Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Therapy Research Articles

Elevated Serum Direct Bilirubin and Smoking Status Are Prognostic Factors for EGFR-Mutated Non-Small Cell Lung Cancer Patients Receiving Tyrosine Kinase Inhibitor Therapy

Background: Recent research has revealed a correlation between serum bilirubin levels and cancer risk and mortality. This study explored the potential of bilirubin as a significant predictor of the therapeutic efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Methods: This multicenter cohort study included patients diagnosed with EGFR-mutated NSCLC and treated with EGFR-TKIs (discovery cohort, n = 113; validation cohort, n = 53). Serum direct bilirubin (DBIL) was measured before and 3–4 months after treatment. Patients were categorized into DBILlow and DBILhigh groups around the median DBIL and DBILin or DBILde groups according to whether DBIL increased or decreased after treatment. Results: Multivariate Cox regression analysis of the discovery cohort revealed that smoking (HR, 1.4357; 95% CI, 1.0459–10.9709; p = 0.0253) and DBIL (HR, 1.3006; 95% CI, 1.0054–1.6824; p = 0.0454) were independent risk factors for overall survival (OS). Kaplan–Meier analysis revealed significantly shorter OS in the DBILhigh (p = 0.0273) and Smoking+ (p < 0.001) groups. When these factors were combined, the DBILhigh Smoking+ group had the shortest OS, whereas the DBILlow Smoking− group had the longest OS (p = 0.0011). This trend was consistent with that in the validation cohort (p = 0.0449). Additionally, the DBIL level did not significantly change in the survival group (p = 0.3208, p = 0.1204), whereas the post-treatment DBIL level significantly increased in the nonsurviving group (p = 0.0457, p = 0.0297) in both cohorts. The DBILin group demonstrated shorter OS in both cohorts (p = 0.0229 and p = 0.0424, respectively). Conclusions: Serum DBIL and smoking status were significant biomarkers for prognosis in EGFR-mutated NSCLC patients receiving EGFR-TKI therapy.

Prognostic impact of PD-L1 expression in surgically resected EGFR-mutant lung adenocarcinoma: A real-world database study in Japan (CReGYT-01 EGFR study).

The expression of programmed cell death-ligand 1 (PD-L1) and mutation in epidermal growth factor receptor (EGFR) are biomarkers used for perioperative treatment of lung adenocarcinoma. However, the clinical significance of PD-L1 expression in surgically resected EGFR-mutant lung adenocarcinoma remains unclear. We conducted a real-world database of patients with surgically resected lung adenocarcinoma from 2015 to 2018 was constructed across 21 centers in Japan. The association among PD-L1 expression, EGFR mutations, and prognosis was evaluated. Among 847 patients, PD-L1 expression was negative (tumor proportion score [TPS] < 1%) in 429 (51%), weakly positive (TPS = 1%-49%) in 275 (32%), and strongly positive (TPS ≥50%) in 143 (17%) patients. EGFR mutations were detected in 331 (39%) patients. PD-L1 expression was associated with poor recurrence-free survival (RFS) (p < .001) in both EGFR-mutant and wild-type patients. However, in EGFR-mutant patients, PD-L1 expression was not associated with overall survival (OS) (p = .506). Multivariable analysis confirmed an association between PD-L1 expression and RFS but not OS. Furthermore, in EGFR-mutant patients treated with EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment post-relapse, PD-L1 expression was not associated with overall response rate (p = .714), disease control rate (p = .554), or progression-free survival (p = .660). In conclusion, PD-L1 expression predicted poor RFS-independent EGFR status but did not show any association with OS in EGFR-mutant patients. The efficacy of post-relapse EGFR-TKI treatment was independent of PD-L1 expression. The significance of PD-L1 expression in perioperative EGFR-TKI therapy should be evaluated.

Sintilimab plus chemotherapy with or without bevacizumab biosimilar IBI305 in EGFR-mutated non-squamous NSCLC patients who progressed on EGFR TKI therapy: A China-based cost-effectiveness analysis.

This study aims to compare the cost-effectiveness of sintilimab in combination with chemotherapy, with or without bevacizumab biosimilar IBI305, versus chemotherapy alone for patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) who have progressed on tyrosine-kinase inhibitor (TKI) treatment from the perspective of the Chinese healthcare system. 10-year Markov model was developed using a 21-day cycle length. Transition probabilities were derived from the ORIENT-31 trial, while cost and health state utilities were obtained from publicly databases, local hospitals, and published literature. Incremental cost-effectiveness ratios (ICERs) were calculated as the primary model output and compared to a willingness-to-pay (WTP) threshold range of $15,289.34 to $38,223.34 per quality-adjusted life-years (QALY). Sensitivity analyses were performed to assess the robustness of the model. In the base-case analysis, sintilimab plus IBI305 and chemotherapy had an ICER of $53,266.32/QALYs, exceeding the upper WTP threshold. Sintilimab plus chemotherapy had an ICER of $15,329.11/QALY, slightly above the lower WTP threshold. Subgroup analysis yielded consistent results. Deterministic sensitivity analyses found no ICER for sintilimab plus chemotherapy beyond the upper WTP threshold. Most model input changes did not decrease the ICER of sintilimab plus IBI305 and chemotherapy below the upper WTP threshold. Probabilistic sensitivity analyses further demonstrated the cost-effectiveness superiority of sintilimab plus chemotherapy over sintilimab plus IBI305 and chemotherapy. This study supports the cost-effectiveness of using sintilimab in combination with chemotherapy. Nevertheless, the cost-effectiveness of combining sintilimab with IBI305 and chemotherapy in this particular patient group may be lacking.

Benmelstobart plus anlotinib in patients with EGFR-positive advanced NSCLC after failure of EGFR TKIs therapy: a phase I/II study

The effect of immune‐based therapies on patients with epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitor (TKI) therapy remains unclear. The ALTER-L038 study aimed to evaluate efficacy and safety of a chemotherapy-free combination of benmelstobart, an anti-programmed cell death ligand 1 antibody, and anlotinib, a small-molecule multi-target anti-angiogenic TKI, in EGFR-positive advanced NSCLC patients who progressed after EGFR TKI therapy. Patients were enrolled in a phase I/II study. In phase I (dose-escalation), patients received anlotinib (8, 10, 12 mg) plus benmelstobart (1200 mg). Recommended phase II dose, determined during phase I, was used in phase II dose-expansion cohort. Primary endpoints were maximum tolerable dose in phase I and progression-free survival (PFS) in phase II. At the data cutoff date (March 10, 2024), 55 patients were enrolled in phase II dose-expansion cohort. Median PFS of patients included in phase II cohort was 9.0 months, median overall survival was 28.9 months, objective response rate was 25.5%, disease control rate was 87.3%, and median duration of response was 19.8 months. Incidence of grade ≥3 treatment-related adverse events in study population was 25.5% (14/55), whereas grade ≥3 immune-related adverse events occurred in 10.9% (6/55) of patients. Benmelstobart plus anlotinib showed promising anti-tumor efficacy with tolerable safety profile, supporting the value of further development of this convenient chemotherapy-free regimen for patients with EGFR-positive advanced NSCLC who progressed after EGFR TKI therapy. Trial Registration: ChiCTR1900026273.

Updated overall survival and ctDNA analysis in patients with EGFR T790M-positive advanced non-small cell lung cancer treated with lazertinib in the phase 1/2 LASER201 study.

Lazertinib is a potent, irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with significant efficacy in patients with EGFR T790M-mutated non-small cell lung cancer (NSCLC). This is the final overall survival (OS) report from the phase 1/2 LASER201 study in patients with advanced NSCLC with disease progression on or after prior EGFR TKI therapy. Eligible patients were aged ≥ 20years, with advanced EGFR-mutated NSCLC and previous therapy with EGFR TKI. Patients in this integrated analysis received oral lazertinib 240mg/day. Endpoints included efficacy and safety; exploratory analyses included associations between circulating EGFR-mutant tumor DNA (ctDNA) and efficacy parameters. This integrated analysis included 78 patients in Korea who received second- or later-line lazertinib. The median OS was 38.9months; estimated survival rates at 12, 24, and 36months were 89.5%, 73.9%, and 52.8%, respectively. The cumulative 12-month incidence of central nervous system progression was 9.4%. EGFR-mutant ctDNA was detected in 46 patients (62.2%) at baseline. The presence of ctDNA at baseline significantly predicted progression-free survival (PFS), disease control rate (DCR), and OS. PFS, response rate, and DCR were significantly associated with EGFR-mutant ctDNA clearance at cycle 3; PFS and OS were significantly associated with ctDNA clearance at cycle 5. The safety profile of lazertinib 240mg/day was consistent with previous findings. Lazertinib is a promising treatment option for patients with EGFR T790M-positive NSCLC following disease progression on prior EGFR-directed TKIs. Patients in LASER201 experienced prolonged OS, regardless of their EGFR mutation, brain metastases, or prior brain radiation status. Clearance of plasma EGFR mutations after lazertinib was associated with patient outcomes. ClinicalTrials.gov identifier NCT03046992.

CtDNA SNORD3F Hypermethylation is a Prognostic Indicator in EGFR-TKI-Treated Advanced Non-Small Cell Lung Cancer.

DNA methylation plays a regulatory role in the oncogenesis and tumor progression and is valuable in the diagnosis and prognosis of cancer. While circulating tumor DNA (ctDNA) is widely used in the detection of oncogenic mutations and the guidance of treatment in advanced non-small cell lung cancer (NSCLC), studies of ctDNA methylation remains insufficient. We aim to investigate the methylation profiles of ctDNA in patients with advanced NSCLC undergoing EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy and to discover novel biomarkers with predictive or prognostic value. We recruited 49 patients with EGFR-mutated advanced NSCLC undergoing EGFR-TKI as first-line treatment. Utilizing next-generation sequencing, we examined the somatic mutations and methylation signatures within the tumor-associated genomic regions of ctDNA from pre-treatment blood. Subsequently, we explored the association of these molecular features with the patients' response to therapy and their progression-free survival (PFS). Genomic mutation profiling revealed no significant association of PFS or best overall response (BOR) and ctDNA status. Evaluation of ctDNA methylation showed a negative correlation between the methylation of small nucleolar RNA (snoRNA) genes and PFS (R=-0.31, P=0.043). Furthermore, high-level methylation of SNORD3F was associated with poorer PFS (mPFS 346d vs 243d, HR 0.49, 95% CI 0.24-0.93, P=0.029). Our study explored the prognostic value of ctDNA methylation in patients with advanced NSCLC undergoing targeted therapies and first revealed the predictive role of SNORD3F.

Predictive value of serum magnesium levels for prognosis in patients with non-small cell lung cancer undergoing EGFR-TKI therapy.

The aim of this study is to assess the impact of serum magnesium (Mg) levels on prognostic outcomes in patients with non-small cell lung cancer (NSCLC) undergoing treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). A cohort comprising 91 patients with NSCLC with epidermal growth factor receptor mutations received EGFR-TKI therapy. Assessments of liver and kidney function and electrolyte levels were conducted before treatment initiation and after completing two cycles of EGFR-TKI therapy. Data on variables such as age, gender, presence of distant metastasis, smoking history, other therapeutic interventions, and the specific TKI used were collected for analysis. Cox regression analysis revealed that patients with higher Mg levels prior to EGFR-TKI therapy had significantly longer progression-free survival (PFS) and overall survival (OS). Elevated Mg levels remained predictive of PFS and OS after two cycles of EGFR-TKI therapy. Multiple regression analysis confirmed these findings. Additionally, it was observed that smokers might represent a unique population, demonstrating a correlation between OS and Mg levels. Our findings indicate that serum Mg level is a prognostic factor in patients with NSCLC undergoing EGFR-TKI therapy. This may provide new insights into the underlying mechanisms of EGFR-TKI therapy related to electrolyte balance.

EGFR Mutation and TKI Treatment Promote Secretion of Small Extracellular Vesicle PD-L1 and Contribute to Immunosuppression in NSCLC.

In Asian populations with non-small-cell lung cancer (NSCLC), EGFR mutations are highly prevalent, occurring in roughly half of these patients. Studies have revealed that individuals with EGFR mutation typically fare worse with immunotherapy. In patients who received EGFR tyrosine kinase inhibitor (TKI) treatment followed by anti-PD-1 therapy, poor results were observed. The underlying mechanism remains unclear. We used high-resolution flow cytometry and ELISA to detect the circulating level of small extracellular vesicle (sEV) PD-L1 in NSCLC individuals with EGFR mutations before and after receiving TKIs. The secretion amount of sEV PD-L1 of lung cancer cell lines with EGFR mutations under TKI treatment or not were detected using high-resolution flow cytometry and Western blotting. The results revealed that patients harboring EGFR mutations exhibit increased levels of sEV PD-L1 in circulation, which inversely correlated with the presence of CD8+ T cells in tumor tissues. Furthermore, tumor cells carrying EGFR mutations secrete a higher quantity of PD-L1-positive sEVs. TKI treatment appeared to amplify the levels of PD-L1-positive sEVs in the bloodstream. Mutation-induced and TKI-induced sEVs substantially impaired the functionality of CD8+ T cells. Importantly, our findings indicated that EGFR mutations and TKI therapies promote secretion of PD-L1-positive sEVs via distinct molecular mechanisms, namely the HRS and ALIX pathways, respectively. In conclusion, the increased secretion of PD-L1-positive sEVs, prompted by genetic alterations and TKI administration, may contribute to the limited efficacy of immunotherapy observed in EGFR-mutant patients and patients who have received TKI treatment.

Significance of Runt-related transcription factor 1 and Notch1 expression in non-small-cell lung cancer: involvement in epithelial-mesenchymal transition and epidermal growth factor receptor-tyrosine kinase inhibitor therapy resistance

Objective One of the main obstacles to treating patients with non-small-cell lung cancers (NSCLC) is the emergence of drug resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy. Aim To investigate the prognostic relevance of Runt-related transcription factor 1 (RUNX1) and Notch1 in NSCLC and to evaluate their potential involvement in induction of epithelial-mesenchymal transition and resistance to EGFR-TKI therapy. Materials and methods Immunohistochemical study of RUNX1, Notch1, E-cadherin, and hypoxia-inducible factor 1α (HIF-1α) was conducted upon 83 cases diagnosed as NSCLC. The research was conducted in the departments of pathology, chest, and medical oncology of the Faculty of Medicine, Benha University. Results A significant relation was found between RUNX1 and sex (P=0.001), smoking history (P=0.002), and tumor grade (P=0.002). High RUNX1 expression was associated with poor OS and DFS (P=0.003 and 0.005), respectively. Cases with positive Notch1 expression were significantly associated with tumor grade (P=0.005) and tumor stage (P=0.024). A significant association was detected between Notch1 expression and poor OS and DFS (P=0.025 and 0.011), respectively. A statistically significant correlation was found between RUNX1 and Notch1 expressions (P=0.040). Moreover, high RUNX1 and positive Notch1 expressions were significantly associated with negative E-cadherin and positive HIF-1α expressions. Resistance against EGFR–TKI therapy was significantly associated with high RUNX1, positive Notch1, negative E-cadherin, and positive HIF-1α expressions, in EGFR-mutated cases. Conclusions RUNX1 and Notch1 may be involved in therapy resistance through the induction of epithelial–mesenchymal transition and may serve as prognostic markers in patients with NSCLC.

Therapeutic Resistance in G-CSF Producing Lung Cancer With EGFR Mutation.

Granulocyte colony-stimulating factor (G-CSF)-producing neoplasms are relatively rare; however, little is known on the clinical features of G-CSF-producing lung cancer harboring activating epidermal growth factor receptor (EGFR) mutations. A 66-year-old female was definitively diagnosed with G-CSF-producing lung cancer that was positive for EGFR mutations. She repeatedly received epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib and afatinib. However, she developed resistance to these molecular-targeting drugs within 2 to 3 months after immediate shrinkage. Thus, the patient was treated with chemoimmunotherapy including bevacizumab, and demonstrated a slight survival benefit. Overall, G-CSF-producing lung cancers positive for EGFR mutations were resistant to different treatment modalities. Clinicians should be attentive to the potential resistance of G-CSF-producing EGFR mutant lung cancer to EGFR-TKI therapy.

Ivonescimab Plus Chemotherapy in Non–Small Cell Lung Cancer With EGFR Variant

For patients with non-small cell lung cancer whose disease progressed while receiving EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, particularly third-generation TKIs, optimal treatment options remain limited. To compare the efficacy of ivonescimab plus chemotherapy with chemotherapy alone for patients with relapsed advanced or metastatic non-small cell lung cancer with the epidermal growth factor receptor (EGFR) variant. Double-blind, placebo-controlled, randomized, phase 3 trial at 55 sites in China enrolled participants from January 2022 to November 2022; a total of 322 eligible patients were enrolled. Participants received ivonescimab (n = 161) or placebo (n = 161) plus pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy of ivonescimab plus pemetrexed or placebo plus pemetrexed. The primary end point was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee (IRRC) per Response Evaluation Criteria in Solid Tumors version 1.1. The results of the first planned interim analysis are reported. Among 322 enrolled patients in the ivonescimab and placebo groups, the median age was 59.6 vs 59.4 years and 52.2% vs 50.9% of patients were female. As of March 10, 2023, median follow-up time was 7.89 months. Median progression-free survival was 7.1 (95% CI, 5.9-8.7) months in the ivonescimab group vs 4.8 (95% CI, 4.2-5.6) months for placebo (difference, 2.3 months; hazard ratio [HR], 0.46 [95% CI, 0.34-0.62]; P < .001). The prespecified subgroup analysis showed progression-free survival benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including patients whose disease progressed while receiving third-generation EGFR-TKI therapy (HR, 0.48 [95% CI 0.35-0.66]) and those with brain metastases (HR, 0.40 [95% CI, 0.22-0.73]). The objective response rate was 50.6% (95% CI, 42.6%-58.6%) with ivonescimab and 35.4% (95% CI, 28.0%-43.3%) with placebo (difference, 15.6% [95% CI, 5.3%-26.0%]; P = .006). The median overall survival data were not mature; at data cutoff, 69 patients (21.4%) had died. Grade 3 or higher treatment-emergent adverse events occurred in 99 patients (61.5%) in the ivonescimab group vs 79 patients (49.1%) in the placebo group, the most common of which were chemotherapy-related. Grade 3 or higher immune-related adverse events occurred in 10 patients (6.2%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Grade 3 or higher vascular endothelial growth factor-related adverse events occurred in 5 patients (3.1%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Ivonescimab plus chemotherapy significantly improved progression-free survival with tolerable safety profile in TKI-treated non-small cell lung cancer. ClinicalTrials.gov Identifier: NCT05184712.

Polyphyllin I ameliorates gefitinib resistance and inhibits the VEGF/VEGFR2/p38 pathway by targeting HIF-1a in lung adenocarcinoma

BackgroundLung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been administered as the first-line therapy for patients with EGFR mutations in LUAD, but it is almost inevitable that resistance to EGFR-TKIs therapy eventually arises. Polyphyllin I (PPI), derived from Paris polyphylla rhizomes, has been shown to have potent anti-cancer properties in a range of human cancer types including LUAD. However, the role of PPI in gefitinib resistance and the underlying mechanism remain elusive. PurposeTo evaluate the antitumor impacts of PPI on gefitinib resistance cells and investigate its molecular mechanism. MethodsCCK-8, wound healing, transwell assay, and xenograft model were performed to determine the anti-cancer effects of PPI as well as its ability to overcome gefitinib resistance. Immunoblotting, co-immunoprecipitation, phospho-RTK antibody array, qRT-PCR, and immunofluorescence were utilized to explore the mechanism by which PPI overrides gefitinib resistance. ResultsPPI inhibited cell survival, growth, and migration/invasion in both gefitinib-sensitive (PC9) and -resistant (PC9/GR) LUAD cells (IC50 at 2.0 μM). Significantly, treatment with PPI at 1.0 μM resensitized the resistant cells to gefitinib. Moreover, cell-derived xenograft experiments revealed that the combination of PPI and gefitinib overcame gefitinib resistance. The phospho-RTK array and immunoblotting analyses showed PPI significant inhibition of the VEGFR2/p38 pathway. In addition, molecular docking suggested the interaction between PPI and HIF-1α. Mechanistically, PPI reduced the protein expression of HIF-1α in both normoxia and hypoxia conditions by triggering HIF-1α degradation. Moreover, HIF-1α protein but not mRNA level was elevated in gefitinib-resistant LUAD. We further demonstrated that PPI considerably facilitated the binding of HIF-1α to VHL. ConclusionsWe present a novel discovery demonstrating that PPI effectively counteracts gefitinib resistance in LUAD by modulating the VEGF/VEGFR2/p38 pathway. Mechanistic investigations unveil that PPI facilitates the formation of the HIF-1α /VHL complex, leading to the degradation of HIF-1α and subsequent inhibition of angiogenesis. These findings uncover a previously unidentified mechanism governing HIF-1α expression in reaction to PPI, providing a promising method for therapeutic interventions targeting EGFR-TKI resistance in LUAD.

Effects of EGFR-TKI on epidermal melanin unit integrity: Therapeutic implications for hypopigmented skin disorders.

Epidermal melanin unit integrity is crucial for skin homeostasis and pigmentation. Epidermal growth factor (EGF) receptor (EGFR) is a pivotal player in cell growth, wound healing, and maintaining skin homeostasis. However, its influence on skin pigmentation is relatively unexplored. This study investigates the impact and underlying mechanisms of EGFR inhibitors on skin pigmentation. We evaluated EGF and EGFR expression in various skin cells using quantitative real-time PCR, Western blot, and immunofluorescence. EGF and EGFR were predominantly expressed in epidermal keratinocytes, and treatment with the EGFR tyrosine kinase inhibitors (EGFR-TKIs) gefitinib and PD153035 significantly increased stem cell factor (SCF) and endothelin-1 (ET-1) expression in cultured keratinocytes. Enhanced melanocyte migration and proliferation were observed in co-culture, as evidenced by time-lapse live imaging and single-cell tracking assays. Furthermore, topical application of gefitinib to guinea pig dorsal skin induced increased pigmentation and demonstrated efficacy in mitigating rhododendrol-induced leukoderma. Suppression of EGF signaling indirectly enhanced skin pigmentation by upregulating SCF and ET-1 in epidermal keratinocytes. This novel mechanism highlights the pivotal role of EGF signaling in regulating skin pigmentation, and topical EGFR-TKI therapy at an appropriate dose may be a promising approach for depigmentation disorder management.

Interstitial Pneumonitis Following Sequential Administration of Programmed Death-1/Programmed Death-Ligand1 Inhibitors and Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors For Non-Small Cell Lung Cancer: A Matched‐Pair Cohort Study Using a Nationwide Inpatient Database

BackgroundIt is unclear whether the sequential administration of programmed death (PD)-1/programmed death-ligand 1 (PD-L1) inhibitors and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is associated with the development of severe interstitial pneumonitis (IP). Patients and MethodsWe identified 69,107 eligible patients with non-small cell lung cancer (NSCLC) from a Japanese national inpatient database, who initiated EGFR-TKI therapy. The study population was divided into the PD-1/PD-L1 inhibitor and non-prior PD-1/PD-L1 groups based on PD-1/PD-L1 administration before EGFR-TKI therapy. We conducted 1:4 matched-pair cohort analyses (n = 9,725) to compare the incidence of IP and in-hospital mortality within 90 days of administration of EGFR-TKI between the two groups after adjusting for the clinical background. Furthermore, we performed subgroup analyses categorized according to the duration of prior PD-1/PD-L1 inhibitor use. ResultsIP occurred in 4.4% of patients in the matched-pair cohort. PD-1/PD-L1 inhibitor-use before EGFR-TKI therapy was significantly associated with IP (odds ratio [OR], 1.79; 95% confidence interval [CI], 1.34-2.38) and in-hospital mortality (OR, 2.10; 95% CI, 1.72-2.55). Prior PD-1/PD-L1 inhibitor use in an interval of <6 months before EGFR-TKI administration was associated with a higher risk of IP than EGFR-TKI administration without prior PD-1/PD-L1 inhibitor. In-hospital mortality was higher in patients with prior PD-1/PD-L1 inhibitor use than that in those without prior PD-1/PD-L1 inhibitor use, irrespective of the treatment duration. ConclusionSequential use of PD-1/PD-L1 inhibitors and EGFR-TKIs in patients with non-small cell lung cancer was significantly associated with IP compared to EGFR-TKIs without prior PD-1/PD-L1 inhibitor administration.

The EGFR inhibitor exerts a suppressive influence on the response of CD8+ T cells in Non-Small Cell Lung Cancer

Abstract Lung cancer is the leading cause of death worldwide, predominantly characterized by non-small cell lung cancer (NSCLC). The foremost treatment for NSCLC patients with EGFR mutations involves EGFR-tyrosine kinase inhibitors (EGFR-TKIs), demonstrating notable enhancements in patient survival and the preservation of quality of life. Immune checkpoint blockade (ICB) that reinvigorates T cell response is a promising immunotherapeutic approach to treat NSCLC patients with an efficacy of approximately 20%. Thus, comprehending the intricate interplay between EGFR-TKIs and immune regulation is pivotal, laying the groundwork for strategic combination therapies. Despite its critical importance, the relationship between EGFR-TKIs and immune regulation remains elusive, necessitating further investigation into the immunomodulatory role of EGFR-TKIs. This study unveils that EGFR-TKIs contribute to the reduced proliferation and effector cytokine production of CD8+ T cells. Treatment with EGFR-TKIs suppresses the response of tumor-infiltrating T cells in two syngeneic tumor mouse models. Furthermore, employing EGFR-TKI-specific antibodies and mass spectrum analysis, we identified the target profile of EGFR-TKIs. Remarkably, NSCLC patients undergoing EGFR-TKI therapy exhibited a diminished frequency of IFNγ-producing CD8+ T cells. These findings significantly inform the future development of therapeutic strategies and the optimization of drug administration timing for NSCLC patients.

Real-world outcomes on platinum-containing chemotherapy for EGFR-mutated advanced nonsquamous NSCLC with prior exposure to EGFR tyrosine kinase inhibitors.

Front-line therapy with an EGFR tyrosine kinase inhibitor (TKI) is the standard of care for treating patients with advanced nonsquamous NSCLC with the common sensitizing EGFR exon 19 deletion and exon 21 L858R point mutations. However, EGFR TKI resistance inevitably develops. The optimal subsequent therapy remains to be identified, although platinum-containing chemotherapy regimens are often administered. Our objectives were to describe baseline characteristics, survival, and subsequent treatment patterns for patients with advanced nonsquamous NSCLC with EGFR exon 19 deletion or L858R mutation who received a platinum-based combination regimen after front-line EGFR TKI therapy. This retrospective study used a nationwide electronic health record-derived deidentified database to select adult patients with advanced nonsquamous NSCLC, evidence of EGFR exon 19 deletion or L858R mutation, and ECOG performance status of 0-2 who initiated platinum-containing chemotherapy, with or without concomitant immunotherapy, from 1-January-2011 to 30-June-2020 following receipt of any EGFR TKI as first-line therapy or, alternatively, a first- or second-generation EGFR TKI (erlotinib, afatinib, gefitinib, dacomitinib) as first-line therapy followed by the third-generation EGFR TKI osimertinib as second-line therapy. Data cut-off was 30-June-2022. The Kaplan-Meier method was used to estimate overall survival (OS) after initiation of pemetrexed-platinum (n=119) or any platinum-based combination regimen (platinum cohort; n=311). The two cohorts included two-thirds women (65%-66%) and 57%-58% nonsmokers; median ages were 66 and 65 years in pemetrexed-platinum and platinum cohorts, respectively. Median OS was 10.3 months (95% CI, 8.1-13.9) from pemetrexed-platinum initiation and 12.4 months (95% CI, 10.2-15.2) from platinum initiation; 12-month survival rates were 48% and 51%, respectively; 260 patients (84%) had died by the end of the study. The suboptimal survival outcomes recorded in this study demonstrate the unmet need to identify more effective subsequent treatment regimens for patients with EGFR-mutated advanced nonsquamous NSCLC after EGFR TKI resistance develops.

Clinical efficacy and safety analysis of aumolertinib in real-world treatment of EGFR-mutated advanced non-small-cell lung cancer.

Background: This study aims to determine the efficacy and safety profile of aumolertinib in the real-word treatment setting for advanced non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations. Methods: We retrospectively analyzed the clinical data of 173 EGFR-mutated advanced NSCLC patients who received aumolertinib treatment at Henan Cancer Hospital from April 2020 to December 2022. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier survival curves, while a Cox regression model was used for multifactorial analysis and prognostic factor assessment. Results: Among patients administered first-line aumolertinib (n = 77), the objective remission rate (ORR) of 77.92% was observed, along with a disease control rate (DCR) of 100%. The median progression-free survival (mPFS) was 24.97 months, which did not reach the median overall survival (mOS). The patients treated with aumolertinib after progression on prior EGFR-tyrosine kinase inhibitor (TKI) therapy (n = 96) exhibited an ORR of 46.88%, a DCR of 89.58%, an mPFS of 15.17 months, and an mOS of 21.27 months. First-line treatment multivariate Cox regression analysis demonstrated a statistically significant impact of elevated creatine kinase on PFS (p = 0.016) and a similar significant influence of co-mutation on OS (p = 0.034). Furthermore, subsequent-line treatment multivariate Cox regression analysis showed a statistically significant impact of elevated creatine kinase on median PFS (p = 0.026) and a significant effect on the number of metastatic organs (p = 0.017), co-mutation (p = 0.035), and elevated creatine kinase (p = 0.014) on median OS. Conclusion: Aumolertinib has shown clinical significance and can safely be used in the real-world setting for patients with EGFR mutation-positive NSCLC.

Abstract CT282: MK-2870-004: A phase 3 study of MK-2870 (SKB264) versus chemotherapy for previously treated advanced or metastatic nonsquamous non-small-cell lung cancer (NSCLC) with EGFR mutations or other genomic alterations

Abstract Background: Trophoblast cell-surface antigen 2 (TROP2), a cell surface glycoprotein involved in the regulation of tumor growth and invasion, is broadly expressed and upregulated in several cancers, including NSCLC. MK-2870 (SKB264) is an antibody-drug conjugate (ADC) composed of the humanized anti-TROP2 monoclonal antibody, a hydrolytically cleavable linker, and the cytotoxic drug KL610023. MK-2870 has demonstrated encouraging antitumor activity and manageable toxicity in phase 1 and 2 studies of patients with solid tumors, including heavily pretreated EGFR-mutant NSCLC. We describe the design of the ongoing phase 3 MK-2870-004 study (NCT06074588) that will evaluate the efficacy and safety of MK-2870 vs chemotherapy for previously treated advanced or metastatic nonsquamous NSCLC with EGFR mutations or other genomic alterations. Trial design: The global, randomized, open-label, phase 3 MK-2870-004 study will enroll ~556 patients, including 456 with exon 19del or L858R EGFR mutations, and 100 with other genomic alterations. Eligible patients are aged ≥18 years with histologically or cytologically documented advanced (stage III not eligible for resection or curative radiation) or metastatic nonsquamous NSCLC with exon 19del or exon 21 L858R EGFR mutations or other genomic alterations in ALK, ROS1, BRAF V600E, NTRK, MET exon 14 skipping, or RET and those with less common EGFR mutations (exon 20 S768I, exon 21 L861Q, and/or exon 18 G719X). Patients must have progressive disease on or after 1 or 2 lines of prior tyrosine kinase inhibitor (TKI) therapy and a platinum-based therapy (may contain anti-PD-[L]1), measurable disease per RECIST v1.1, an available tumor sample, and adequate organ function. Prior EGFR TKI therapy must include a third-generation TKI for patients with T790M EGFR-mutant NSCLC. Patients with active central nervous system metastases or carcinomatous meningitis are ineligible, although those with previously treated and untreated stable brain metastasis are eligible for enrollment. Patients will be randomized (1:1) to MK-2870 4 mg/kg Q2W on Days 1, 15, and 29 of every 6-week cycle, or chemotherapy (docetaxel 75 mg/m2 Q3W or pemetrexed 500 mg/m2 Q3W) on Days 1 and 22 of every 6-week cycle. Randomization will be stratified by EGFR mutations with prior third generation TKI vs EGFR mutations with no prior third generation TKI vs other genomic alterations, brain metastasis (yes vs no), and TROP2 expression (low vs medium vs high). Dual primary endpoints are PFS (per RECIST v1.1 by blinded independent central review) and OS in patients with EGFR-mutant NSCLC. Key secondary endpoints include PFS and OS in all patients with NSCLC, ORR, DOR, patient-reported outcomes, and safety. Enrollment started in November 2023 and is currently ongoing. Citation Format: Federico Cappuzzo, Edward B. Garon, Myung-Ju Ahn, Shun Lu, Terufumi Kato, Enriqueta Felip, Parneet Cheema, Nicolas Girard, Mark Shamoun, Guoqing Wang, Bin Zhao, Rina Hui. MK-2870-004: A phase 3 study of MK-2870 (SKB264) versus chemotherapy for previously treated advanced or metastatic nonsquamous non-small-cell lung cancer (NSCLC) with EGFR mutations or other genomic alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT282.

Abstract 1226: Genomically encoded lineage plasticity drives resistance to EGFR targeted therapy in lung adenocarcinoma

Abstract EGFR-mutant lung adenocarcinoma (LUAD) represents 20% of all non-small cell lung carcinomas, with most patients presenting with incurable metastatic disease. Treatment with mutant-selective EGFR tyrosine kinase inhibitor (TKI) therapies such as osimertinib, the current standard of care for metastatic EGFR-mutant LUAD, results in greater overall and progression-free survival. However, all patients eventually relapse. Uncovering the mechanisms driving primary and acquired resistance to osimertinib is therefore critical to improving disease management. Here, we use clinical genomic sequencing (n=47) and single-nucleus RNA (snRNA) sequencing (n=62) to profile a cohort of unmatched treatment-naïve (n=26), on-treatment (n=6), and post-treatment relapsed (n=30) EGFR-mutant LUADs treated with osimertinib. Relapsed tumors are marked by increased tumor mutation burden, along with elevated rates of genome doubling and loss-of-heterozygosity. We derived expression-based signatures of LUAD, lung squamous cell carcinoma (LUSC), and small cell lung carcinoma (SCLC) and applied them to tumor cells across our cohort. Relapsed tumors had a marked decrease in LUAD gene signature expression compared to untreated tumors and accompanying increases in epithelial-mesenchymal transition (EMT) and stemness markers, consistent with dedifferentiation. Notably, tumors harboring secondary mutations to EGFR, MET, or other MAPK pathway genes and showing sustained MAPK signaling retained a more differentiated state. Patients lacking these secondary on-target or bypass mutations were more likely to experience relapse with histological transdifferentiation, marked by complete loss of LUAD signatures, and accompanying increases in LUSC or SCLC signatures. Phenotype matching of tumor cells to normal cells from the developing fetal lung revealed enrichment of airway progenitor populations in non-histologically transformed treatment-resistant patients, in contrast to a proportion of late bud-tip and club-like epithelial cells which predominated in treatment-naïve samples. In rare cases, we observed subpopulations of basal stem-like progenitors in otherwise well-differentiated pre-treatment tumors. In summary, single-cell mapping of histological and developmental phenotypes has revealed divergent evolutionary trajectories during the acquisition of resistance to osimertinib, defined by MAPK signaling reactivation or by loss of LUAD identity and histological transformation respectively. Citation Format: Matthew Zatzman, Alvaro Quintanal-Villalonga, Sohrab Salehi, Christina Falcon, Nicholas Ceglia, Sohrab P. Shah, Charles M. Rudin, Helena A. Yu. Genomically encoded lineage plasticity drives resistance to EGFR targeted therapy in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1226.

13P Tislelizumab (TIS) plus chemotherapy (chemo) with or without bevacizumab (beva) for patients with EGFR-mutated nonsquamous non-small cell lung cancer (nsq-NSCLC) after progression on EGFR tyrosine kinase inhibitor (TKI) therapy

13P Tislelizumab (TIS) plus chemotherapy (chemo) with or without bevacizumab (beva) for patients with EGFR-mutated nonsquamous non-small cell lung cancer (nsq-NSCLC) after progression on EGFR tyrosine kinase inhibitor (TKI) therapy