antitumor immunity triggered by Ad-SGE-REIC in Egfr-mutant lung cancer.
Lung cancer (Amsterdam, Netherlands)
OBJECTIVES:No immunotherapeutic protocol has yet been established in never-smoking patients with lung cancer harboring driver oncogenic mutations, such as epidermal growth factor receptor (EGFR) mutations. The immunostimulatory effect of Ad-REIC, a genetically engineered adenovirus vector expressing a tumor suppressor gene, reduced expression in immortalized cells (REIC), has been investigated in clinical trials for various solid tumors. However, the immunostimulatory effect of the Ad-REIC in EGFR-mutant lung cancer with a non-inflamed tumor microenvironment (TME) has not been explored. MATERIALS AND METHODS:We used a syngeneic mouse model developed by transplanting Egfr-mutant lung cancer cells into single or double flanks of C57BL/6J mice. Ad-SGE-REIC, a 2nd-generation vector with an enhancer sequence, was injected only into the tumors from one flank, and its antitumor effects were assessed. Tumor-infiltrating cells were evaluated using immunohistochemistry or flow cytometry. The synergistic effects of Ad-SGE-REIC and PD-1 blockade were also examined. RESULTS:Injection of Ad-SGE-REIC into one side of the tumor induced not only a local antitumor effect but also a bystander abscopal effect in the non-injected tumor, located on the other flank. The number of PD-1CD8 T cells increased in both injected and non-injected tumors. PD-1 blockade augmented the local and abscopal antitumor effects of Ad-SGE-REIC by increasing the number of CD8 T cells in the TME of Egfr-mutant tumors. Depletion of CD8 cells reverted the antitumor effect, suggesting they contribute to antitumor immunity. CONCLUSION:Ad-SGE-REIC induced systemic antitumor immunity by modifying the TME status from non-inflamed to inflamed, with infiltration of CD8 T cells. Additionally, in Egfr-mutant lung cancer, this effect was enhanced by PD-1 blockade. These findings pave the way to establish a novel combined immunotherapy strategy with Ad-SGE-REIC and anti-PD-1 antibody for lung cancer with a non-inflamed TME.
10.1016/j.lungcan.2023.01.018
Exploratory analysis of immunochemotherapy compared to chemotherapy after EGFR-TKI in non-small cell lung cancer patients with EGFR mutation: A multicenter retrospective study.
Thoracic cancer
BACKGROUND:Patients with epidermal growth factor receptor (EGFR)-mutated, advanced non-small cell lung cancer have received immunochemotherapy as one of the treatment options after tyrosine kinase inhibitor (TKI) failure. METHODS:We retrospectively examined EGFR-mutant patients treated with atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) therapy or platinum-based chemotherapy (Chemo) after EGFR-TKI therapy at five institutions in Japan. RESULTS:A total of 57 patients with EGFR mutation were analyzed. The median progression-free survival (PFS) and overall survival (OS) in the ABCP (n = 20) and Chemo (n = 37) were 5.6 and 20.9 months, 5.4 and 22.1 months, respectively (PFS, p = 0.39; OS, p = 0.61). In programmed death-ligand 1 (PD-L1)-positive patients, median PFS in the ABCP group was longer than in the Chemo group (6.9 vs. 4.7 months, p = 0.89). In PD-L1-negative patients, median PFS in the ABCP group was significantly shorter than in the Chemo group (4.6 vs. 8.7 months, p = 0.04). There was no difference in median PFS between the ABCP and Chemo groups in the subgroups of brain metastases, EGFR mutation status, or chemotherapy regimens, respectively. CONCLUSION:The effect of ABCP therapy and chemotherapy was comparable in EGFR-mutant patients in a real-world setting. The indication for immunochemotherapy should be carefully considered, especially in PD-L1-negative patients.
10.1111/1759-7714.14836
Role of the dynamic tumor microenvironment in controversies regarding immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations.
Molecular cancer
Immunotherapy has been incorporated into the first- and second-line treatment strategies for non-small cell lung cancer (NSCLC), profoundly ushering in a new treatment landscape. However, both adaptive signaling and oncogenic (epidermal growth factor receptor (EGFR)-driven) signaling may induce PD-L1 upregulation in NSCLC. Nevertheless, the superiority of immune checkpoint inhibitors (ICIs) in advanced EGFR-mutant NSCLC is only moderate. ICIs appear to be well tolerated, but clinical activity for some advanced EGFR-mutant NSCLC patients has only been observed in a small proportion of trials. Hence, there are still several open questions about PD-L1 axis inhibitors in patients with NSCLC whose tumors harbor EGFR mutations, such as the effect of EGFR tyrosine kinase inhibitors (TKIs) or EGFR mutations in the tumor microenvironment (TME). Finding the answers to these questions requires ongoing trials and preclinical studies to identify the mechanisms explaining this possible increased susceptibility and to identify prognostic molecular and clinical markers that may predict benefits with PD-1 axis inhibition in this specific NSCLC subpopulation. The presence of multiple mechanisms, including dynamic immune TME profiles, changes in PD-L1 expression and low tumor mutational burdens, may explain the conflicting data regarding the correlation between PD-L1 axis inhibitors and EGFR mutation status. We conducted a review of this currently controversial topic in an attempt to aid in the decision-making process.
10.1186/s12943-019-1062-7
Comparison of Chemotherapy Plus Pembrolizumab vs. Chemotherapy Alone in EGFR-Mutant Non-small-Cell Lung Cancer Patients.
Clinical lung cancer
INTRODUCTION:Platinum doublet chemotherapy is the standard of care in patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation who had disease progression after tyrosine kinase inhibitor (TKI). We aimed to assess immune checkpoint inhibitors efficacy in EGFR-mutant advanced NSCLC. MATERIALS AND METHODS:We retrospectively reviewed the data of sensitive EGFR-mutant NSCLC patients who progressed after EGFR-TKIs and received platinum doublet chemotherapy plus immunotherapy between 2015 and 2021. Efficacy outcomes, including overall response rate, progression-free survival, and overall survival, were assessed and compared with those of patients who had received platinum-based doublet chemotherapy. RESULTS:Of the total 869 patients, 82 treated with pembrolizumab and chemotherapy and 82 with only chemotherapy were selected. The median progression-free survival in patients administered pembrolizumab was significantly longer than those not administered pembrolizumab (6.7 months; 95% confidence interval [CI] 5.0-8.5 vs. 4.2 months; 95% CI 3.3-5.0, hazard ratio [HR] 0.64, 95% CI 0.46-0.89, P = .0076). Improved median overall survival was also observed in patients receiving pembrolizumab plus chemotherapy (26.7 [95% CI 22.6-30.8] vs. 13.4 months [95% CI 10.4-16.4], HR, 0.49 [95% CI 0.31-0.75], P = .0052). In addition, the overall response rate was higher in patients treated with than patients treated without pembrolizumab (34.1% and 20.7%, respectively). CONCLUSION:The combination of pembrolizumab with chemotherapy is associated with improved efficacy and survival in patients with EGFR-mutant NSCLC after TKI resistance, but these findings need to be confirmed in further prospective studies.
10.1016/j.cllc.2022.12.003
Comparison of the outcome between immunotherapy alone or in combination with chemotherapy in EGFR-mutant non-small cell lung cancer.
Shen Chia-I,Chao Heng-Sheng,Shiao Tsu-Hui,Chiang Chi-Lu,Huang Hsu-Ching,Luo Yung-Hung,Chiu Chao-Hua,Chen Yuh-Min
Scientific reports
Whether ICIs combined with chemotherapy can improve outcomes in EGFR-mutant non-small cell lung cancer (NSCLC) remains uncertain. Patients with EGFR-mutant NSCLC and who progressed on first-line EGFR-TKIs treatment were retrospectively collected. We reviewed the outcome of these patients treated with ICIs or ICIs combined chemotherapy (ICI + C). Total 30 patients were included. The ORR were 9.1% and 25.0% for the ICI and ICI + C groups. The ICI + C group showed the trend of longer progression-free survival and overall survival periods. Patients without the T790M mutation had a significantly longer PFS than did those without this mutation (4.23 [95% CI: 2.75-5.72] vs. 1.70 [95% CI: 0.00-3.51] months, HR:4.45, p = 0.019). ICIs combined with chemotherapy tended to be more effective than ICIs alone in pretreated EGFR-mutant NSCLC. The T790M mutation may be a potential biomarker.
10.1038/s41598-021-95628-w
Efficacy and safety of anlotinib with and without EGFR-TKIs or immunotherapy in the treatment of elder patients with non-small-cell lung cancer: a retrospective study.
BMC pulmonary medicine
BACKGROUND:Anlotinib is a multitarget tyrosine kinase inhibitor for treating patients with advanced non-small cell lung cancer (NSCLC). We aimed to assess the efficacy and safety of anlotinib in elder patients with advanced NSCLC. METHODS:Elder patients with advanced NSCLC who received anlotinib were enrolled. They were all age ≥ 65 years and with demonstrated records of EGFR gene status. All patients had received treatment with anlotinib or immune checkpoint inhibitors (ICIs)/EGFR-TKIs. The efficacy was evaluated according to the efficacy evaluation criteria for solid tumors (RECIST 1.1). Common Adverse Events Evaluation Criteria (CTCAE 4.03) were used to evaluate adverse drug reactions. RESULTS:A total of 91 patients were included in this study. We divided the patients into two groups (EGFR wild type: 60 patients; EGFR mutation: 31 patients). Among EGFR negative patients, the progression-free survival (PFS) for anlotinib monotherapy and anlotinib combination ICI therapy was 3.2 months and 5.0 months, respectively (P = 0.012). The difference in overall survival (OS) between monotherapy and combination therapy was also significant (9.5 vs. 18.4 months, respectively P = 0.010). Interestingly, we further analyzed differences between patients with hypertension and without hypertension, and found that hypertension was associated with better prognosis (5.7 vs. 1.4 months, P < 0.0001). In the EGFR mutation group, the PFS for anlotinib and EGFR-TKI combination treatment indicated better efficacy than that of anlotinib monotherapy (1.83 months vs. 7.03 months, respectively, P = 0.001). The median OS for monotherapy and combination therapy in the EGFR mutation group showed no statistical difference (28.34 months vs. 31.37 months, P = 0.223). The most common adverse reactions were hypertension, fatigue, and hand-foot syndrome, mainly of grade 1 or 2. No significant increase in adverse reactions was observed in patients ≥ 70 years of age. CONCLUSIONS:Anlotinib treatment and combination regimens resulted in good efficacy and controllable adverse reactions in elder patients with advanced NSCLC.
10.1186/s12890-022-01981-5
Risk stratification for lung adenocarcinoma on EGFR and TP53 mutation status, chemotherapy, and PD-L1 immunotherapy.
Wu Chih-Hsun,Hwang Ming-Jing
Cancer medicine
The overall survival rates for lung cancer remain unsatisfactorily low, even for patients with biomarkers for which target therapies or immunotherapies are recommended. Better identification of at-risk patients is needed to achieve more effective personalized treatment. Here, we derived a risk-stratifying gene signature consisting of five genes that had the greatest differential expression by stage from lung adenocarcinoma (LUAD) transcriptomes. The new gene signature enabled survival prognosis for multiple LUAD datasets from different platforms of transcriptomics and risk stratification for patients with and without a mutation in TP53 or EGFR, with high and low levels of PD-L1, and with and without adjuvant chemotherapy treatment. Using these evaluations, it was also shown to be more robust compared to several other gene signatures. Functional analysis of the five genes and their protein-protein interaction partners indicated that they are functionally enriched in cell cycle, endocytosis, and EGFR regulation, which are biological processes associated with lung cancer and drug resistance. Extensive discussions on related experimental studies suggest that the five genes are novel and sensible targets for developing new drugs and/or tackling drug resistance problems for LUAD.
10.1002/cam4.2492
Changes of tumor microenvironment in non-small cell lung cancer after TKI treatments.
Frontiers in immunology
Non-small cell lung cancer (NSCLC) is the most common lung cancer diagnosis, among which epidermal growth factor receptor (EGFR), Kirsten rat sarcoma (KRAS), and anaplastic lymphoma kinase (ALK) mutations are the common genetic drivers. Their relative tyrosine kinase inhibitors (TKIs) have shown a better response for oncogene-driven NSCLC than chemotherapy. However, the development of resistance is inevitable following the treatments, which need a new strategy urgently. Although immunotherapy, a hot topic for cancer therapy, has shown an excellent response for other cancers, few responses for oncogene-driven NSCLC have been presented from the existing evidence, including clinical studies. Recently, the tumor microenvironment (TME) is increasingly thought to be a key parameter for the efficacy of cancer treatment such as targeted therapy or immunotherapy, while evidence has also shown that the TME could be affected by multi-factors, such as TKIs. Here, we discuss changes in the TME in NSCLC after TKI treatments, especially for EGFR-TKIs, to offer information for a new therapy of oncogene-driven NSCLC.
10.3389/fimmu.2023.1094764
Correlation of distribution characteristics and dynamic changes of gut microbiota with the efficacy of immunotherapy in EGFR-mutated non-small cell lung cancer.
Journal of translational medicine
BACKGROUND:The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. METHODS:We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. RESULTS:The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients' fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. CONCLUSIONS:The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.
10.1186/s12967-024-05135-5
Multi-target angiogenesis inhibitor combined with PD-1 inhibitors may benefit advanced non-small cell lung cancer patients in late line after failure of EGFR-TKI therapy.
International journal of cancer
Treatments for NSCLC patients with EGFR-TKI resistance are limited. Given that immunotherapy and antiangiogenic agents may have synergistic antitumor effects, we aimed to analyze the effect of multi-target angiogenesis inhibitor anlotinib and immune checkpoint inhibitors (ICIs) combination therapy in NSCLC patients who failed EGFR-TKI. The medical records of lung adenocarcinoma (LUAD) patients with EGFR-TKI resistance were reviewed. After EGFR-TKI resistance, patients who simultaneously received anlotinib and ICIs were enrolled in the observation group, and those who received platinum-pemetrexed chemotherapy were included in the control group. A total of 80 LUAD patients were reviewed and allocated to the anlotinib and ICIs combination therapy (n = 38) and chemotherapy (n = 42) groups. A re-biopsy was performed in all patients in the observation group before the administration of anlotinib and ICIs. The median follow-up was 15.63 months (95% CI: 12.19-19.08). Combination therapy exhibited better PFS (median PFS: 4.33 months [95% CI: 2.62-6.05] vs 3.60 months [95% CI: 2.48-4.73], P = .005), and better OS (median OS: 14.17 months [95% CI: 10.17-18.17] vs 9.00 months [95% CI: 6.92-11.08], P = .029) than chemotherapy. Most patients (73.7%) received combination therapy as fourth and later lines of therapy, with a median PFS of 4.03 months (95% CI: 2.05-6.02) and a median OS of 13.80 months (95% CI: 8.25-19.36). The disease control rate was 92.1%. Four patients discontinued the combination therapy due to adverse events, but the other adverse reactions were manageable and reversible. The combination of anlotinib and PD-1 inhibitors is a promising regimen for the late-line treatment of LUAD patients with EGFR-TKI resistance.
10.1002/ijc.34536
Interleukin-10 induces expression of CD39 on CD8+T cells to potentiate anti-PD1 efficacy in EGFR-mutated non-small cell lung cancer.
Journal for immunotherapy of cancer
BACKGROUND:Anti-PD-1(L1) therapies are less efficacious in patients with -mutated non-small-cell lung cancer. However, the underlying mechanism is poorly understood. METHODS:The characteristics of T cells in -mutated and wild-type tumors were analyzed based on The Cancer Genome Atlas database and clinical samples. Plasma levels of 8 T-cell-related cytokines were evaluated and its association with immunotherapy efficacy were explored. Association between EGFR signaling pathway and IL-10 was examined through tumor cell lines and clinical tumor samples. restimulation model of human CD8T cells isolated from peripheral blood was used to analyze the impact of IL-10 on T cells. Doxycycline-inducible transgenic mouse models were used to investigate the efficacy of combining recombinant mouse IL-10 protein and PD-1 blockade and its underlying mechanism . RESULTS:-mutated tumors showed a lack of CD8T cell infiltration and impaired CD8T cell cytotoxic function. The incompetent CD8T cells in -mutated tumors were characterized as absence of CD39 expression, which defined hallmarks of cytotoxic and exhausted features and could not be reinvigorated by anti-PD-1(L1) treatment. Instead, CD39 expression defined functional states of CD8T cells and was associated with the therapeutic response of anti-PD-1(L1) therapies. Mechanically, IL-10 upregulated CD39 expression and was limited in -mutated tumors. IL-10 induced hallmarks of CD8T cells immunity in CD39-dependent manner. Using autochthonous -driven lung cancer mouse models, combining recombinant mouse IL-10 protein and PD-1 blockade optimized antitumor effects in -mutated lung tumors. CONCLUSIONS:Our study suggested that owing to low level of IL-10 to induce the expression of CD39 on CD8T cells, fewer phenotypically cytotoxic and exhausted CD39CD8T cells in -mutated tumors could be potentially reinvigorated by anti-PD-1(L1) treatment. Hence, IL-10 could potentially serve as a cytokine-based strategy to enhance efficacy of anti-PD-1(L1) treatment in -mutated tumors.
10.1136/jitc-2022-005436
EGFR mutation status in non-small cell lung cancer receiving PD-1/PD-L1 inhibitors and its correlation with PD-L1 expression: a meta-analysis.
Cancer immunology, immunotherapy : CII
Meta-analysis was performed on the Web of Science, PubMed, Embase, and Cochrane databases to evaluate the effect of epidermal growth factor receptor (EGFR) mutation status on programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors, and the association between EGFR mutation status and PD-L1 expression in non-small cell lung cancer (NSCLC) patients. Pooled effect (hazard ratio/odds ratio, HR/OR) with 95% confidence interval (CI) was calculated, and the source of heterogeneity was explored by subgroup analysis and meta-regression using Stata/SE 15.0. Meta-analysis of the association between EGFR mutation status and overall survival (OS) in NSCLC with immunotherapy was calculated from four randomized controlled trials. We found that immune checkpoint inhibitors significantly prolonged OS over docetaxel overall (HR 0.71, 95% CI 0.64-0.79) and in the EGFR wild type (HR = 0.67, 95% CI = 0.60-0.75), but not in the EGFR mutant subgroup (HR = 1.11, 95% CI = 0.80-1.52). Meta-analysis of the association between EGFR mutation status and PD-L1 expression in NSCLC included 32 studies. The pooled OR and 95% CI were 0.60 (0.46-0.80), calculated by random effects model. No source of heterogeneity was found in subgroup analysis. Sensitivity analysis was carried out with a fixed model, and the influence of a single study on the pooled results showed no significant change with robust meta-analysis methods. Harbord's weighted linear regression test (P = 0.956) and Peters regression test (P = 0.489) indicated no significant publication bias. The limited benefit of single-agent PD-1/PD-L1 inhibitors in the second-line or later setting for EGFR-mutated NSCLC may be partly due to the lower expression of PD-L1.
10.1007/s00262-021-03030-2
CD8+ T-cell Responses Are Boosted by Dual PD-1/VEGFR2 Blockade after EGFR Inhibition in Egfr-Mutant Lung Cancer.
Cancer immunology research
Epidermal growth factor receptor (EGFR) is the most frequently mutated driver oncogene in nonsmoking-related, non-small cell lung cancer (NSCLC). EGFR-mutant NSCLC has a noninflamed tumor microenvironment (TME), with low infiltration by CD8+ T cells and, thus, immune-checkpoint inhibitors, such as antiprogrammed cell death-1 (anti-PD-1), have weak antitumor effects. Here, we showed that CD8+ T-cell responses were induced by an EGFR-tyrosine kinase inhibitor (TKI) in syngeneic Egfr-mutant NSCLC tumors, which was further pronounced by the sequential dual blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2). However, the simultaneous triple blockade had no such effect. The PD-1/VEGFR2 dual blockade did not exert tumor-inhibitory effects without pretreatment with the EGFR-TKI, suggesting that the treatment schedule is crucial for the efficacy of the dual blockade therapy. Pretreatment with EGFR-TKI increased the CD8+ T-cell/regulatory T-cell (Treg) ratio, while also increasing the expression of immunosuppressive chemokines and chemokine receptors, as well as increasing the number of M2-like macrophages, in the TME. Discontinuing EGFR-TKI treatment reversed the transient increase of immunosuppressive factors in the TME. The subsequent PD-1/VEGFR2 inhibition maintained increased numbers of infiltrating CD8+ T cells and CD11c+ dendritic cells. Depletion of CD8+ T cells in vivo abolished tumor growth inhibition by EGFR-TKI alone and the sequential triple therapy, suggesting that EGFR inhibition is a prerequisite for the induction of CD8+ T-cell responses. Our findings could aid in developing an alternative immunotherapy strategy in patients with cancers that have driver mutations and a noninflamed TME.
10.1158/2326-6066.CIR-21-0751
Combining Genomic Biomarkers to Guide Immunotherapy in Non-Small Cell Lung Cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research
PURPOSE:The clinical value of STK11, KEAP1, and EGFR alterations for guiding immune checkpoint blockade (ICB) therapy in non-small cell lung cancer (NSCLC) remains controversial, as some patients with these proposed resistance biomarkers show durable ICB responses. More specific combinatorial biomarker approaches are urgently needed for this disease. EXPERIMENTAL DESIGN:To develop a combinatorial biomarker strategy with increased specificity for ICB unresponsiveness in NSCLC, we performed a comprehensive analysis of 254 patients with NSCLC treated with ligand programmed death-ligand 1 (PD-L1) blockade monotherapy, including a discovery cohort of 75 patients subjected to whole-genome sequencing (WGS), and an independent validation cohort of 169 patients subjected to tumor-normal large panel sequencing. The specificity of STK11/KEAP1/EGFR alterations for ICB unresponsiveness was assessed in the contexts of a low (<10 muts/Mb) or high (≥10 muts/Mb) tumor mutational burden (TMB). RESULTS:In low TMB cases, STK11/KEAP1/EGFR alterations were highly specific biomarkers for ICB resistance, with 0/15 (0.0%) and 1/34 (2.9%) biomarker-positive patients showing treatment benefit in the discovery and validation cohorts, respectively. This contrasted with high TMB cases, where 11/13 (85%) and 15/34 (44%) patients with at least one STK11/KEAP1/EGFR alteration showed durable treatment benefit in the discovery and validation cohorts, respectively. These findings were supported by analyses of progression-free survival and overall survival. CONCLUSIONS:The unexpected ICB responses in patients carrying resistance biomarkers in STK11, KEAP1, and EGFR were almost exclusively observed in patients with a high TMB. Considering these alterations in context, the TMB offered a highly specific combinatorial biomarker strategy for limiting overtreatment in NSCLC.
10.1158/1078-0432.CCR-23-4027
Immunotherapy-based combination strategies for treatment of EGFR-TKI-resistant non-small-cell lung cancer.
Future oncology (London, England)
The rapid development of molecular targeted therapy brings hope to patients with advanced non-small-cell lung cancer (NSCLC). However, drug resistance inevitably occurs during treatment with EGFR-tyrosine kinase inhibitors (TKIs). Osimertinib, a third-generation EGFR-TKI, shows a favorable prognosis in T790M-positive NSCLC. Unfortunately, acquired resistance is still a challenge for both patients and clinicians. There is still no consensus on the optimal treatment. PD-1 and its ligand receptor 1 (PD-L1) inhibitors have yielded great progress, especially in patients with no actionable mutations. In this review, the authors take stock of the relationship between mutations and PD-L1 expression and summarize the important clinical studies on immunotherapy-inhibitor-based treatment in patients with EGFR-TKI-resistant NSCLC.
10.2217/fon-2021-0862
Immunotherapy for EGFR-mutant advanced non-small-cell lung cancer: Current status, possible mechanisms and application prospects.
Frontiers in immunology
Immune checkpoint inhibitors (ICIs) are effective against advanced and even perioperative non-small-cell lung cancer (NSCLC) and result in durable clinical benefit, regardless of programmed death ligand-1 (PD-L1) expression status in cancer. Existing clinical evidence shows that the effect of immunotherapy in patients with EGFR-mutant NSCLC after the development of tyrosine kinase inhibitor (TKI) resistance is not satisfactory. However, compared with monotherapy, ICIs combined with chemotherapy can improve the efficacy. Encouragingly, compared with that of patients with sensitive mutations, the progression-free survival of patients with rare mutations who were treated with ICIs was increased. Adequately maximizing the efficacy of ICIs in EGFR-mutant NSCLC patients is worth exploring. In this review, we described preclinical and clinical studies of ICIs or combined therapy for EGFR-mutant NSCLC. We further focused on EGFR mutations and the cancer immune response, with particular attention given to the role of EGFR activation in the cancer-immunity cycle. The mechanisms for the natural resistance to ICIs were explored to identify corresponding countermeasures that made more EGFR-mutant NSCLC patients benefit from ICIs.
10.3389/fimmu.2022.940288
Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR-Driven Lung Cancer.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
Lung cancer is the leading cause of cancer death worldwide. Vaccination against EGFR can be one of the venues to prevent lung cancer. Blocking glutamine metabolism has been shown to improve anticancer immunity. Here, the authors report that JHU083, an orally active glutamine antagonist prodrug designed to be preferentially activated in the tumor microenvironment, has potent anticancer effects on EGFR-driven mouse lung tumorigenesis. Lung tumor development is significantly suppressed when treatment with JHU083 is combined with an EGFR peptide vaccine (EVax) than either single treatment. Flow cytometry and single-cell RNA sequencing of the lung tumors reveal that JHU083 increases CD8 T cell and CD4 Th1 cell infiltration, while EVax elicits robust Th1 cell-mediated immune responses and protects mice against EGFR mutation-driven lung tumorigenesis. JHU083 treatment decreases immune suppressive cells, including both monocytic- and granulocytic-myeloid-derived suppressor cells, regulatory T cells, and pro-tumor CD4 Th17 cells in mouse models. Interestingly, Th1 cells are found to robustly upregulate oxidative metabolism and adopt a highly activated and memory-like phenotype upon glutamine inhibition. These results suggest that JHU083 is highly effective against EGFR-driven lung tumorigenesis and promotes an adaptive T cell-mediated tumor-specific immune response that enhances the efficacy of EVax.
10.1002/advs.202105885
Antitumour immunity regulated by aberrant ERBB family signalling.
Nature reviews. Cancer
Aberrant signalling of ERBB family members plays an important role in tumorigenesis and in the escape from antitumour immunity in multiple malignancies. Molecular-targeted agents against these signalling pathways exhibit robust clinical efficacy, but patients inevitably experience acquired resistance to these molecular-targeted therapies. Although cancer immunotherapies, including immune checkpoint inhibitors (ICIs), have shown durable antitumour response in a subset of the treated patients in multiple cancer types, clinical efficacy is limited in cancers harbouring activating gene alterations of ERBB family members. In particular, ICI treatment of patients with non-small cell lung cancers with epidermal growth factor receptor (EGFR) alterations and breast cancers with HER2 alterations failed to show clinical benefits, suggesting that EGFR and HER2 signalling may have an essential role in inhibiting antitumour immune responses. Here, we discuss the mechanisms by which the signalling of ERBB family members affects not only autonomous cancer hallmarks, such as uncontrolled cell proliferation, but also antitumour immune responses in the tumour microenvironment and the potential application of immune-genome precision medicine into immunotherapy and molecular-targeted therapy focusing on the signalling of ERBB family members.
10.1038/s41568-020-00322-0
Current WHO guidelines and the critical role of immunohistochemical markers in the subclassification of non-small cell lung carcinoma (NSCLC): Moving from targeted therapy to immunotherapy.
Osmani Lais,Askin Frederic,Gabrielson Edward,Li Qing Kay
Seminars in cancer biology
Recent large scale genomic studies from the Clinical Lung Cancer Genome Project have identified different driver gene mutations in the subtypes of non-small cell lung carcinoma (NSCLC). These findings not only lead to remarkable progress in targeted therapies for lung cancer patients, but also provide fundamental knowledge for the subclassification of NSCLC. More recently, the advancement and clinical application of immunotherapy have reinforced the need for the accurate subclassification of NSCLC. In 2015, the World Health Organization (WHO) and the International Association for the Study of Lung Cancer (IASLC) updated their guidelines for the subclassification of lung cancers. These guidelines emphasize: (1) the subclassification of NSCLC, (2) the critical role of molecular characterization of tumors for targeted therapy, (3) the unique terminology for subclassifying NSCLC using small biopsy specimens, and (4) the utility of IHC biomarkers in the accurate diagnosis and subclassification of lung cancer. The guidelines have significant prognostic impact on oncologic practice and patient care. In this review, we summarize the current WHO guidelines for the classification of lung cancer, discuss advancements of targeted therapy and immunotherapy, and address the utility and limitation of immunomarkers in the subclassification of NSCLC, as well as the prospective future of the field.
10.1016/j.semcancer.2017.11.019
Immune Checkpoint Inhibitors in EGFR-Mutated NSCLC: Dusk or Dawn?
Qiao Meng,Jiang Tao,Liu Xinyu,Mao Shiqi,Zhou Fei,Li Xuefei,Zhao Chao,Chen Xiaoxia,Su Chunxia,Ren Shengxiang,Zhou Caicun
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
Although immune checkpoint inhibitors (ICIs) that target programmed cell death protein-1/programmed cell death ligand-1 axis have significantly shifted the treatment paradigm in advanced NSCLC, clinical benefits of these agents are limited in patients with EGFR-mutated NSCLC. Several predictive biomarkers (e.g., programmed cell death ligand-1 expression, tumor mutation burden), which have been validated in EGFR-wild type NSCLC, however, are not efficacious in EGFR-mutated tumors, suggesting the unique characteristics of tumor microenvironment of EGFR-mutated NSCLC. Here, we first summarized the clinical evidence on the efficacy of ICIs in patients with EGFR-mutated NSCLC. Then, the cancer immunogram features of EGFR-mutated NSCLC was depicted to visualize the state of cancer-immune system interactions, including tumor foreignness, tumor sensitivity to immune effectors, metabolism, general immune status, immune cell infiltration, cytokines, and soluble molecules. We further discussed the potential subpopulations with EGFR mutations that could benefit from ICI treatment. Lastly, we put forward future strategies to adequately maximize the efficacy of ICI treatment in patients with EGFR-mutated NSCLC in the upcoming era of combination immunotherapies.
10.1016/j.jtho.2021.04.003
Immunotherapy in EGFR-Mutant and ALK-Positive Lung Cancer: Implications for Oncogene-Driven Lung Cancer.
Gavralidis Alexander,Gainor Justin F
Cancer journal (Sudbury, Mass.)
Non-small cell lung cancer (NSCLC) is a heterogeneous disease, commonly defined by genetic alterations in oncogenic drivers. Targeted therapies have transformed the management of oncogene-driven lung cancers, with targeted agents now approved in the United States for 7 distinct molecular alterations. Nonetheless, acquired resistance remains an ongoing challenge, underscoring the need for alternative therapeutic approaches. Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) axis have emerged as important therapies in the management of advanced NSCLC, but the role of these agents in patients with oncogenic driver mutations remains unclear. Here, we focus on epidermal growth factor receptor-mutant and anaplastic lymphoma kinase-rearranged NSCLC as paradigms to explore the role of immune checkpoint inhibitors in oncogene-driven NSCLC. We provide an overview of the clinical data examining programmed death ligand 1 (PD-L1) inhibitor monotherapy, PD-(L)1 inhibitors, and tyrosine kinase inhibitor combinations, as well as combinations of PD-(L)1 inhibitors and chemotherapy.
10.1097/PPO.0000000000000491
Single-cell transcriptome analysis revealed a suppressive tumor immune microenvironment in EGFR mutant lung adenocarcinoma.
Yang Lei,He Yun-Ting,Dong Song,Wei Xue-Wu,Chen Zhi-Hong,Zhang Bo,Chen Wei-Dong,Yang Xiao-Rong,Wang Fen,Shang Xue-Meng,Zhong Wen-Zhao,Wu Yi-Long,Zhou Qing
Journal for immunotherapy of cancer
BACKGROUNDS:Immunotherapy is less effective in patients with epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC). Lower programmed cell death-ligand 1 (PD-L1) expression and tumor mutation burden (TMB) are reported to be the underlying mechanism. Being another important factor to affect the efficacy of immunotherapy, tumor microenvironment (TME) characteristics of this subgroup of NSCLC are not comprehensively understood up to date. Hence, we initiated this study to describe the specific TME of EGFR-mutant lung adenocarcinoma (LUAD) from cellular compositional and functional perspectives to better understand the immune landscape of this most common subtype of NSCLC. METHODS:We used single-cell transcriptome sequencing and multiplex immunohistochemistry to investigate the immune microenvironment of EGFR-mutant and EGFR wild-type LUADs and determined the efficacy of immunotherapy. We analyzed single cells from nine treatment-naïve samples and compared them to three post-immunotherapy samples previously reported from single cell perspective using bioinformatics methods. RESULTS:We found that EGFR-mutant malignant epithelial cells had similar characteristics to the epithelial cells in non-responders. EGFR-mutant LUAD lacked CD8 tissue-resident memory (TRM) cells, which could promote tertiary lymphoid structure generation by secreting CXCL13. In addition, other cell types, including tumor-associated macrophages and cancer-associated fibroblasts, which are capable of recruiting, retaining, and expanding CD8 TRM cells in the TME, were also deficient in EGFR-mutant LUAD. Furthermore, EGFR-mutant LUAD had significantly less crosstalk between T cells and other cell types via programmed cell death-1 (PD-1) and PD-L1 or other immune checkpoints compared with EGFR wild-type LUAD. CONCLUSIONS:Our findings provide a comprehensive understanding of the immune landscape of EGFR-mutant LUAD at the single-cell level. Based on the results, many cellular components might have negative impact on the specific TME of EGFR-mutant LUAD through influencing CD8 TRM. Lack of CD8 TRM might be a key factor responsible for the suppressive TME of EGFR-mutant LUAD.
10.1136/jitc-2021-003534
Blockade of EGFR improves responsiveness to PD-1 blockade in -mutated non-small cell lung cancer.
Sugiyama Eri,Togashi Yosuke,Takeuchi Yoshiko,Shinya Sayoko,Tada Yasuko,Kataoka Keisuke,Tane Kenta,Sato Eiichi,Ishii Genichiro,Goto Koichi,Shintani Yasushi,Okumura Meinoshin,Tsuboi Masahiro,Nishikawa Hiroyoshi
Science immunology
The clinical efficacy of anti-PD-1 (programmed cell death-1) monoclonal antibody (mAb) against cancers with oncogenic driver gene mutations, which often harbor a low tumor mutation burden, is variable, suggesting different contributions of each driver mutation to immune responses. Here, we investigated the immunological phenotypes in the tumor microenvironment (TME) of epidermal growth factor receptor ()-mutated lung adenocarcinomas, for which anti-PD-1 mAb is largely ineffective. Whereas -mutated lung adenocarcinomas had a noninflamed TME, CD4 effector regulatory T cells, which are generally present in the inflamed TME, showed high infiltration. The EGFR signal activated cJun/cJun N-terminal kinase and reduced interferon regulatory factor-1; the former increased CCL22, which recruits CD4 regulatory T cells, and the latter decreased CXCL10 and CCL5, which induce CD8 T cell infiltration. The EGFR inhibitor erlotinib decreased CD4 effector regulatory T cells infiltration in the TME and in combination with anti-PD-1 mAb showed better antitumor effects than either treatment alone. Our results suggest that EGFR inhibitors when used in conjunction with anti-PD-1 mAb could increase the efficacy of immunotherapy in lung adenocarcinomas.
10.1126/sciimmunol.aav3937
Atezolizumab with or without bevacizumab and platinum-pemetrexed in patients with stage IIIB/IV non-squamous non-small cell lung cancer with EGFR mutation, ALK rearrangement or ROS1 fusion progressing after targeted therapies: A multicentre phase II open-label non-randomised study GFPC 06-2018.
European journal of cancer (Oxford, England : 1990)
BACKGROUND:Previous reports showed limited efficacy of immune checkpoint inhibitors as single-agent treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation or ALK/ROS1 fusion. We aimed at evaluating the efficacy and safety of immune checkpoint inhibitor combined with chemotherapy and bevacizumab (when eligible) in this patient subgroup. METHODS:We conducted a French national open-label multicentre non-randomised non-comparative phase II study in patients with stage IIIB/IV NSCLC, oncogenic addiction (EGFR mutation or ALK/ROS1 fusion), with disease progression after tyrosine kinase inhibitor and no prior chemotherapy. Patients received platinum, pemetrexed, atezolizumab, bevacizumab (PPAB cohort) or, if not eligible to bevacizumab, platinum-pemetrexed-atezolizumab (PPA cohort). The primary end-point was the objective response rate (RECIST v1.1) after 12 weeks, evaluated by blind independent central review. RESULTS:71 patients were included in PPAB cohort and 78 in PPA cohort (mean age, 60.4/66.1 years; women 69.0%/51.3%; EGFR mutation, 87.3%/89.7%; ALK rearrangement, 12.7%/5.1%; ROS1 fusion, 0%/6.4%, respectively). After 12 weeks, objective response rate was 58.2% (90% confidence interval [CI], 47.4-68.4) in PPAB cohort and 46.5% (90% CI, 36.3-56.9) in PPA cohort. Median progression-free survival and overall survival were 7.3 (95% CI 6.9-9.0) months and 17.2 (95% CI 13.7-NA) months in PPAB cohort and 7.2 (95% CI 5.7-9.2) months and 16.8 (95% CI 13.5-NA) months in PPA cohort, respectively. Grade 3-4 adverse events occurred in 69.1% of patients in PPAB cohort and 51.4% in PPA cohort; Grade 3-4 atezolizumab-related adverse events occurred in 27.9% and 15.3%, respectively. CONCLUSION:Combination approach with atezolizumab with or without bevacizumab and platinum-pemetrexed achieved promising activity in metastatic EGFR-mutated or ALK/ROS1-rearranged NSCLC after tyrosine kinase inhibitor failure, with acceptable safety profile.
10.1016/j.ejca.2023.01.014
Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer.
Negrao Marcelo V,Skoulidis Ferdinandos,Montesion Meagan,Schulze Katja,Bara Ilze,Shen Vincent,Xu Hao,Hu Sylvia,Sui Dawen,Elamin Yasir Y,Le Xiuning,Goldberg Michael E,Murugesan Karthikeyan,Wu Chang-Jiun,Zhang Jianhua,Barreto David S,Robichaux Jacqulyne P,Reuben Alexandre,Cascone Tina,Gay Carl M,Mitchell Kyle G,Hong Lingzhi,Rinsurongkawong Waree,Roth Jack A,Swisher Stephen G,Lee Jack,Tsao Anne,Papadimitrakopoulou Vassiliki,Gibbons Don L,Glisson Bonnie S,Singal Gaurav,Miller Vincent A,Alexander Brian,Frampton Garrett,Albacker Lee A,Shames David,Zhang Jianjun,Heymach John V
Journal for immunotherapy of cancer
BACKGROUND:Non-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome. METHODS:Three cohorts of NSCLC patients with oncogene alterations (n=4189 total) were analyzed. Two clinical cohorts of advanced NSCLC patients treated with ICB monotherapy [MD Anderson (MDACC; n=172) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB; n=894 patients)] were analyzed for clinical outcome. The FMI biomarker cohort (n=4017) was used to assess the association of oncogene alterations with TMB and PD-L1 expression. RESULTS:High PD-L1 expression (PD-L1 ≥50%) rate was 19%-20% in classic , exon 20 and -mutant tumors, and 34%-55% in tumors with , V600E, , , or alterations. Compared with mutant tumors, non-V600E group had higher TMB (9.6 vs 7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (p<0.001). In the two clinical cohorts treated with ICB, molecular groups with , , , , , or alterations had short progression-free survival (PFS; 1.8-3.7 months), while V600E group was associated with greater clinical benefit from ICB (CGDB cohort: PFS 9.8 months vs 3.7 months, HR 0.66, p=0.099; MDACC cohort: response rate 62% vs 24%; PFS 7.4 vs 2.8 months, HR 0.36, p=0.026). G12C and non-G12C subgroups had similar clinical benefit from ICB in both cohorts. In a multivariable analysis, V600E mutation (HR 0.58, p=0.041), PD-L1 expression (HR 0.57, p=0.022), and high TMB (HR 0.66, p<0.001) were associated with longer PFS. CONCLUSIONS:High TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile and mutations and , , , and fusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations.
10.1136/jitc-2021-002891
Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial.
The Lancet. Oncology
BACKGROUND:VEGF inhibitors can enhance the efficacy of immunotherapy. However, despite high initial response rates, almost all patients eventually develop treatment resistance to EGFR tyrosine-kinase inhibitors. We aimed to evaluate the efficacy and safety of sintilimab with or without IBI305 plus pemetrexed and cisplatin, compared with pemetrexed and cisplatin alone, for the treatment of patients with locally advanced or metastatic EGFR-mutated non-small-cell lung cancer (NSCLC) who had disease progression after receiving EGFR tyrosine-kinase inhibitor therapy. METHODS:This randomised, double-blind, multicentre, phase 3 trial was conducted at 52 hospitals in China. Eligible participants were adults aged 18-75 years with locally advanced or metastatic NSCLC and EGFR who progressed after receiving a EGFR tyrosine-kinase inhibitor, had an Eastern Cooperative Oncology Group performance status of 0 or 1 with at least one measurable lesion, and an estimated life expectancy of at least 3 months. Participants were randomly assigned (1:1:1) to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m) and cisplatin (75 mg/m), sintilimab plus pemetrexed and cisplatin, or pemetrexed and cisplatin (chemotherapy alone) using block randomisation with stratification according to sex and presence or absence of brain metastases. All study drugs were administered intravenously on day 1 of each cycle, once every 3 weeks. Except for cisplatin, which was only given in the first four cycles, treatment was given for 24 months or until disease progression, intolerable toxic effects, withdrawal of consent, death, or other protocol-specified conditions, whichever occurred first. The primary endpoint was progression-free survival in the intention-to-treat population. We herein report the first planned interim analysis, with progression-free survival results for the comparison between sintilimab plus IBI305 plus chemotherapy versus chemotherapy alone. The progression-free survival results for the sintilimab plus pemetrexed and cisplatin group are immature and not reported here. This study is registered with ClinicalTrials.gov, NCT03802240 (recruiting). FINDINGS:Between July 11, 2019, and July 31, 2021, 936 patients were screened and 444 were randomly assigned (148 to the sintilimab plus IBI305 plus chemotherapy group, 145 to the sintilimab plus chemotherapy group, and 151 to the chemotherapy alone group). Data cutoff for this interim analysis was July 31, 2021. After a median follow-up of 9·8 months (IQR 4·4-13·3), progression-free survival was significantly longer in the sintilimab plus IBI305 plus chemotherapy group versus the chemotherapy alone group (median 6·9 months [95% CI 6·0-9.3] vs 4·3 months [4·1-5·4]; hazard ratio 0·46 [0·34-0·64]; p<0·0001). The most common grade 3 or 4 treatment-related adverse events were decreased neutrophil count (30 [20%] in the sintilimab plus IBI305 plus chemotherapy group vs 26 [18%] in the sintilimab plus chemotherapy group vs 27 [18%] in the chemotherapy alone group), decreased white blood cell count (17 [11%] vs 12 [8%] vs 13 [9%]), and anaemia (18 [12%] vs ten [7%] vs 15 [10%]). Potentially treatment-related deaths occurred in six patients (intestinal obstruction, gastrointestinal haemorrhage, and myelosuppression in one patient each, and three deaths of unknown cause) in the sintilimab plus IBI305 plus chemotherapy group, and in one patient in the chemotherapy alone group (unknown cause). INTERPRETATION:In this interim analysis, sintilimab plus IBI305 plus cisplatin and pemetrexed was generally efficacious and well tolerated in patients with EGFR-mutated NSCLC who progressed after receiving EGFR tyrosine-kinase inhibitor therapy. FUNDING:Innovent Biologics and the National Natural Science Foundation of China. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.
10.1016/S1470-2045(22)00382-5
Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.
Nature reviews. Cancer
The impressive clinical activity of small-molecule receptor tyrosine kinase inhibitors for oncogene-addicted subgroups of non-small-cell lung cancer (for example, those driven by activating mutations in the gene encoding epidermal growth factor receptor (EGFR) or rearrangements in the genes encoding the receptor tyrosine kinases anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1) and rearranged during transfection (RET)) has established an oncogene-centric molecular classification paradigm in this disease. However, recent studies have revealed considerable phenotypic diversity downstream of tumour-initiating oncogenes. Co-occurring genomic alterations, particularly in tumour suppressor genes such as TP53 and LKB1 (also known as STK11), have emerged as core determinants of the molecular and clinical heterogeneity of oncogene-driven lung cancer subgroups through their effects on both tumour cell-intrinsic and non-cell-autonomous cancer hallmarks. In this Review, we discuss the impact of co-mutations on the pathogenesis, biology, microenvironmental interactions and therapeutic vulnerabilities of non-small-cell lung cancer and assess the challenges and opportunities that co-mutations present for personalized anticancer therapy, as well as the expanding field of precision immunotherapy.
10.1038/s41568-019-0179-8
Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer.
Wu Shang-Gin,Shih Jin-Yuan
Molecular cancer
Recent advances in diagnosis and treatment are enabling a more targeted approach to treating lung cancers. Therapy targeting the specific oncogenic driver mutation could inhibit tumor progression and provide a favorable prognosis in clinical practice. Activating mutations of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) are a favorable predictive factor for EGFR tyrosine kinase inhibitors (TKIs) treatment. For lung cancer patients with EGFR-exon 19 deletions or an exon 21 Leu858Arg mutation, the standard first-line treatment is first-generation (gefitinib, erlotinib), or second-generation (afatinib) TKIs. EGFR TKIs improve response rates, time to progression, and overall survival. Unfortunately, patients with EGFR mutant lung cancer develop disease progression after a median of 10 to 14 months on EGFR TKI. Different mechanisms of acquired resistance to first-generation and second-generation EGFR TKIs have been reported. Optimal treatment for the various mechanisms of acquired resistance is not yet clearly defined, except for the T790M mutation. Repeated tissue biopsy is important to explore resistance mechanisms, but it has limitations and risks. Liquid biopsy is a valid alternative to tissue re-biopsy. Osimertinib has been approved for patients with T790M-positive NSCLC with acquired resistance to EGFR TKI. For other TKI-resistant mechanisms, combination therapy may be considered. In addition, the use of immunotherapy in lung cancer treatment has evolved rapidly. Understanding and clarifying the biology of the resistance mechanisms of EGFR-mutant NSCLC could guide future drug development, leading to more precise therapy and advances in treatment.
10.1186/s12943-018-0777-1
Anti-PD1/PD-L1 Immunotherapy for Non-Small Cell Lung Cancer with Actionable Oncogenic Driver Mutations.
Dantoing Edouard,Piton Nicolas,Salaün Mathieu,Thiberville Luc,Guisier Florian
International journal of molecular sciences
Anti-PD1/PD-L1 immunotherapy has emerged as a standard of care for stage III-IV non-small cell lung cancer (NSCLC) over the past decade. Patient selection is usually based on PD-L1 expression by tumor cells and/or tumor mutational burden. However, mutations in oncogenic drivers such as , , , or modify the immune tumor microenvironment and may promote anti-PD1/PD-L1 resistance. In this review, we discuss the molecular mechanisms associated with these mutations, which shape the immune tumor microenvironment and may impede anti-PD1/PD-L1 efficacy. We provide an overview of the current clinical data on anti-PD1/PD-L1 efficacy in NSCLC with oncogenic driver mutation.
10.3390/ijms22126288
Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance.
Journal of hematology & oncology
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the preferential options for advanced non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. Osimertinib is a potent irreversible third-generation EGFR-TKI targeting EGFR mutations but has little effect on wild-type EGFR. In view of its remarkable efficacy and manageable safety, osimertinib was recommended as the standard first-line treatment for advanced or metastatic NSCLC patients with EGFR mutations. However, as the other EGFR-TKIs, osimertinib will inevitably develop acquired resistance, which limits its efficacy on the treatment of EGFR-mutated NSCLC patients. The etiology of triggering osimertinib resistance is complex including EGFR-dependent and EGFR-independent pathways, and different therapeutic strategies for the NSCLC patients with osimertinib resistance have been developed. Herein, we comprehensively summarized the resistance mechanisms of osimertinib and discuss in detail the potential therapeutic strategies for EGFR-mutated NSCLC patients suffering osimertinib resistance for the sake of the improvement of survival and further achievement of precise medicine.
10.1186/s13045-022-01391-4