Positive Non-small Cell Lung Cancer Patients Research Articles

Chinese Expert Consensus on the Standardized Diagnosis and Treatment of Non‑small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations (2024 Edition)

The standard clinical practice of managing the non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations was elaborated in Chinese expert consensus on non‑small cell lung cancer with EGFR exon 20 insertion mutations (2023 edition), and this rare subset has gradually attracted attention recently. With the deepening of treatment area exploration and the approval of new targeted drugs, there are more options for the diagnosis and treatment of EGFR ex20ins positive NSCLC patients. Therefore, based on the previous version of consensus, the expert panel has updated this consensus on the standardized clinical diagnosis and treatment of EGFR ex20ins mutation NSCLC through reference to literature and clinical data, and combined with the experts' own clinical experience. The updated recommendations includes disease congnition, testing methods, therapy and recent relevant clinical trials for NSCLC patients with EGFR ex20ins mutation, in order to provide better medication reference for clinical physicians. .

Machine learning-based radiomics strategy for prediction of acquired EGFR T790M mutation following treatment with EGFR-TKI in NSCLC

The epidermal growth factor receptor (EGFR) Thr790 Met (T790M) mutation is responsible for approximately half of the acquired resistance to EGFR-tyrosine kinase inhibitor (TKI) in non-small-cell lung cancer (NSCLC) patients. Identifying patients at diagnosis who are likely to develop this mutation after first- or second-generation EGFR-TKI treatment is crucial for better treatment outcomes. This study aims to develop and validate a radiomics-based machine learning (ML) approach to predict the T790M mutation in NSCLC patients at diagnosis. We collected retrospective data from 210 positive EGFR mutation NSCLC patients, extracting 1316 radiomics features from CT images. Using the LASSO algorithm, we selected 10 radiomics features and 2 clinical features most relevant to the mutations. We built models with 7 ML approaches and assessed their performance through the receiver operating characteristic (ROC) curve. The radiomics model and combined model, which integrated radiomics features and relevant clinical factors, achieved an area under the curve (AUC) of 0.80 (95% confidence interval [CI] 0.79–0.81) and 0.86 (0.87–0.88), respectively, in predicting the T790M mutation. Our study presents a convenient and noninvasive radiomics-based ML model for predicting this mutation at the time of diagnosis, aiding in targeted treatment planning for NSCLC patients with EGFR mutations.

Early Onset Pulmonary Events and Management Strategies during the Treatment of ALK Positive NSCLC Patients with Brigatinib

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase and its rearrangements occur in non-small cell lung cancer (NSCLC), resulting in signal dysregulation in kinase domain. As a new generation of potent ALK tyrosine kinase inhibitors (TKIs), Brigatinib was approved in China in March 2022 as a treatment for locally advanced or metastatic NSCLC patients with ALK rearrangement positive. Brigatinib significantly improved the survival, cranial efficacy and quality of life compared to Crizotinib in clinical trials. Brigatinib is generally well tolerated. Brigatinib has been one of the preferred treatments and an addition of options in ALK-rearranged NSCLC. Pulmonary toxicity is one of the adverse effects observed during the treatment of TKIs and deserves the intense attention of clinicians, despite of its low incidence rate. Pulmonary toxicity reported during the treatment of Brigatinib has shown distinct clinical presentations, such as early-onset (median time to onset, 2 days) and rapid tolerance and reversibility of symptoms. In view of this, the concept of early-onset pulmonary events (EOPEs) was proposed and established during the submission for regulatory review and approval. We focused on clinical characteristics, potential mechanism of etiology, and management strategies of EOPEs to provide clinicians evidence for better clinical decision support. .

A Small Molecule Targeting the Intracellular Tyrosine Kinase Domain of ROR1 (KAN0441571C) Induced Significant Apoptosis of Non-Small Cell Lung Cancer (NSCLC) Cells.

The ROR1 receptor tyrosine kinase is expressed in embryonic tissues but is absent in normal adult tissues. ROR1 is of importance in oncogenesis and is overexpressed in several cancers, such as NSCLC. In this study, we evaluated ROR1 expression in NSCLC patients (N = 287) and the cytotoxic effects of a small molecule ROR1 inhibitor (KAN0441571C) in NSCLC cell lines. ROR1 expression in tumor cells was more frequent in non-squamous (87%) than in squamous (57%) carcinomas patients, while 21% of neuroendocrine tumors expressed ROR1 (p = 0.0001). A significantly higher proportion of p53 negative patients in the ROR1+ group than in the p53 positive non-squamous NSCLC patients (p = 0.03) was noted. KAN0441571C dephosphorylated ROR1 and induced apoptosis (Annexin V/PI) in a time- and dose-dependent manner in five ROR1+ NSCLC cell lines and was superior compared to erlotinib (EGFR inhibitor). Apoptosis was confirmed by the downregulation of MCL-1 and BCL-2, as well as PARP and caspase 3 cleavage. The non-canonical Wnt pathway was involved. The combination of KAN0441571C and erlotinib showed a synergistic apoptotic effect. KAN0441571C also inhibited proliferative (cell cycle analyses, colony formation assay) and migratory (scratch wound healing assay) functions. Targeting NSCLC cells by a combination of ROR1 and EGFR inhibitors may represent a novel promising approach for the treatment of NSCLC patients.

Prognostic value of CYFRA 21 − 1 and Ki67 in advanced NSCLC patients with wild-type EGFR

BackgroundThe prognostic value of cytokeratin 19 fragment (CYFRA 21 − 1) and Ki67 in advanced non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor (EGFR) remains to be explored.MethodsIn this study, 983 primary NSCLC patients from January 2016 to December 2019 were retrospectively reviewed. Finally, 117 advanced NSCLC patients with wild-type EGFR and 37 patients with EGFR mutation were included and prognostic value of CYFRA 21 − 1 and Ki67 were also identified.ResultsThe patients age, smoking history and the Eastern Corporative Oncology Group (ECOG) performance scores were significantly different between CYFRA21-1 positive and negative groups (p < 0.05), while no significant differences were found in Ki67 high and low groups. The results of over survival (OS) demonstrated that patients with CYFRA21-1 positive had markedly shorter survival time than CYFRA21-1 negative (p < 0.001, For whole cohorts; p = 0.002, For wild-type EGFR). Besides, patients with wild-type EGFR also had shorter survival times than Ki67 high group. Moreover, In CYFRA 21 − 1 positive group, patients with Ki67 high had obviously shorter survival time compared to patients with Ki67 low (median: 24vs23.5 months; p = 0.048). However, Ki67 could not be used as an adverse risk factor for patients with EGFR mutation. Multivariate cox analysis showed that age (HR, 1.031; 95%CI, 1.003 ~ 1.006; p = 0.028), Histopathology (HR, 1.760; 95%CI,1.152 ~ 2.690; p = 0.009), CYFRA 21 − 1 (HR, 2.304; 95%CI,1.224 ~ 4.335; p = 0.01) and Ki67 (HR, 2.130; 95%CI,1.242 ~ 3.652; p = 0.006) served as independent prognostic risk factor for advanced NSCLC patients.ConclusionsOur finding indicated that CYFRA 21 − 1 was an independent prognostic factor for advanced NSCLC patients and Ki67 status could be a risk stratification marker for CYFRA 21 − 1 positive NSCLC patients with wild-type EGFR.

Savolitinib versus crizotinib for treating MET positive non-small cell lung cancer.

The c-MET protein, encoded by the mesenchymal-epithelial transition factor (MET) gene, can regulate cell proliferation, migration and invasion. Studies have shown that it is one of the essential driver genes for non-small cell lung cancer (NSCLC). Currently, several clinical studies have carried out objective assessments on the efficacy and safety of different types of MET tyrosine kinase inhibitors (TKIs). However, direct cross-sectional comparisons between different agents are still not available. Our study was a single-center retrospective clinical study, which collected the data from MET positive NSCLC patients treated with MET TKIs at the Lung Cancer Center of Peking Union Medical College Hospital. We explored the efficacy and safety of crizotinib versus savolitinib in patients with METex14 skipping and MET amplification, separately. Patients with METex14 skipping (median PFS=10.7months) had a better clinical response to MET TKIs than MET amplification patients (median PFS=4.1months). In the METex14 skipping subgroup, savolitinib did not show better survival benefit with significance than crizotinib (p > 0.05). In the MET amplification subgroup, savolitinib (median PFS=7.1months) demonstrated a better progression-free survival benefit than crizotinib (median PFS=1.4months), p=0.05. The most common adverse effects of both MET TKIs were peripheral edema (41.2%), gastrointestinal reactions (23.5%), and liver injury (14.7%). The incidence rate of peripheral edema was higher in savolitinib than crizotinib. In METex14 skipping NSCLC patients,the efficacy of savolitinib and crizotinib did not show significant difference. In MET amplification patients, savolitinib showed better efficacy than crizotinib.

A Real-world Study on the Expression Characteristics of PD-L1 in Patients with Advanced EGFR Positive NSCLC and Its Relationship with the Therapeutic Efficacy of EGFR-TKIs

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the first choice for first-line treatment of advanced patients with EGFR positive non-small cell lung cancer (NSCLC). For advanced NSCLC patients with negative drive gene and positive programmed cell death ligand 1 (PD-L1) or highly expressed NSCLC patients, the first-line treatment recommends immune checkpoint inhibitors (ICIs) monotherapy or ICIs combined chemotherapy. Therefore, the first-line treatment strategy for advanced NSCLC patients with EGFR positive at different PD-L1 expression levels is worth further exploring. Many previous studies have suggested that the expression of PD-L1 is obviously affected by EGFR mutation, and the expression of PD-L1 is likely to be related to the mechanism of EGFR-TKIs resistance. The purpose of this study was to analyze the expression characteristics of PD-L1 in patients with advanced EGFR positive NSCLC and its relationship with the efficacy of EGFR-TKIs. 159 patients with newly diagnosed advanced NSCLC with EGFR positive (including 141 patients with EGFR sensitive mutations) were enrolled to analyze the relationship between clinicopathological characteristics and PD-L1 expression. The factors affecting the therapeutic effect of EGFR-TKIs in 141 patients with EGFR sensitive mutations were also explored. The PD-L1 expression of the included patients was classified according to the tumor promotion score (TPS): negative (TPS<1%) accounted for 47.2%, low expression (1%≤TPS<50%) accounted for 32.1%, and high expression (TPS≥50%) accounted for 20.7%. Among them, patients with solid predominant cancer cell pathomorphology classification are more likely to have high expression of PD-L1, accounting for 52.9% (P<0.0001). The median progression-free survival (mPFS) of patients with PD-L1 negative expression, low expression and high expression who received first generation EGFR-TKIs treatment were 12.4 months, 10.5 months and 3.7 months, respectively, with significant statistical difference (P<0.0001). During the EGFR-TKIs treatment, patients with a history of radiotherapy for lung lesions have a longer PFS benefit than those without a history of radiotherapy (mPFS: 17.0 months vs 9.3 months, P<0.0001). The expression level of PD-L1 in advanced EGFR positive NSCLC patients was significantly correlated with the pathomorphology classification of cancer cells. The efficacy of EGFR-TKIs in patients with PD-L1 overexpression NSCLC was significantly poor. PFS can be significantly prolonged during targeted therapy combined with radiotherapy of lung lesions.

Efficacy and safety of original EGFR-TKI combined with bevacizumab in advanced lung adenocarcinoma patients harboring EGFR-mutation experiencing gradual progression after EGFR-TKI treatment: a single-arm study.

Keeping on original epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment is the standard treatment for gradual progression EGFR-positive metastatic non-small cell lung cancer (NSCLC). Angiogenic pathway can lead to EGFR-TKI resistance, but the effectiveness of combination strategies in this group is still controversial. This study aimed to assess the efficacy and safety of the original EGFR-TKI combined with bevacizumab in advanced and metastatic lung adenocarcinoma patients harboring EGFR-mutation who experience gradual progression in a real-world setting. From June 2019 to December 2021, a total of 35 metastatic EGFR positive NSCLC patients experienced gradual progression after EGFR-TKI treatments and received original TKI combined with bevacizumab were identified at Chongqing University Cancer Hospital, China. All patients were confirmed EGFR positive by rebiopsy before treatment. Patients were treated with EGFR-TKI and bevacizumab (15 mg/kg Q3W) after gradual progression until rapid progression or intolerable toxicity. The overall survival (OS), progression-free survival 1 (PFS1, period from the beginning of EGFR-TKI treatment to the rapid progression of the disease), PFS2 (period from the beginning of EGFR-TKI combined with bevacizumab treatment to the rapid progression of the disease), disease control rate (DCR), and adverse events of the combined treatment were collected and analyzed. A total of 33 patients could participate the efficacy evaluation. Median PFS1 and PFS2 were 20.5 and 8 months, respectively; DCR was 93.94%; median OS was immature. Multivariate Cox proportional hazards model showed that smoking status [hazard ratio (HR) =3.692, 95% confidence interval (CI): 1.450-9.404, P=0.006], combined EGFR T790M mutation or rare mutation (HR =2.480, 95% CI: 1.073-5.729, P=0.034), and malignant pleural effusion (HR =3.707, 95% CI: 1.460-9.414, P=0.006) were independent risk factors for PFS2. The most common treatment-related adverse events greater than grade 3 included hypertension (23.7%), proteinuria (8.3%), and increased alanine aminotransferase (ALT; 4.1%) and aspartate aminotransferase (AST; 2.9%). Continuous original TKI combined with bevacizumab showed partly favorable efficacy and safety and may represent a therapeutic option for metastatic EGFR-mutation NSCLC patients experiencing gradual progression after EGFR-TKI treatment.

CNS Outcomes in ALK Fusion Positive NSCLC Patients with BM Who Received Alectinib with or without Local Therapy

<h3>Purpose/Objective(s)</h3> Brain metastases (BM) are common in patients (pts) with anaplastic lymphoma kinase (<i>ALK</i>) fusion positive non-small cell lung cancer (NSCLC). <i>ALK</i>-rearrangements are observed in approximately 5% of NSCLC patients. Alectinib is a highly selective, central nervous system (CNS)-penetrant tyrosine kinase inhibitor which may allow patients with BMs to defer local therapy (LT) such as surgery, stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT). We characterized the CNS outcomes in pts with <i>ALK</i> fusion positive NSCLC BM treated with alectinib with or without LT. <h3>Materials/Methods</h3> We retrospectively reviewed <i>ALK</i> fusion-positive NSCLC pts with BMs who received alectinib at the diagnosis of BM from 1/2012 and 5/2021. CNS response rates (RR) were assessed via modified Response Assessment in Neuro-Oncology (RANO)-BM criteria. Surgically resected lesions were excluded from this analysis. A complete response (CR) was defined as complete disappearance of the lesion and a partial response (PR) was defined as a >30% decrease in size relative to baseline. Intracranial progression (iPFS) was analyzed using the Kaplan-Meier (KM) method with log-rank test, with death factored in as a competing risk. <h3>Results</h3> We identified 39 pts with <i>ALK</i> fusion positive NSCLC who initiated alectinib at BM diagnosis: 27 pts received alectinib only and 12 pts received alectinib and upfront LT including surgical resection (<i>n</i> = 2, 17%), comprehensive surgical resection followed by SRS (<i>n</i> = 2, 17%), SRS 4 (<i>n</i> = 4, 33%) or WBRT (<i>n</i> = 4; 33%). Alectinib was first-line therapy for 26 (67%) pts and second-line therapy for 12 (31%) pts. Median follow-up from BM diagnosis was 50.6 months (IQR 33.3-56.7). Patients treated with alectinib and LT were more likely to have pre-treatment neurologic symptoms (83% vs 33%), larger median BM size (median 12 mm vs 5 mm), and BM > 1 cm in size (83% vs 30%) compared to pts who received alectinib only. Despite these negative factors, there were no differences between both groups with regards to iPFS (TKI only, HR 1.31, 95% CI 0.55-3.11; p=0.54). A total of 28 and 55 lesions were assessed for CNS RR in the alectinib + LT and alectinib only groups, respectively. At 6-months, the CNS RR were 46% (PR) and 54% (CR) vs. 19% (PR) and 74% (CR) in the alectinib + LT and alectinib only groups, respectively. <h3>Conclusion</h3> To our knowledge, this study represents the largest yet reported series of alectinib-treated NSCLC BM with detailed patient and lesion-level CNS-specific outcomes. Despite the fact that patients with <i>ALK</i> fusion positive NSCLC treated with alectinib + LT had larger BM and a greater likelihood of pre-treatment neurologic symptoms, the iPFS was similar between the patients treated with alectinib only and alectinib + LT. With newer generation TKIs which may have CNS penetrance, further prospective studies are required to identify which patients are most likely to benefit from the addition of LT to <i>ALK</i>-directed therapy.

Correlation Study on the Expression of INSR, IRS-1, and PD-L1 in Nonsmall Cell Lung Cancer.

Objective To study the expression and correlation of insulin receptor (INSR), insulin receptor substrate-1 (IRS-1), and programmed cell death ligand-1 (PD-L1) in nonsmall cell lung cancer (NSCLC). Methods 45 lung cancer tissues and 30 adjacent normal tissues of NSCLC patients diagnosed in the Second Affiliated Hospital of Shandong First Medical University from June 2019 to August 2020 were selected. The expressions of INSR, IRS-1, and PD-L1 proteins in tumor tissues and adjacent tissues of NSCLC were detected by immunohistochemical staining. Results The expression of INSR and IRS-1 in NSCLC was significantly higher than that in adjacent normal lung tissue (P < 0.05). INSR expression had statistical significance with the degree of pathological differentiation of nonsmall cell carcinoma (P = 0.031), but had no significant association with age, gender, pathological type, TNM stage, and lymph node metastasis status (P > 0.05). There was no significant correlation between IRS-1 positive expression and NSCLC patients' age, gender, pathological typing, degree of differentiation, TNM stage, and lymph node metastasis (P > 0.05). PD-L1 positive expression was correlated with lymph node metastasis of NSCLC (P = 0.028), while there was no significant correlation with gender, age, pathological type, TNM stage, and pathological differentiation degree of NSCLC patients (P > 0.05). Spearman correlation analysis showed that PD-L1 protein expression had a significant positive correlation with IRS-1 protein expression (r = 0.373), but was not correlated with the expression of INSR protein. Conclusion IRS-1 may be involved in the regulation of PD-L1 expression and mediate the occurrence of tumor immune escape, which is expected to become a new target for NSCLC immunotherapy and provide new clinical evidence for immunosuppressive therapy.

Evaluation of the Molecular Landscape in PD-L1 Positive Metastatic NSCLC: Data from Campania, Italy.

Background: Immune-checkpoint inhibitors (ICIs) have increased and improved the treatment options for patients with non-oncogene-addicted advanced stage non-small cell lung cancer (NSCLC). However, the role of ICIs in oncogene-addicted advanced stage NSCLC patients is still debated. In this study, in an attempt to fill in the informational gap on the effect of ICIs on other driver mutations, we set out to provide a molecular landscape of clinically relevant oncogenic drivers in programmed death-ligand 1 (PD-L1) positive NSCLC patients. Methods: We retrospectively reviewed data on 167 advanced stage NSCLC PD-L1 positive patients (≥1%) who were referred to our clinic for molecular evaluation of five driver oncogenes, namely, EGFR, KRAS, BRAF, ALK and ROS1. Results: Interestingly, n = 93 (55.7%) patients showed at least one genomic alteration within the tested genes. Furthermore, analyzing a subset of patients with PD-L1 tumor proportion score (TPS) ≥ 50% and concomitant gene alterations (n = 8), we found that n = 3 (37.5%) of these patients feature clinical benefit with ICIs administration, despite the presence of a concomitant KRAS gene alteration. Conclusions: In this study, we provide a molecular landscape of clinically relevant biomarkers in NSCLC PD-L1 positive patients, along with data evidencing the clinical benefit of ICIs in patient NSCLC PD-L1 positive alterations.

Abstract 1097: First-line therapy based on kinase inhibitors and antibodies prevents resistance in EGFR-mutated lung cancer

Abstract Introduction: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are commonly used to treat patients with EGFR+ non-small cell lung cancer (NSCLC). Unfortunately, despite the initial response, the long-term efficacy of the five clinically approved TKIs (i.e., gefitinib, erlotinib, afatinib, dacomitinib, osimertinib) is limited by the onset of resistance. Several mechanisms of resistance have been described, including the appearance of new EGFR mutations (e.g., T790M, C797S), activation of bypass pathways (e.g., AXL, HER2, MET and IGF1R) and phenotypic alterations (e.g., epithelial to mesenchymal transition, EMT). Additionally, in vitro treatment using EGFR TKIs leads to the establishment of drug tolerant persisters (DTPs), a cell population that might be responsible for the onset of resistance. In order to prevent resistance, the data we present herein propose to simultaneously target EGFR and other survival receptors (e.g., HER2 or HER3) by combining TKIs and specific monoclonal antibodies. Materials and methods: Cultures of NSCLC cell lines, patient-derived and cell line xenografts were employed to test the efficacy of the drug combinations. In parallel, to better understand resistance to EGFR-TKIs we established NSCLC dacomitinib resistant (DR) cell lines that were used in vivo and in vitro. Results: DR cells showed upregulation of AXL and IGF1R, features shared with the persister cells. We also demonstrate that combining TKIs and monoclonal antibodies successfully prevented TKI acquired resistance, by downregulating receptor kinases previously implicated in resistance to TKIs (e.g., MET and AXL), as well as by blocking pathways essential for mitosis (e.g., FOXM1). Conclusions: Combining kinase inhibitors and antibodies in first line settings effectively avoids TKI resistance in animal models of lung cancer and might represent a long-term solution for EGFR positive NSCLC patients. Citation Format: Ilaria Marrocco, Yuya Haga, Yosef Yarden. First-line therapy based on kinase inhibitors and antibodies prevents resistance in EGFR-mutated lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1097.

The efficacy and safety of taletrectinib in patients with TKI-naïve or crizotinib-pretreated ROS1-positive non–small cell lung cancer (NSCLC).

8572 Background: Taletrectinib (AB-106 / DS-6051b) is a next-generation, potent, CNS- penetrant, selective ROS1 tyrosine kinase inhibitor. The ongoing TRUST study (NCT04395677) is a multicenter, open-label, single-arm, Phase 2 study of taletrectinib in Chinese ROS1-positive NSCLC patients who are TKI -naïve or crizotinib-pretreated. Here we present the updated efficacy and safety results of the study. Methods: The eligible ROS1-positive NSCLC patients were enrolled into either TKI-naïve or crizotinib-pretreated cohorts, and treated with taletrectinib 600mg once daily. The study endpoints included overall response rate (ORR), duration of response (DOR), disease control rate (DCR), overall intracranial response rate (IC-ORR), progression-free survival (PFS), and safety profile. Results: As of the data cutoff date of September 7, 2021, 61 of the 86 stage IV patients enrolled in the study have at least three postbaseline tumor assessment of which 40 patients in the TKI-naïve cohort, and 21 patients in the crizotinib-pretreated cohort (50% patients having at least one prior chemotherapy). In the TKI -naïve cohort, the confirmed ORR by investigators per RECIST 1.1 was 90.0%: [95%CI: 76.3%; 97.2%] (36/40); and the DCR was 95% [95%CI: 83.1%; 99.4%] (38/40). In the crizotinib-pretreated cohort, the confirmed ORR by investigators was 47.6% [95%CI: 25.7%; 70.2%] (10/21); and DCR was 76.2%: [52.8%; 91.8%] (16/21). The mDOR and mPFS are not reached yet for both cohorts. Of 6 patients having brain metastasis and measurable target brain lesions at baseline, the intracranial ORR and IC-DCR were 83.3% and 100%, respectively. Of 4 patients with ROS1 G2032R mutation, 3 patients achieved partial response (PR), and 1 patient achieved stable disease (SD). The most common treatment-related adverse events (TRAEs) include diarrhea, nausea, vomiting, transaminase elevation, anemia, neutrophil count decrease, etc. were Grade 1 or 2, and the most common AEs (below 10%) were ALT/AST increased but reversible. Conclusions: Taletrectinib demonstrated meaningful clinical efficacy in both TKI-naïve and crizotinib-pretreated ROS1 positive NSCLC patients. In particular, taletrectinib showed clinical effectiveness in patients with ROS1 secondary G2032 mutations and patients with brain metastasis. Taletrectinib was well tolerated in this patient population. Clinical trial information: NCT04395677.

Effect of EGFR amplification on survival of patients with EGFR mutation-positive non-small cell lung cancer.

e21000 Background: Epidermal growth factor receptor (EGFR) mutation is a common mutation in non-small cell lung cancer (NSCLC). Patients with EGFR mutation generally respond well to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). EGFR mutation are often co-occurring with EGFR amplification. However, the effect of EGFR amplification on the survival of patients with EGFR mutations remained unclear. Methods: Treatment-naïve adult patients with advanced NSCLC and EGFR mutation confirmed by next generation sequencing (NGS) at Fujian Provincial Hospital between April 2017 and October 2021 were enrolled in this retrospective clinical study. The patients’ clinical characteristics, gene mutations, treatment and clinical outcomes were extracted. progression-free survival (PFS) and overall response rate (ORR) were compared between EGFR amplification and non-EGFR amplification groups using the Kaplan-Meier method and log-rank test. Results: EGFR amplification and non-EGFR amplification were identified in 55 patients (36.67%) and 95 patients (63.33%), and there were no significant differences in clinical characteristics. No significant differences between the EGFR amplification and non-EGFR amplification groups in median PFS (247 vs. 214 days, P = 0.605). The ORR in EGFR amplification group is higher than non-EGFR amplification group (60.87% vs 32.69%). Conclusions: There is a tendency that EGFR amplification might not be a well predictor in EGFR mutation positive NSCLC patients treated with EGFR-TKIs.

Elevated expression of miR-494-3p is associated with resistance to osimertinib in EGFR T790M-positive non-small cell lung cancer

BackgroundNon-small cell lung cancer (NSCLC) harboring activating mutations in the gene encoding epidermal growth factor receptor (EGFR) is amenable for targeted therapy with tyrosine kinase inhibitors (TKIs). Eventually, resistance to TKI-therapy occurs resulting in disease progression. A substantial fraction of resistance mechanisms is unknown and may involve alterations in the RNA or protein landscape. MicroRNAs (miRNAs) have been frequently suggested to play roles in various forms of cancer including NSCLC. However, a role of miRNAs in acquired resistance to EGFR TKIs remains elusive. In this work, we aimed to investigate the potential involvement of miRNAs in acquired resistance to the third-generation EGFR TKI osimertinib in NSCLC.MethodsWe combined miRNA expression profiling with miRNA-inhibitory screening to identify miRNAs involved in conferring resistance to osimertinib. Finally, we validated our top miRNA candidate by profiling longitudinal plasma exosomal RNA from patients receiving osimertinib as second-line therapy in a clinical trial.ResultsVarious miRNAs displayed differential expression in parental versus osimertinib-refractory NSCLC cells. miRNA-inhibitory screening revealed miR-494-3p to partially confer resistance to osimertinib in vitro. Expression of miR-494-3p was significantly elevated in plasma sampled at disease progression compared to plasma sampled at treatment baseline in a cohort of 21 EGFR T790M-mutation positive NSCLC patients receiving osimertinib.ConclusionsOur results highlight the need for further therapeutic exploration of miR-494-3p in in vivo models of EGFR-mutant NSCLC.

A Randomized, Open-Label Phase II Study Evaluating Emibetuzumab Plus Erlotinib and Emibetuzumab Monotherapy in MET Immunohistochemistry Positive NSCLC Patients with Acquired Resistance to Erlotinib

IntroductionThe hepatocyte growth factor receptor MET represents a resistance mechanism to epidermal growth factor receptor (EGFR) inhibition in EGFR mutant (mt) non–small cell lung cancer (NSCLC). This Phase 2 study tested whether acquired resistance to erlotinib in MET protein positive NSCLC patients enriched for EGFRmt can be overcome by emibetuzumab plus erlotinib. Patient and MethodsPatients with Stage IV NSCLC with acquired resistance to erlotinib and MET diagnostic (+) (≥ 10% of cells expressing MET at ≥ 2+ IHC staining intensity at any time) were randomized (3:1) to receive emibetuzumab 750 mg every 2 weeks with or without erlotinib 150 mg once daily. The primary objective was to evaluate the overall response rate (ORR) relative to historic control, with a co-primary objective of ORR in patients with MET expression in ≥ 60% of cells ≥ 2+ (MET ≥ 60%). ResultsOne hundred and eleven MET+ patients received emibetuzumab plus erlotinib (N = 83) or emibetuzumab monotherapy (N = 28). 89 of 111 MET+ samples were post-erlotinib. ORR was 3.0% for emibetuzumab plus erlotinib (95% CI: 0.4, 10.5) and 4.3% for emibetuzumab (95% CI: 0.1, 21.9), in patients with post-erlotinib progression biopsies available (n = 89). Similar results were observed in patients with MET ≥ 60% expression (n = 74). Disease control rate and progression-free survival were higher for emibetuzumab plus erlotinib (50%/3.3 months) than for emibetuzumab (26%/1.6 months). No unexpected safety signals emerged. Partial responses were observed in patients with and without EGFRmt or MET amplification. EGFR sensitizing mutations were identified retrospectively in 84.2% of those with available tissue (85/101). ConclusionAcquired resistance to erlotinib in MET diagnostic (+) patients was not reversed by emibetuzumab plus erlotinib or emibetuzumab monotherapy, although a subset of patients obtained clinical benefit.

Molecular Testing and Treatment Strategies in RET-Rearranged NSCLC Patients: Stay on Target to Look Forward

RET alterations are recognized as key oncogenic drivers in different cancer types, including non-small cell lung cancer (NSCLC). Multikinase inhibitors (MKIs) with anti-RET activities resulted in variable efficacy with significant toxicities because of low target specificity. Selective RET kinase inhibitors, such as pralsetinib and selepercatinib, demonstrated high efficacy and favorable tolerability in advanced RET-rearranged NSCLC patients, leading to their introduction in the clinical setting. Among the different approaches available for the identification of RET rearrangements, next-generation sequencing (NGS) assays present substantial advantages in terms of turnaround time and diagnostic accuracy, even if potentially limited by accessibility issues. The recent advent of novel effective targeted therapies raises several questions regarding the emergence of resistance mechanisms and the potential ways to prevent/overcome them. In this review, we discuss molecular testing and treatment strategies to manage RET fusion positive NSCLC patients with a focus on resistance mechanisms and future perspectives in this rapidly evolving scenario.

Short communication: The activity of brigatinib in patients with disease progression after next generation anaplastic lymphoma tyrosine kinase inhibitors and an exploratory analysis of circulating tumor DNA

BackgroundBrigatinib, a second generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is central nervous system (CNS) penetrant and active against anaplastic lymphoma kinase (ALK) resistance mutations. We prospectively studied the activity of brigatinib in patients with disease progression after second generation ALK TKIs. MethodsPatients with stage IIIB/IV ALK + non-small cell lung cancer (NSCLC), and progressive disease after second ALK TKIs were eligible. Cohort A enrolled patients with disease progression on any second ALK TKI, cohort B enrolled patients with disease progression after first-line therapy with alectinib, and cohort C enrolled patients who experienced disease progression on standard dose brigatinib. Brigatinib treatment was 90 mg daily for seven days and then escalated to 180 mg daily in cohorts A and B, and 240 mg daily in cohort C. The primary endpoint was objective response rate (ORR), and a 2-stage design was used. The intended enrollment was 20 patients in stage 1, and 20 patients in stage 2. ResultsThe study was closed due to slow accrual. Between March 2017 and June 2020, 32 patients received study therapy; three patients in cohort A moved to cohort C after initial progression for a total of 35 study subjects. Of the 32 patients, 16 (50%) were male, the median age was 55 years (range 32–76), and patients received a median number of 2 prior ALK TKI’s (range 1–3). Cohort A enrolled 27 patients, cohort B enrolled four patients, and cohort C enrolled four patients. The ORR in cohorts A, B, and C was 33% (95% confidence interval (CI: 16% to 54%), 25% (95% CI: 0.63% to 81%), and 0%, respectively. ConclusionBrigatinib has activity in ALK positive NSCLC patients with disease progression after second generation ALK TKIs.

Evaluation of Pembrolizumab Monotherapy Efficacy in Advanced Non-Small-Cell Lung Cancer by Serial Monitoring of Circulating Tumor DNA Using Next-Generation Sequencing.

Introduction:Pembrolizumab is widely used in advanced non-small-cell lung cancer (NSCLC) patients with positive programmed death-ligand 1 (PD-L1). However, efficacy evaluation along treatment by serial monitoring of circulating tumor DNA (ctDNA) using next-generation sequencing remained to be well studied.Methods:Nine PD-L1 positive advanced NSCLC patients were prospectively enrolled and received pembrolizumab monotherapy. Pretreatment tissue and/or plasma samples were collected as baseline reference. Serial plasma samples were collected after 3 and 6 weeks of treatment as well as at disease progression. All samples underwent targeted next-generation sequencing.Results:The median progression-free survival (mPFS) and median overall survival (mOS) were 4.43 and 25.53 months, respectively. In total, 3 patients achieved partial response (PR) or stable disease (SD) for more than 6 months and were thus classified into the durable clinical benefit (DCB) group, whereas the rest 6 were grouped as nondurable benefit (NDB) patients. Molecular profiling of baseline samples revealed that TP53 and APC were the 2 most frequently mutated genes in all patients, whereas POT1 and SETD2 mutations were enriched in DCB and NDB groups, respectively. Higher tumor mutational burden (TMB) was observed in DCB patients than NDB group. During serial ctDNA monitoring, 2 DCB patients showed a dramatic ctDNA reduction while 75% of NDB patients’ ctDNA concentration increased at week 6. Several acquired mutations might contribute to the pembrolizumab resistance, including CDKN2A frameshift and MITF nonsense mutations.Conclusions:Genomic profiling of peripheral blood samples can be applied to dynamically monitor disease progression. The reduction in ctDNA concentration during treatment implied DCBs.

P45.04 Phase II Study of Brigatinib in ROS1 Positive Non-Small Cell Lung Cancer (NSCLC) Patients Previously Treated with Crizotinib: Barossa Cohort 2

Brigatinib is a next-generation tyrosine kinase inhibitor targeting ALK and ROS1. Crizotinib is the first drug approved for the treatment of ROS1 fusion-positive NSCLC. Standard treatment for crizotinib-resistant ROS1 positive NSCLC is not established. Barossa is a multicenter, phase II basket study of brigatinib in patients with ROS1 positive solid tumors. This study is composed of three cohorts. ROS1 inhibitor-naïve ROS1 positive NSCLC patients were enrolled in the cohort 1, and ROS1 positive NSCLC patients previously treated with crizotinib were enrolled in the cohort 2.