RESUMEN
BACKGROUND: In the initial analysis of a pivotal phase 2 single-arm study (NCT03861156), befotertinib (D-0316) showed clinical benefit with a manageable safety profile in pretreated patients with EGFR T790M mutated non-small cell lung cancer (NSCLC), including those with brain metastases. METHODS: Eligible patients received oral befotertinib of 50 mg (cohort A) or 75-100 mg (cohort B) once daily until disease progression, withdrawal of informed consent, or death. The primary endpoint for the initial analysis was objective response rate (ORR) assessed by an independent review committee. OS and safety were secondary endpoints. Herein, we present the final OS and safety data. RESULTS: A total of 176 patients in cohort A and 290 patients in cohort B were finally enrolled. At data cutoff (May 31, 2023), the median duration of follow-up was 47.9 months (95 % CI: 47.1-48.3) in cohort A and 36.7 months (35.9-37.9) in cohort B. The median OS was 23.9 months (95 % CI: 21.1-27.2) in cohort A and 31.5 months (26.8-35.3) in cohort B. The median OS for patients with and without brain metastasis in cohort A was 18.6 months (95 % CI: 14.9-26.3) and 26.4 months (95 % CI: 23.0-29.0), respectively. In cohort B, these data was 23.0 months (95 % CI: 18.6-29.1) and 35.5 months (95 % CI: 29.3-NE), respectively. The safety profile of befotertinib remained consistent with previous data. Grade 3 or higher treatment-emergent adverse events were 38.1 % in the cohort A and 50.3 % in the cohort B, and 22.2 % and 31.7 % were related to the study drug. CONCLUSION: Befotertinib demonstrated a more profound OS benefit compared to other 3rd-generation EGFR TKI, despite that cross trial data comparison should be interpreted with caution. The safety profile was manageable and consistent with previously report data in pretreated patients with confirmed T790M mutation-positive NSCLC.
RESUMEN
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths and represents a substantial disease burden worldwide. Immune checkpoint inhibitors combined with chemotherapy are the standard first-line therapy for advanced NSCLC without driver mutations. Programmed death-ligand 1 (PD-L1) is currently the only approved immunotherapy marker. PD-L1 detection methods are diverse and have developed rapidly in recent years, such as improved immunohistochemical detection methods, the application of liquid biopsy in PD-L1 detection, genetic testing, radionuclide imaging, and the use of machine learning methods to construct PD-L1 prediction models. This review focuses on the detection methods and challenges of PD-L1 from different sources, and discusses the influencing factors of PD-L1 detection and the value of combined biomarkers. Provide support for clinical screening of immunotherapy-advantage groups and formulation of personalized treatment decisions.
Asunto(s)
Antígeno B7-H1 , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , Inmunoterapia , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Inmunoterapia/métodos , Biomarcadores de Tumor/análisis , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , InmunohistoquímicaRESUMEN
Tumor mutational burden (TMB) and T-cell receptor (TCR) might predict the response to immunotherapy in patients with non-small cell lung cancer (NSCLC). However, the predictive value of the combination of TMB and TCR was not clear. Targeted DNA and TCR sequencing were performed on tumor biopsy specimens. We combined TMB and TCR diversity into a TMB-and-TCR (TMR) score using logistic regression. In total, 38 patients with advanced NSCLC were divided into a discovery set (n = 17) and validation set (n = 21). A higher TMR score was associated with better response and longer progression-free survival to immunotherapy in both the discovery set and validation set. The performance of TMR score was confirmed in the two external validation cohorts of 225 NSCLC patients and 306 NSCLC patients. Tumors with higher TMR scores were more likely to combine with LRP1B gene mutation (p = 0.027) and top 1% CDR3 sequences (p = 0.001). Furthermore, LRP1B allele frequency was negatively correlated with the top 1% CDR3 sequences (r = -0.55, p = 0.033) and positively correlated with tumor shrinkage (r = 0.68, p = 0.007). The TMR score could serve as a potential predictive biomarker for the response to immunotherapy in advanced NSCLC.
RESUMEN
Background: Somatic mutations in epidermal growth factor receptor (EGFR) exon 18 are classified as uncommon or rare mutations in non-small cell lung cancer (NSCLC), in this context, other than G719X or E709X exon 18 mutations are even more rare and heterogeneous. In such scenario, first line treatment options are still debated. The aim of this study was to investigate the response of NSCLC patients harboring very rare exon 18 mutations to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Methods: This retrospective descriptive study included 105 patients with NSCLC harboring mutations in EGFR exon 18 diagnosed at West China Hospital. The clinical response to EGFR-TKIs was evaluated according to different classifications of mutations in 45 NSCLC patients: 39 harboring G719X or E709X mutations and 6 harboring very rare mutations in EGFR exon 18. Results: Among 105 patients, 84% (88/105) harbored rare mutations in EGFR exon 18, including G719X and E709X mutations. The remaining 16% (17/105) had very rare mutations in EGFR exon 18, including E709_710delinsX and G724S. For the subsequent efficacy analysis of EGFR-TKI in 45 NSCLC patients, patients harboring very rare mutations achieved a favorable disease control rate (DCR) of 100% and had a median progression-free survival (PFS) of 17.2 months, which was not significantly different compared to patients harboring G719X or E709X (P=0.59). Conclusions: EGFR-TKIs showed great efficacy in terms of responses and survival in patients harboring exon 18 EGFR rare mutations. This may justify the use of targeted therapies as a potential treatment strategy for these patients.
RESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICI) combined with chemotherapy are efficacious for treating advanced non-small cell lung cancer (NSCLC); however, the effectiveness of this approach in the malignant pleural effusion (MPE) population is unclear. This study evaluated ICI plus chemotherapy in NSCLC patients with MPE. METHODS: Patients from 3 centers in China with NSCLC and MPE who received ICI plus chemotherapy (ICI Plus Chemo) or chemotherapy alone (Chemo) between December 2014 and June 2023 were enrolled. Clinical outcomes and adverse events (AEs) were compared. RESULTS: Of 155 eligible patients, the median age was 61.0 years old. Males and never-smokers accounted for 73.5% and 39.4%, respectively. Fifty-seven and 98 patients received ICI Plus Chemo or Chemo, respectively. With a median study follow-up of 10.8 months, progression-free survival (PFS) was significantly longer with ICI Plus Chemo than with Chemo (median PFS: 7.4 versus 5.7 months; HR = 0.594 [95% CI: 0.403-0.874], P = 0.008). Median overall survival (OS) did not differ between groups (ICI Plus Chemo: 34.2 versus Chemo: 28.3 months; HR = 0.746 [95% CI: 0.420-1.325], P = 0.317). The most common grade 3 or worse AEs included decreased neutrophil count (3 [5.3%] patients in the ICI Plus Chemo group vs. 5 [5.1%] patients in the Chemo group) and decreased hemoglobin (3 [5.3%] versus 10 [10.2%]). CONCLUSIONS: In patients with untreated NSCLC with MPE, ICI plus chemotherapy resulted in significantly longer PFS than chemotherapy and had a manageable tolerability profile, but the effect on OS may be limited.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Derrame Pleural Maligno , Humanos , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/tratamiento farmacológico , Derrame Pleural Maligno/tratamiento farmacológico , Derrame Pleural Maligno/patología , Estudios Retrospectivos , FemeninoRESUMEN
In recent years, there has been a consensus regarding the enhancement of prognosis in patients with advanced non-small cell lung cancer (NSCLC) through the utilization of immune checkpoint inhibitors (ICIs). Numerous clinical studies have also demonstrated the substantial value of immunotherapy for resectable NSCLC patients. Nevertheless, there remain controversies surrounding the exploration of immune combination strategies, treatment-related side effects, prognostic biomarkers, as well as other issues in the neoadjuvant therapy setting. Consequently, this article presents a comprehensive overview of the recent advancements in neoadjuvant immunotherapy for resectable NSCLC, stimulating fresh perspectives and delving into its merits and challenges in clinical application.â©.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Terapia Neoadyuvante , Consenso , InmunoterapiaRESUMEN
BACKGROUND: Several studies have indicated that intrapleural infusion of bevacizumab is an effective treatment for non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE). However, the impact of bevacizumab administered through an indwelling pleural catheter (IPC) on the prognosis of these patients is unknown. METHODS: Consecutive advanced NSCLC patients with symptomatic MPE receiving an IPC alone or bevacizumab through an IPC were identified in a tertiary hospital. The patient characteristics and clinical outcomes were collected. RESULTS: A total of 149 patients were included, and the median age was 60.3 years. Males and nonsmokers accounted for 48.3% and 65.8%, respectively. A total of 69.8% (104/149) of patients harbored actionable mutations, including 92 EGFR-activating mutations, 11 ALK fusions, and 1 ROS1 fusion. A total of 81.9% (122/149) of patients received IPC alone, and 18.1% (27/149) received bevacizumab through an IPC. The incidence of spontaneous pleurodesis during the first 6 months was greater in the bevacizumab-treated group than in the IPC-treated group in the subgroup with actionable mutations (64.3% vs. 46.9%, P = 0.28). The median overall survival (OS) in patients with actionable mutations treated with bevacizumab through an IPC was 42.2 months, which was significantly longer than the 26.7 months in patients who received an IPC alone (P = 0.045). However, the median OS did not differ between the two arms in the subgroup without actionable mutations (10.8 vs. 41.0 months, P = 0.24). No significant difference between the bevacizumab through an IPC group and the IPC group was detected in the number of participants who had adverse events, either in patients with actionable mutations (14.3% vs. 8.4%; P = 0.42) or in patients without actionable mutations (16.7% vs. 12.8%; P = 1.00). CONCLUSIONS: Bevacizumab through an IPC resulted in a significantly improved prognosis for NSCLC patients with MPE and actionable mutations. However, patients without actionable mutations do not benefit from bevacizumab through IPC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Derrame Pleural Maligno , Masculino , Humanos , Persona de Mediana Edad , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Bevacizumab/uso terapéutico , Derrame Pleural Maligno/etiología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas , Catéteres de Permanencia/efectos adversosRESUMEN
Fungal pleural infections are infrequent and insidious, for which there are neither large clinical studies nor targeted guidelines to provide standardized treatment options. We reported 4 cases of fungal pleural infection and reviewed the cases of fungal pleural infections in previous studies to provide a basis for the diagnosis and treatment of fungal pleural infections. There were 2 females and 2 males with a mean age of 58.5 years in our data. The average time from onset to diagnosis was 30.25 days. Risk factors most frequently included pulmonary diseases (nâ =â 4) and malignancy (nâ =â 1). Two patients underwent pleural biopsy through a thoracoscope, and no pathogens were detected. Pleural fluid culture was positive in 2 out of 3 cases. The diagnoses were "possible" (nâ =â 1), "probable" (nâ =â 1), and "proven" (nâ =â 2). All patients received systemic antifungal therapy, and 3 received combined thoracic drainage. The outcomes were cured (nâ =â 1), improved (nâ =â 2) and lost to follow-up (nâ =â 1). We reviewed 12 cases of fungal pleural infection in previous studies. The diagnosis was confirmed via culture in 7 cases and via biopsy in 8 cases. The pathogen was Aspergillus in 7 cases. After a combination of systemic antifungal (nâ =â 12) and local treatment (nâ =â 11), 10 patients improved and 2 patients died. Diagnosis of fungal pleural infection should incorporate risk factors, clinical presentation and fungal evidence, with pleural fluid culture being an important and feasible mean of confirming the diagnosis; and treatment should be based on systemic antifungal therapy supplemented by topical therapy.
Asunto(s)
Enfermedades Transmisibles , Micosis , Enfermedades Pleurales , Masculino , Femenino , Humanos , Persona de Mediana Edad , Antifúngicos/uso terapéutico , Micosis/terapia , Micosis/tratamiento farmacológico , Pleura , Pronóstico , Enfermedades Transmisibles/tratamiento farmacológico , Enfermedades Pleurales/diagnóstico , Enfermedades Pleurales/terapiaRESUMEN
Background: Patients with non-small cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) fusions may benefit from ALK-tyrosine kinase inhibitors (ALK-TKIs). However, few studies have analyzed the clinical outcome in patients harboring multiple ALK fusions, including double or triple ALK fusions. Here, our study aimed to analyze the impact of harboring multiple ALK fusions on the efficacy of receiving ALK-TKIs in NSCLC patients. Methods: A total of 125 patients with ALK-rearranged NSCLC detected by targeted capture DNA-based next-generation sequencing (NGS) at West China Hospital were enrolled. The literature on patients harboring multiple ALK fusions was systematically reviewed. The clinical response to ALK-TKIs was evaluated according to ALK fusion patterns in 62 patients: 56 from our center and 6 from the literature. Results: Among the 125 patients, a single canonical echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion was detected in 65.6% (82/125), a single non-EML4-ALK fusion was detected in 13.6% (17/125), and multiple ALK fusions were detected in 20.8% (26/125). Among the 62 patients with ALK fusion treated with ALK-TKIs, the median progression-free survival (PFS) was significantly longer in patients with multiple ALK fusions than in those with a single ALK fusion (26.9 vs. 11.2 months, P=0.009), irrespective of brain metastasis, type of TKI drug, and treatment lines. The multiple ALK fusion group also tended to have a longer overall survival (OS) (P=0.26). Multivariate Cox regression analysis revealed that harboring multiple ALK fusions had the potential to be an independent predictor of better PFS for ALK-positive NSCLC [hazard ratio (HR) =0.490; 95% confidence interval (CI): 0.229-1.049]. Conclusions: Harboring multiple ALK fusions could serve as an independent predictive marker of better clinical outcome for patients with NSCLC and ALK rearrangement who have received ALK-TKIs treatment.
RESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) therapy lacks viable biomarkers for response and prognosis prediction. This study aimed to investigate the correlation of peripheral blood laboratory test results combined with lymphocyte subset ratios to the response and prognosis of immunotherapy in advanced lung cancer. METHODS: Advanced lung cancer patients admitted to West China Hospital, Sichuan University from May 2021 to July 2023 were prospectively enrolled in this study. Clinical data and peripheral blood were collected before and after treatment and lymphocyte subset ratios were analyzed by flow cytometry. Logistic regression was used to identify factors correlated to ICIs treatment efficacy. Cox modeling was applied to explore the prognostic factors. RESULTS: Logistic regression showed that the baseline level of transcription factor T cell factor 1 (TCF1)+CD8+ T cell ratio and peripheral white blood cell (WBC) count, lymphocyte percentage, cytokeratin 19 fragment (CYFRA21-1) after 1 cycle of ICIs treatment were the potential predictors for ICIs response (P<0.05). Cox regression analysis showed that the baseline level of TCF1+CD8+ T cell ratio (P=0.020) and peripheral WBC count after 1 cycle of ICIs treatment (P<0.001) were prognostic factors. CONCLUSIONS: Patients with high baseline TCF1+CD8+ T cell ratio combined with low WBC counts and low CYFRA21-1 level after 1 cycle of ICIs treatment are more likely to benefit from ICIs therapy.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Factor 1 de Transcripción de Linfocitos T/genética , Pronóstico , Linfocitos T CD8-positivos , InmunoterapiaRESUMEN
BACKGROUND: Patients with malignant pleural effusion (MPE) typically have poor prognoses, and predicting survival is challenging. The present study aimed to identify prognostic factors of overall survival (OS) in non-small cell lung cancer (NSCLC) patients with MPE in the time of immunotherapy and targeted therapy. METHODS: Data of 344 consecutive NSCLC patients with MPE on clinical, radiological, and molecular characteristics and treatment options were collected. The risk factors in the training cohort were assessed using univariate and multivariate proportional hazards analyses. A clinical prognostic score was established and validated. RESULTS: According to the results of the multivariable survival analysis, the Eastern Cooperative Oncology Group (ECOG) performance score (PS), antiangiogenic therapy, immunotherapy, and lactic dehydrogenase (LDH) in pleural fluid (CAIL) prognostic score was developed (n = 275) and subsequently validated (n = 69). Patients who underwent risk stratification into low-, moderate-, and high-risk groups had median OS of 46.1, 23.1, and 9.6 months, respectively (P < 0.0001). The area under the curve (AUC) analysis showed the CAIL score to be superior at predicting survival compared with the LENT score at 6 (0.84 vs. 0.77, P < 0.01), 12 (0.87 vs. 0.82, P < 0.01), and 36 months (0.80 vs. 0.77, P < 0.01). CONCLUSIONS: For NSCLC patients with MPE, the validated CAIL prognostic score integrates clinical characteristics and therapeutic modalities to predict survival.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Derrame Pleural Maligno , Humanos , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/terapia , Derrame Pleural Maligno/tratamiento farmacológico , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/terapia , Pronóstico , Análisis de SupervivenciaRESUMEN
BACKGROUND: Small cell lung cancer (SCLC) is a highly malignant cancer characterized by metastasis and an extremely poor prognosis. Although combined chemoimmunotherapy improves the prognosis of extensive-stage (ES)-SCLC, the survival benefits remain limited. Furthermore, no reliable biomarker is available so far to predict the treatment outcomes for chemoimmunotherapy. METHODS: This retrospective study included patients with ES-SCLC treated with first-line combined atezolizumab or durvalumab with standard chemotherapy between Janauray 1, 2019 and October 1, 2022 at five medical centers in China as the chemoimmunotherapy group. The patients were divided into one training cohort and two independent external validation cohorts. Additionally, we created a control group of ES-SCLC who was treated with first-line standard chemotherapy alone. The Radiomics Score was derived using machine learning algorithms based on the radiomics features extracted in the regions of interest delineated on the chest CT obtained before treatment. Cox proportional hazards regression analysis was performed to identify clinical features associated with therapeutic efficacy. The log-rank test, time-dependent receiver operating characteristic curve, and Concordance Index (C-index) were used to assess the effectiveness of the models. RESULTS: A total of 341 patients (mean age, 62±8.7 years) were included in our study. After a median follow-up time of 12.1 months, the median progression-free survival (mPFS) was 7.1 (95% CI 6.6 to 7.7) months, whereas the median overall survival (mOS) was not reached. The TNM stage, Eastern Cooperative Oncology Group performance status, and Lung Immune Prognostic Index showed significant correlations with PFS. We proposed a predictive model based on eight radiomics features to determine the risk of chemoimmunotherapy resistance among patients with SCLC (validation set 1: mPFS, 12.0 m vs 5.0 m, C-index=0.634; validation set 2: mPFS, 10.8 m vs 6.1 m, C-index=0.617). By incorporating the clinical features associated with PFS into the radiomics model, the predictive efficacy was substantially improved. Consequently, the low-progression-risk group exhibited a significantly longer mPFS than the high-progression-risk group in both validation set 1 (mPFS, 12.8 m vs 4.5 m, HR=0.40, p=0.028) and validation set 2 (mPFS, 9.2 m vs 4.6 m, HR=0.30, p=0.012). External validation set 1 and set 2 yielded the highest 6-month area under the curve and C-index of 0.852 and 0.820, respectively. Importantly, the integrated prediction model also exhibited considerable differentiation power for survival outcomes. The HR for OS derived from the low-progression-risk and high-progression-risk groups was 0.28 (95% CI 0.17 to 0.48) in all patients and 0.20 (95% CI 0.08 to 0.54) in validation set. By contrast, no significant differences were observed in PFS and OS, between high-progression-risk patients receiving chemoimmunotherapy and the chemotherapy cohort (mPFS, 5.5 m vs 5.9 m, HR=0.90, p=0.547; mOS, 14.5 m vs 13.7 m, HR=0.97, p=0.910). CONCLUSIONS: The integrated clinical and radiomics model can predict the treatment outcomes in patients with ES-SCLC receiving chemoimmunotherapy, rendering a convenient and low-cost prognostic model for decision-making regarding patient management.
Asunto(s)
Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Persona de Mediana Edad , Anciano , Carcinoma Pulmonar de Células Pequeñas/diagnóstico por imagen , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Estudios Retrospectivos , Resultado del Tratamiento , Inmunoterapia , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
BACKGROUND: Treatment options are limited for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after treatment failure with EGFR tyrosine kinase inhibitors (TKIs). This multicenter open-label, phase II study aims to evaluate the efficacy and safety of tislelizumab plus chemotherapy (cohort 1, TIS+chemo) or tislelizumab plus chemotherapy and bevacizumab (cohort 2, TIS+chemo+ beva) in EGFR-mutated non-squamous NSCLC patients who progressed on EGFR TKI therapies. Here, the primary analysis of the TIS+chemo cohort is reported. METHODS: In the TIS+chemo cohort, patients with EGFR-sensitizing mutations with prior EGFR TKI failure received tislelizumab plus carboplatin and nab-paclitaxel as induction treatment, followed by maintenance with tislelizumab plus pemetrexed. The primary endpoint was 1-year progression-free survival (PFS) rate. The planned sample size was 66 with a historical control of 7%, an expected value of 20%, a one-sided α of 0.05, and a power of 85%. RESULTS: Between July 11, 2020 and December 13, 2021, 69 patients were enrolled. As of June 30, 2022, the median follow-up was 8.2 months. Among the 62 patients in the efficacy analysis set, estimated 1-year PFS rate was 23.8% (90% CI 13.1% to 36.2%), and its lower bound of 90% CI was higher than the historical control of chemotherapy (7%), which met the primary endpoint. The median PFS was 7.6 (95% CI 6.4 to 9.8) months. Median overall survival (OS) was not reached (95% CI 14.0 to not estimable), with a 1-year OS rate of 74.5% (95% CI 56.5% to 86.0%). The objective response rate and disease control rate were 56.5% (95% CI 43.3% to 69.0%) and 87.1% (95% CI 76.1% to 94.3%), respectively. Patients who had progressed on first-generation/second-generation and third-generation EGFR-TKIs at baseline had shorter PFS than those who progressed on first-generation/second-generation EGFR-TKIs (median 7.5 vs 9.8 months, p=0.031). Patients with positive ctDNA had shorter PFS (median 7.4 vs 12.3 months, p=0.031) than those with negative ctDNA. No grade 5 treatment-emergent adverse events (TEAEs) were observed. Grades 3-4 TEAEs occurred in 40.6% (28/69) of patients. Grades 3-4 immune-related AEs occurred in 5 (7.2%) patients. CONCLUSION: The study met the primary endpoint for the TIS+chemo cohort. Tislelizumab plus chemotherapy is effective with an acceptable safety profile for EGFR-mutated non-squamous NSCLC after EGFR TKI failure.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Receptores ErbB/genéticaAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Mutación , Receptores ErbB/genéticaRESUMEN
High tumour programmed cell death-ligand 1 (PD-L1) expression is associated with poor progression-free survival (PFS) after tyrosine kinase inhibitor (TKI) therapy in ALK-rearranged non-small cell lung cancer (NSCLC). However, the characteristics of the tumour microenvironment (TME) and their prognostic values in ALK-rearranged NSCLC are unknown. Here, we collected tumour tissues from pretreated ALK-rearranged NSCLC patients, immunohistochemical staining was used to assess PD-L1 expression, and tumour-infiltrating immune cells were determined via multiplex immunofluorescence staining (mIF). Our data showed that the median values of PFS for the high PD-L1 group and low PD-L1 group who received ALK-TKI treatment were 4.4 and 16.4 months, respectively (p = 0.008). The median overall survival (OS) of the two groups was 24.0 months and not reached, respectively (p = 0.021). Via univariate and multivariate analyses, a high PD-L1 expression and a worse ECOG PS were determined to be independent prognostic factors of OS (HR = 3.35, 95% CI: 1.23-9.11, p = 0.018; HR = 6.42, 95% CI: 1.45-28.44, p = 0.014, respectively). In addition, the high PD-L1 group had increased Tregs and exhausted CD8+ T cells in both the tumour and stroma (all p < 0.05). High PD-L1 expression was an adverse predictive and prognostic biomarker for ALK-rearranged NSCLC. The characteristics of the TME in patients with high PD-L1 expression were shown to have an immunosuppressive status.
Asunto(s)
Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Microambiente Tumoral , Humanos , Antígeno B7-H1/biosíntesis , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Pronóstico , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/inmunología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND: Befotertinib (D-0316) is a novel, selective oral third-generation epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor. This phase 3 trial compared the efficacy and safety of befotertinib with icotinib as a first-line treatment for patients with EGFR mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: This study was a multicentre, open-label, randomised, controlled phase 3 study at 39 hospitals in China. Eligible patients were 18 years of age or older, had histologically confirmed locally advanced or metastatic stage IIIB, IIIC, or IV unresectable NSCLC, and had confirmed exon 19 deletions or exon 21 Leu858Arg mutation. Patients were randomly assigned (1:1) via an interactive web response system to receive either oral befotertinib (75-100 mg once daily) or oral icotinib (125 mg three times per day) in 21-day cycles until disease progression or withdrawal criteria were met. Randomisation was stratified by type of EGFR mutation, CNS metastasis status, and gender, and participants, investigators, and data analysts were not masked to treatment allocation. The primary endpoint was independent review committee (IRC)-assessed progression-free survival in the full analysis set, which comprised all randomly assigned patients. All patients who received at least one dose of the study drug were included in safety analyses. This study was registered with ClinicalTrials.gov, NCT04206072, and the overall survival follow-up is still in progress. FINDINGS: Between Dec 24, 2019, and Dec 18, 2020, 568 patients were screened, of whom 362 were randomly assigned to the befotertinib (n=182) or icotinib (n=180) group; all 362 patients were included in the full analysis set. Median follow-up was 20·7 months (IQR 10·2-23·5) in the befotertinib group and 19·4 months (10·3-23·5) in the icotinib group. Median IRC-assessed progression-free survival was 22·1 months (95% CI 17·9-not estimable) in the befotertinib group and 13·8 months (12·4-15·2) in the icotinib group (hazard ratio 0·49 [95% CI 0·36-0·68], p<0·0001). Grade 3 or higher treatment-related adverse events occurred in 55 (30%) of 182 patients in the befotertinib group and in 14 (8%) of 180 patients in the icotinib group. Treatment-related serious adverse events were reported in 37 (20%) patients in the befotertinib group and in five (3%) patients in the icotinib group. Two (1%) patients in the befotertinib group and one (1%) patient in the icotinib group died due to treatment-related adverse events. INTERPRETATION: Befotertinib demonstrated superior efficacy compared with icotinib in first-line treatment for patients with EGFR mutation-positive NSCLC. Although serious adverse events were more common in the befotertinib than the icotinib arm, the safety profile of befotertinib was manageable overall. FUNDING: Betta Pharmaceuticals (China). TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adolescente , Adulto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Inhibidores de Proteínas QuinasasRESUMEN
Background: Atezolizumab may provide clinical benefits to patients with advanced non-small cell lung cancer (NSCLC). However, the price of atezolizumab is relatively high, and its economic outcomes have remained unclear. In this study, we used two models to examine the cost-effectiveness of initial atezolizumab monotherapy versus chemotherapy for patients with PD-L1 high-expressing EGFR and ALK wild-type advanced NSCLC in the context of the Chinese healthcare system. Methods: Partitioned Survival model and Markov model were performed to evaluate the cost-effectiveness of first-line single-agent atezolizumab versus platinum-based chemotherapy for patients with advanced NSCLC with PD-L1 high-expressing EGFR and ALK wild-type disease. Clinical outcomes and safety information were obtained from the most recent data from the IMpower110 trial, while cost and utility values were obtained from Chinese hospitals and relevant literature. Total costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were estimated. One-way and probabilistic sensitivity analyses were performed to explore model uncertainty. Scenario analyses were also conducted for the Patient Assistance Program (PAP) and various provinces in China. Results: In the Partitioned Survival model, the total cost of atezolizumab was $145,038, providing 2.92 LYs and 2.39 QALYs, while the total cost of chemotherapy was $69,803, providing 2.12 LYs and 1.65 QALYs. The ICER for atezolizumab versus chemotherapy was $102,424.83/QALY; in the Markov model, the ICER was $104,806.71/QALY. Atezolizumab was not cost-effective at the WTP threshold of three times China's per capita gross domestic product (GDP). Sensitivity analysis showed that the cost of atezolizumab, the utility of PFS, and the discount rate had a significant impact on ICER; PAP significantly reduced ICER, but atezolizumab was still not cost-effective in China. Conclusion: First-line monotherapy with atezolizumab for patients with PD-L1 high-expressing EGFR and ALK wild-type advanced NSCLC was estimated to be less cost-effective than chemotherapy in terms of the Chinese healthcare system; offering PAP increased the likelihood that atezolizumab would be cost-effective. In some areas of China with higher levels of economic development, atezolizumab was likely to be cost-effective. To improve the cost-effectiveness of atezolizumab, drug prices would need to be reduced.
RESUMEN
Immunotherapy has significantly improved clinical outcomes of non-small cell lung cancer (NSCLC), however, along with the popularization of immunotherapy, immune resistance has become an unavoidable problem. Immunotherapy can induce extensive cellular and molecular alterations in the tumor microenvironment. Considering the mechanisms of immune resistance are not yet fully understood and the efficacy of standard chemotherapy regimens is limited, more effective coping strategies based on resistance mechanisms are urgently needed. In this review, we intend to summarize the known mechanisms of immune resistance and feasible strategies, so as to provide a foundation for clinicians to develop more individualized and precise regimens and finally improve patients' prognosis.â©.