ABSTRACT
OBJECTIVE: Non-small cell lung cancer (NSCLC) is a prevailing LC characterized by poor outcomes. AlkB homolog 5 (ALKBH5) functions as a tumor suppressor in several cancers. This study delved into the role of ALKBH5 in NSCLC development. METHODS: TCGA database predicted ALKBH5 expression in NSCLC patients. ALKBH5 levels in NSCLC and human bronchial epithelial cells were determined. pcDNA3.1-ALKBH5/NC, pcDNA3.1-SLC7A11/NC, and ferrostatin-1 were used to explore the interactions among ALKBH5, SLC7A11, and ferroptosis. SLC7A11 mRNA and its protein levels were measured by RT-qPCR and Western blot. Cell viability, apoptosis, migration, and invasion were assessed by CCK-8, flow cytometry, and Transwell. Total N6-methyladenosine (m6A) quantification and its enrichment on SLC7A11 mRNA were determined, followed by the observation of Ki67, ALKBH5 and SLC7A11-positive cell numbers. Glutathione (GSH), lipid reactive oxygen species (lipid-ROS), malondialdehyde (MDA), and iron ion contents were determined. Animal experiments further analyzed the role of ALKBH5 in tumor development and glutathione peroxidase 4 (GPX4) expression. RESULTS: Bioinformatics analysis revealed the lowly-expressed ALKBH5 in LC patients. ALKBH5 was downregulated in NSCLC cells and its upregulation repressed proliferation activity, invasion, and migration, and facilitated apoptosis. ALKBH5 upregulation decreased GSH, increased lipid-ROS, MDA, and iron ion contents, and downregulated SLC7A11 by reducing m6A modification. SLC7A11 upregulation partly annulled the effect of ALKBH5 overexpression on cell ferroptosis and malignant behaviors. In vivo assays elucidated the suppression of ALKBH5 upregulation on tumor development and GPX4 levels. CONCLUSION: ALKBH5 upregulation downregulates SLC7A11 transcription by decreasing m6A modification, thus promoting NSCLC cell ferroptosis and ultimately repressing NSCLC progression.
Subject(s)
AlkB Homolog 5, RNA Demethylase , Amino Acid Transport System y+ , Carcinoma, Non-Small-Cell Lung , Ferroptosis , Lung Neoplasms , Ferroptosis/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/metabolism , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , AlkB Homolog 5, RNA Demethylase/metabolism , AlkB Homolog 5, RNA Demethylase/genetics , Amino Acid Transport System y+/genetics , Amino Acid Transport System y+/metabolism , Animals , Cell Line, Tumor , Demethylation , Mice, Nude , Mice , Male , Mice, Inbred BALB C , Gene Expression Regulation, Neoplastic , Cell Proliferation , Adenosine/analogs & derivatives , Adenosine/metabolismABSTRACT
BACKGROUND: Small-cell lung cancer (SCLC) is a highly aggressive and lethal malignancy that accounts for 10-15% of lung cancers, and it is generally divided into limited and extensive stage. The standard of care for patients with newly diagnosed extensive-stage SCLC (ES-SCLC) is still platinum-based chemotherapy and as maintenance therapy scheme. Although most parts of patients experience a significant tumor response to first-line therapy, the disease recurs invariably. Anlotinib hydrochloride, a novel oral multitarget tyrosine kinase inhibitor, has significant inhibitory activity against angiogenesis-related kinases, such as VEGFR, FGFR, PDGFR, and c-Kit kinase associated with tumor cell proliferation. Fluzoparib is a type of inhibitor of poly ADP ribose polymerase (PARP, including PARPl, PARP2 and PARP3). Previous studies have shown that Fluzoparib has a strong inhibitory effect on PARP1 activity at the molecular and cellular levels. METHODS: This is a multi-center, prospective, single-arm phase II clinical study. A total of 50 ES-SCLC patients who experienced disease progression after first-line standard platinum-based chemotherapy with/without immune checkpoint inhibitors scheme, or within 6 months after the completion of treatment will be recruited. Those who had prior treatment with any PARP inhibitor or antiangiogenic agent includes anlotinib, bevacizumab, sorafenib, and thalidomide are excluded. Eligible patients will receive oral anlotinib 8 mg once daily and oral fluzoparib 150 mg twice daily until disease progression or intolerable toxicity. The primary endpoint is objective response rate (ORR). DISCUSSION: The addition of fluzoparib to anlotinib is expected to increase the clinical benefit in ES-SCLC patients after platinum-based chemotherapy. TRIAL REGISTRATION: This study protocol was prospectively registered on June 17, 2021. CLINICALTRIALS: gov Identifier: NCT04933175 .
Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Disease Progression , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Neoplasm Recurrence, Local/drug therapy , Platinum/therapeutic use , Prospective Studies , Protein Kinase Inhibitors , Small Cell Lung Carcinoma/drug therapyABSTRACT
PURPOSE: To explore the impact of intrathecal pemetrexed (IP) on the survival of lung adenocarcinoma (LUAC) patients with leptomeningeal metastasis (LM). METHODS: We analyzed patients with LUAC and LM who received systemic therapy after LM diagnosis at the Fujian Cancer Hospital between July 2018 and March 2022. Patients who underwent IP were assigned to the IP group; those without IP treatment were designated as the non-IP group. Propensity score matching (PSM) was performed between the two groups. RESULTS: 165 patients were enrolled: 83 and 82 in the IP and non-IP groups, respectively. After 1:1 PSM, we included 114 patients in the matched cohort. Median overall survival (OS) was 13.2 months (95% CI 10.8-15.6 months) in the IP group versus 10.1 months (95% CI 5.3-14.9 months) in the non-IP group (P = 0.488). Only Eastern Cooperative Oncology Group Performance Status (ECOG PS) was confirmed as an independent predictor for OS in the matched cohort (hazard ratio (HR) 2.03; P = 0.023). Multivariate competing-risks analysis showed that IP significantly correlated with central nervous system-related death (HR 0.31; P = 0.046). When stratified by ECOG PS, IP improved survival in patients with poor ECOG PS (PS = 2) (14.3 months vs. 1.6 months; P = 0.003). CONCLUSIONS: Intrathecal pemetrexed did not enhance OS for the entire LUAC patient with LM compared to non-intrathecal chemotherapy. However, it exhibited the potential to reduce the risk of central nervous system-related mortality and improve survival in patients with poor ECOG PS.
Subject(s)
Adenocarcinoma of Lung , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Meningeal Carcinomatosis , Humans , Pemetrexed/therapeutic use , Lung Neoplasms/pathology , Propensity Score , Adenocarcinoma of Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Meningeal Carcinomatosis/drug therapy , Meningeal Carcinomatosis/etiology , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
BACKGROUND: PD-1 inhibitor plus chemotherapy had been shown to be an effective first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC). However, there was no robust evidence showing a PD-L1 inhibitor combined with chemotherapy benefited patients with squamous and non-squamous NSCLC. GEMSTONE-302 aimed to evaluate the efficacy and safety of a PD-L1 inhibitor, sugemalimab, plus chemotherapy for patients with metastatic squamous or non-squamous NSCLC. METHODS: This randomised, double-blind, phase 3 trial was done in 35 hospitals and academic research centres in China. Eligible patients were aged 18-75 years, had histologically or cytologically confirmed stage IV squamous or non-squamous NSCLC without known EGFR sensitising mutations, ALK, ROS1, or RET fusions, no previous systemic treatment for metastatic disease, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned (2:1) to receive sugemalimab (1200 mg, intravenously, every 3 weeks) plus platinum-based chemotherapy (carboplatin [area under the curve (AUC) 5 mg/mL per min, intravenously] and paclitaxel [175 mg/m2, intravenously] for squamous NSCLC, or carboplatin [AUC 5 mg/mL per min, intravenously] and pemetrexed [500 mg/m2, intravenously] for non-squamous NSCLC; sugemalimab group) or placebo plus the same platinum-based chemotherapy regimens for squamous or non-squamous NSCLC as in the sugemalimab group; placebo group) for up to four cycles, followed by maintenance therapy with sugemalimab or placebo for squamous NSCLC, and intravenous sugemalimab 500 mg/m2 or matching placebo plus pemetrexed for non-squamous NSCLC. Randomisation was done by an interactive voice-web-response system via permuted blocks (block size was a mixture of three and six with a random order within each stratum) and stratified by ECOG performance status, PD-L1 expression, and tumour pathology. The investigators, patients, and the sponsor were masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one treatment dose. Results reported are from a prespecified interim analysis (ie, when the study met the primary endpoint) and an updated analysis (prespecified final analysis for progression-free survival) with a longer follow-up. This study is registered with ClinicalTrials.gov (NCT03789604), is closed to new participants, and follow-up is ongoing. FINDINGS: Between Dec 13, 2018, and May 15, 2020, 846 patients were assessed for eligibility; 367 were ineligible, and the remaining 479 patients were randomly assigned to the sugemalimab group (n=320) or placebo group (n=159). At the preplanned interim analysis (data cutoff June 8, 2020; median follow-up 8·6 months [IQR 6·1-11·4]), GEMSTONE-302 met its primary endpoint, with significantly longer progression-free survival in the sugemalimab group compared with the placebo group (median 7·8 months [95% CI 6·9-9·0] vs 4·9 months [4·7-5·0]; stratified hazard ratio [HR] 0·50 [95% CI 0·39-0·64], p<0·0001]). At the final analysis (March 15, 2021) with a median follow-up of 17·8 months (IQR 15·1-20·9), the improvement in progression-free survival was maintained (median 9·0 months [95% CI 7·4-10·8] vs 4·9 months [4·8-5·1]; stratified HR 0·48 [95% CI 0·39-0·60], p<0·0001). The most common grade 3 or 4 any treatment-related adverse events were neutrophil count decreased (104 [33%] of 320 with sugemalimab vs 52 [33%] of 159 with placebo), white blood cell count decreased (45 [14%] vs 27 [17%]), anaemia (43 [13%] vs 18 [11%]), platelet count decreased (33 [10%] vs 15 [9%]), and neutropenia (12 [4%] vs seven [4%]). Any treatment-related serious adverse events occurred in 73 (23%) patients in the sugemalimab group and 31 (20%) patients in the placebo group. Any treatment-related deaths were reported in ten (3%) patients in the sugemalimab group (pneumonia with respiratory failure in one patient; myelosuppression with septic shock in one patient; pneumonia in two patients; respiratory failure, abdominal pain, cardiac failure, and immune-mediated pneumonitis in one patient each; the other two deaths had an unspecified cause) and in two (1%) patients in the placebo group (pneumonia and multiple organ dysfunction syndrome). INTERPRETATION: Sugemalimab plus chemotherapy showed a statistically significant and clinically meaningful progression-free survival improvement compared with placebo plus chemotherapy, in patients with previously untreated squamous and non-squamous metastatic NSCLC, regardless of PD-L1 expression, and could be a newfirst-line treatment option for both squamous and non-squamous metastatic NSCLC. FUNDING: CStone Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung , Immune Checkpoint Inhibitors , Lung Neoplasms , Aged , Female , Humans , Male , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Double-Blind Method , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Neoplasm Metastasis , Platinum/administration & dosageABSTRACT
BACKGROUND: Patients with advanced or metastatic oesophageal squamous cell carcinoma have poor prognosis and few treatment options after first-line therapy. We aimed to assess efficacy and safety of the anti-PD-1 antibody camrelizumab versus investigator's choice of chemotherapy in previously treated patients. METHODS: ESCORT is a randomised, open-label, phase 3 study of patients aged 18 to 75 years with a histological or cytological diagnosis of advanced or metastatic oesophageal squamous cell carcinoma done at 43 hospitals in China. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had progressed on, or were intolerant to, first-line standard therapy. Patients were randomly assigned (1:1) to camrelizumab (200 mg every 2 weeks) or chemotherapy with docetaxel (75 mg/m2 every 3 weeks) or irinotecan (180 mg/m2 every 2 weeks), all given intravenously. Central randomisation was done using the Randomization and Trial Supply Management system with block size randomly generated as four or six and stratified by disease and ECOG performance status. The primary endpoint was overall survival, assessed in randomised patients who had received at least one dose of treatment. Safety was assessed in all treated patients. The trial is registered with ClinicalTrials.gov, NCT03099382, and is closed to new participants. FINDINGS: From May 10, 2017, to July 24, 2018, 457 (75%) of 607 screened patients were randomly assigned to treatment, of whom 228 received camrelizumab treatment and 220 received chemotherapy. As of data cutoff on May 6, 2019, with a median follow-up time of 8·3 months (IQR 4·1-12·8) in the camrelizumab group and 6·2 months (3·6-10·1) in the chemotherapy group, median overall survival was 8·3 months (95% CI 6·8-9·7) in the camrelizumab group and 6·2 months (5·7-6·9) in the chemotherapy group (hazard ratio 0·71 [95% CI 0·57-0·87]; two-sided p=0·0010). The most common treatment-related adverse events of grade 3 or worse were anaemia (camrelizumab vs chemotherapy: six [3%] vs 11 [5%]), abnormal hepatic function (four [2%] vs one [<1%]), and diarrhoea (three [1%] vs nine [4%]). Serious treatment-related adverse events occurred in 37 (16%) of 228 patients in the camrelizumab group, and in 32 (15%) of 220 patients in the chemotherapy group. Ten treatment-related deaths occurred, seven (3%) in the camrelizumab group (three deaths from unknown causes, one enterocolitis, one hepatic function abnormal, one pneumonitis, and one myocarditis) and three (1%) in the chemotherapy group (two deaths from unknown causes, and one gastrointestinal haemorrhage). INTERPRETATION: Second-line camrelizumab significantly improved overall survival in patients with advanced or metastatic oesophageal squamous cell carcinoma compared with chemotherapy, with a manageable safety profile. It might represent a potential option of standard second-line treatment for patients with oesophageal squamous cell carcinoma in China. FUNDING: Jiangsu Hengrui Medicine.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Docetaxel/administration & dosage , Esophageal Neoplasms/drug therapy , Esophageal Squamous Cell Carcinoma/drug therapy , Irinotecan/administration & dosage , Adolescent , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , China , Disease Progression , Docetaxel/adverse effects , Esophageal Neoplasms/immunology , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma/immunology , Esophageal Squamous Cell Carcinoma/mortality , Esophageal Squamous Cell Carcinoma/secondary , Female , Humans , Irinotecan/adverse effects , Male , Middle Aged , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Progression-Free Survival , Signal Transduction , Time Factors , Young AdultABSTRACT
The incidence of epidermal growth factor receptor uncommon mutation (EGFRum) is relatively low and patients harboring EGFRum are resistant to the first-generation tyrosine kinase inhibitors (TKI). However, the mechanism of primary resistance remains unclear. Medical records of 98 patients who had never been treated by TKI and who accepted icotinib treatment were collected and followed. The circulating tumor DNA (ctDNA) were detected and analyzed using the next-generation sequencing (NGS) platform after progression on icotinib. The potential primary resistance mechanism of icotinib was explored. A total of 21 (21.4%) and 48 (49%) patients developed primary and acquired resistance to icotinib, respectively. The median progression-free survival (PFS) of primary resistance patients was 1.8 months (0.5-2.3, 95% CI = 1.50-2.10). Before treatment, 52.4% (11/21) of patients carried S768I, 23.8% (5/21) L861Q, 14.3% (3/21) G719X and 14.3% (3/21) exon 20-ins mutations. Approximately 23.8% (5/21) of patients harbored the combined pattern mutations and 76.2% (16/21) of patients harbored the single pattern mutations. The combined pattern with EGFR classical mutation (EGFRcm) had worse PFS than the combined with EGFRum and single pattern (P < .05). There were 6 (28.57%) patients with acquired EGFR extracellular domain mutation, 5 (23.81%) with BCL2L11 loss (BIM deletion polymorphism), 3 (14.29%) with MET amplification, 1 (4.76%) with ERBB2 amplification, 1 (4.76%) with MYC amplification, 1 (4.76%) with PTEN mutation, 1 (4.76%) with PIK3CA mutation and 3 (14.29%) with unknown status. EGFR extracellular domain mutation, BCL2L11 loss, PI3K-AKT-mTOR signaling pathway (PTEN and PIK3CA mutations), MET amplification, ERBB2 amplification or MYC amplification might contribute to molecular mechanisms of primary resistance to icotinib in patients with advanced non-small cell lung cancer harboring uncommon mutant epidermal growth factor receptor. Combined targeted therapy or chemotherapy should be considered in this population.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Crown Ethers/therapeutic use , Drug Resistance, Neoplasm , Gene Regulatory Networks , Lung Neoplasms/drug therapy , Quinazolines/therapeutic use , Carcinoma, Non-Small-Cell Lung/genetics , China , Circulating Tumor DNA/analysis , Disease Progression , ErbB Receptors/genetics , Female , High-Throughput Nucleotide Sequencing , Humans , Lung Neoplasms/genetics , Male , Mutation , Retrospective Studies , Sequence Analysis, DNAABSTRACT
BACKGROUND: MET amplification is associated with acquired resistance to first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in treating non-small-cell lung cancer (NSCLC); however, the therapeutic strategy in these patients is undefined. Herein we report the clinical outcomes of patients with c-MET amplification resistance to EGFR-TKIs treated with crizotinib. METHODS: We retrospectively analyzed advanced NSCLC patients from five sites who were diagnosed with EGFR-mutant NSCLC and received EGFR-TKI treatment. After disease progression, these patients were confirmed to have a MET-to-centromere ratio (MET:CEN) ≥ 1.8 based on fluorescence in situ hybridization (FISH) examination and without a T790M mutation. We assessed the efficacy and safety of crizotinib to overcome EGFR-TKI resistance in EGFR-activating mutations NSCLC with acquired MET amplification. RESULTS: Amplification of the acquired MET gene was identified in 18 patients with EGFR-mutant NSCLC. Fourteen patients received crizotinib treatment after acquired resistance to EGFR-TKIs. Among the 14 patients, 6 (42.9%) received crizotinib plus EGFR-TKI and 8 (57.1%) received crizotinib monotherapy. The overall objective response rate (ORR) and disease control rate (DCR) were 50.0% (7/14) and 85.7% (12/14), respectively. The median PFS (mPFS) of patients receiving crizotinib monotherapy and crizotinib plus EGFR-TKI was 6.0 and 12.6 months, respectively (P = 0.315). Notably, treatment efficacy was more pronounced in patients with crizotinib than patients with chemotherapy (24.0 months vs. 12.0 months, P = 0.046). The mOS for 8 of 14 patients receiving crizotinib monotherapy and 6 of 14 patients receiving crizotinib plus EGFR-TKI was 17.2 and 24.0 months, respectively (P = 0.862). Among the 14 patients, 1 who received crizotinib monotherapy (grade 3 nausea) and 2 who received crizotinib plus EGFR-TKI (grade 3 elevated liver aminotransferase levels) received reduced doses of crizotinib (200 mg twice daily) to better tolerate the dose. CONCLUSIONS: We observed the clinical evidence of efficacy generated by combination of crizotinib and previous EGFR-TKIs after the resistance to first-generation EGFR-TKIs. These results might increase evidence of more effective therapeutic strategies for NSCLC treatment. Combination therapy did not increase the frequency of adverse reactions.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Crizotinib/therapeutic use , ErbB Receptors/genetics , Gene Amplification , Lung Neoplasms/drug therapy , Mutation/genetics , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-met/genetics , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Carcinoma, Non-Small-Cell Lung/genetics , Crizotinib/adverse effects , Crizotinib/pharmacology , Disease Progression , Disease-Free Survival , Female , Humans , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/genetics , Male , Middle Aged , Protein Kinase Inhibitors/adverse effects , Proto-Oncogene Proteins c-met/metabolism , Retrospective Studies , Tomography, X-Ray Computed , Treatment FailureABSTRACT
Nuclear factor-kappa B (NF-κB) as a prognostic marker remains unclear in non-small cell lung cancer (NSCLC). Here, we studied NF-κB-p65 (p65) expression and phosphorylated NF-κB-p105 (p-p105) expression in NSCLC and correlated the finding with overall survival (OS) and clinicopathological features. A total of 186 archival samples from patients with surgically resectable NSCLC were probed with p65 and p-p105 (Ser 932). The p65-positive expression and p-p105-positive expression were defined as distinct nuclear p65 and cytoplasmic p-p105 labelling in at least 1% of tumour cells, respectively. The positive staining of p65 alone, p-p105 alone and co-expression of p65 and p-p105 were observed in 61 (32.8%), 90 (48.4%) and 35 (18.8%) patients, respectively. Co-expression of p65 and p-p105 but not of either p65 or p-p105 alone was associated with a poor prognosis. Patients with co-expression of p65 and p-p105 had a shorter OS than others, median OS 26.5 months versus 64.1 months, HR 1.85 (95% CI: 1.18-2.91), P = 0.007. There was no statistically significant association between clinicopathological characteristics and either p65 or p-p105 alone or co-expression of p65 and p-p105. This indicates that co-expression of p65 and p-p105 was a poor prognostic factor, and pathologic studies of NF-κB expression could include multiple pathway components in NSCLC.
Subject(s)
Adenocarcinoma/genetics , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Squamous Cell/genetics , Gene Expression Regulation, Neoplastic , Lung Neoplasms/genetics , NF-kappa B p50 Subunit/genetics , Transcription Factor RelA/genetics , Adenocarcinoma/diagnosis , Adenocarcinoma/mortality , Adenocarcinoma/surgery , Adult , Aged , Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/surgery , Carcinoma, Squamous Cell/diagnosis , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/surgery , Female , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/mortality , Lung Neoplasms/surgery , Male , Middle Aged , NF-kappa B p50 Subunit/metabolism , Phosphorylation , Prognosis , Prospective Studies , Signal Transduction , Survival Analysis , Transcription Factor RelA/metabolismABSTRACT
BACKGROUND: ALK rearrangement-advanced NSCLC patients respond to crizotinib. ALK rearrangement is currently determined with RT-PCR. VENTANA IHC is a standard method to identify ALK protein overexpression in NSCLC; however, VENTANA IHC has rarely been used to determine the response to crizotinib in Chinese patients with NSCLC and ALK overexpression. To better clarify the clinical implication of VENTANA IHC to detect ALK rearrangements, we conducted this study to analyze VENTANA IHC and RT-PCR in a large cohort of Chinese patients with NSCLC undergoing screening for ALK rearrangements. METHODS: A total of 1720 patients with NSCLC who had ALK rearrangements detected by VENTANA IHC and/or RT-PCR were included in this analysis. We compared the efficacy and survival of ALK-positive patients detected by VENTANA IHC and RT-PCR. We used NGS to identify patients in whom the two methods were inconsistent. RESULTS: Among 1720 patients, 187 (10.87%) were shown to be ALK-positive by VENTANA IHC and/or RT-PCR, and 66 received crizotinib treatment. We identified 10.27% (172/1674) of patients as ALK-positive by the VENTANA IHC method, and 12.73% (41/322) of patients had ALK rearrangements by the RT-PCR method. Twenty-nine of 276 (10.51%) ALK-positive patients were simultaneously analyzed using VENTANA IHC and RT-PCR. The overall response rates were 65.90% (29/44) by VENTANA IHC and 55.88% (19/34) by RT-PCR. The disease control rates were 86.36% (38/44) by VENTANA IHC and 76.47% (26/34) by RT-PCR. In contrast, the median progression-free survival for VENTANA IHC and RT-PCR was 8.5 and 9.2 months, respectively. The VENTANA IHC and RT-PCR results obtained for 6 of 17 ALK-positive patients were inconsistent based on NGS; specifically, 4 patients had EML4-ALK fusions, 2 patients had non EML4-ALK fusions, 1 patient had a KCL1-ALK fusion, and one patient had a FBXO36-ALK fusion. CONCLUSIONS: VENTANA IHC is a reliable and rapid screening tool used in routine pathologic laboratories for the identification of suitable candidates for ALK-targeted therapy. VENTANA IHC has moderate sensitivity and a slightly higher association with response to therapy with ALK inhibitors, and some VENTANA IHC-positive, but RT-PCR-negative cases may benefit from crizotinib.
Subject(s)
Anaplastic Lymphoma Kinase/genetics , Asian People , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/enzymology , Crizotinib/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/enzymology , Reverse Transcriptase Polymerase Chain Reaction/methods , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Crizotinib/pharmacology , Female , High-Throughput Nucleotide Sequencing , Humans , Immunohistochemistry , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Progression-Free Survival , Young AdultABSTRACT
BACKGROUND RET rearrangements have been reported in 30% of papillary thyroid carcinomas and 1-2% of non-small cell lung cancer (NSCLC). In these tumors, RET gene fusion product provides a constitutively active tyrosine kinase (TKR), leading to uncontrolled cellular proliferation, differentiation, and migration. In this investigation we assessed the positivity rate of RET gene rearrangement in primary and metastatic non-small cell lung cancer and explored their relationships. MATERIAL AND METHODS Between January 2013 and May 2015, we collected 384 cases of primary metastatic non-small cell lung cancer, which included 246 matched metastatic tumors cases from multiple centers. The RET rearrangement uniformity in metastatic lymph nodes and tumor specimens were contrasted and the relationships between RET rearrangement and patients' clinical features were investigated. RESULTS For those 384 cases, 7 (1.82%) cases had tumors with identified RET rearrangement. Among the 246 paired cases, 3 (1.22%) cases of primary tumor had identified RET rearrangement and 2 (0.81%) cases of metastases had identified RET rearrangement. The sensitivity was 66.67% (2/3) and the specificity was 100% (243/243). CONCLUSIONS The results of this research indicate that the metastases of non-small cell lung cancer can predict RET rearrangement of the primary tumor tissue in the majority of cases. Testing for RET rearrangement in metastases can be used as an alternative to testing of primary tumor tissue if it is inaccessible.
Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/genetics , Proto-Oncogene Proteins c-ret/genetics , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/enzymology , Female , Gene Rearrangement , Humans , Lung Neoplasms/enzymology , Male , Middle Aged , TransfectionABSTRACT
OBJECTIVE: To explore the safety and efficacy of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in preventing chemotherapy-induced neutropenia in patients with breast cancer and non-small cell lung cancer (NSCLC), and to provide the basis for clinical application. METHODS: According to the principle of open-label, randomized, parallel-group controlled clinical trial, all patients were randomized by 1â¶1â¶1 into three groups to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg, respectively. The patients with breast cancer received two chemotherapy cycles, and the NSCLC patients received 1-2 cycles of chemotherapy according to their condition. All patients were treated with the combination chemotherapy of TAC (docetaxel+ epirubicin+ cyclophosphamide) or TA (docetaxel+ epirubicin), or the chemotherapy of docetaxel combined with carboplatin, with a 21 day cycle. RESULTS: The duration of grade 3-4 neutropenia in the PEG-rhG-CSF 100 µg/kg and PEG-rhG-CSF 6 mg groups were similar with that in the rhG-CSF 5 µg/kg group (P>0.05 for all). The incidence rate of grade 3-4 neutropenia in the PEG-rhG-CSF 100 µg/kg group, PEG-rhG-CSF 6 mg group, and G-CSF 5 µg/kg group were 69.7%, 68.4%, and 69.5%, respectively, with a non-significant difference among the three groups (P=0.963). The incidence rate of febrile neutropenia in the PEG-rhG-CSF 100 µg/kg group, PEG-rhG-CSF 6 mg group and G-CSF 5 µg/kg group were 6.1%, 6.4%, and 5.5%, respectively, showing no significant difference among them (P=0.935). The incidence rate of adverse events in the PEG-rhG-CSF 100 µg/kg group, PEG-rhG-CSF 6 mg group and G-CSF 5 µg / kg group were 6.7%, 4.1%, and 5.5%, respectively, showing a non-significant difference among them (P=0.581). CONCLUSIONS: In patients with breast cancer and non-small cell lung cancer (NSCLC) undergoing TAC/TA chemotherapy, a single 100 µg/kg injection or a single fixed 6 mg dose of PEG-rhG-CSF at 48 hours after chemotherapy show definite therapeutic effect with a low incidence of adverse events and mild adverse reactions. Compared with the continuous daily injection of rhG-CSF 5 µg/kg/d, a single 100 µg/kg injection or a single fixed 6 mg dose of PEG-rhG-CSF has similar effect and is more advantageous in preventing chemotherapy-induced neutropenia.
Subject(s)
Antineoplastic Agents/adverse effects , Breast Neoplasms/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Granulocyte Colony-Stimulating Factor/therapeutic use , Lung Neoplasms/drug therapy , Neutropenia/prevention & control , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols , Carboplatin/administration & dosage , Carboplatin/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Docetaxel , Epirubicin/administration & dosage , Epirubicin/adverse effects , Female , Humans , Incidence , Induction Chemotherapy , Neutropenia/chemically induced , Neutropenia/epidemiology , Polyethylene Glycols , Recombinant Proteins/administration & dosage , Taxoids/administration & dosage , Taxoids/adverse effectsABSTRACT
BACKGROUND: Garsorasib (D-1553; InventisBio, Shangai, China), a potent KRASG12C inhibitor, has shown promising antitumour activity in patients with KRASG12C-mutated (ie, Gly12Cys) non-small-cell lung cancer (NSCLC) in a phase 1 study. We report results from a phase 2 study conducted to evaluate the efficacy and safety of garsorasib in patients with locally advanced or metastatic KRASG12C-mutated NSCLC. METHODS: This open-label, multicentre, single-arm, phase 2 trial enrolled adult patients with KRASG12C-mutated NSCLC who had previously been treated with platinum-based chemotherapy and immune checkpoint inhibitors from 43 hospitals in China. Participants received 600 mg garsorasib orally twice per day. Tumour assessments were performed at baseline, at the end of every two cycles (of 21 days) for the first eight cycles, and at the end of every three cycles thereafter. The primary endpoint was objective response rate (ORR) as assessed by an independent review committee (IRC) following the guidelines in Response Evaluation Criteria in Solid Tumours, version 1.1. Efficacy and safety were assessed in all patients who received at least one dose of garsorasib. This trial is registered at ClinicalTrials.gov, NCT05383898, and is active but no longer recruiting. FINDINGS: From June 17, 2022, to May 17, 2023, of 225 patients screened for eligibility, 123 patients were enrolled and treated with garsorasib. Of these 123 participants, the median age was 64 years (IQR 59-68), 108 (88%) were male and 15 (12%) were female. At data cutoff (Nov 17, 2023), the median follow-up duration was 7·9 months (IQR 6·3-10·4), and 82 (67%) of 123 patients had discontinued treatment. The IRC-confirmed ORR was 50% (61 of 123 patients; 95% CI 41-59). 117 (95%) of 123 patients reported treatment-related adverse events, with 61 (50%) experiencing grade 3 or higher events. The most common types of adverse events of grade 3 or higher associated with garsorasib were hepatic and gastrointestinal events, including increased liver enzymes, such as aspartate aminotransferase (21 [17%] of 123 participants), alanine aminotransferase (19 [15%] of 123 participants), and gamma-glutamyltransferase (28 [23%] of 123 participants); nausea (2 [2%] of 123 participants); and vomiting (2 [2%] of 123 participants). No new safety signals were identified, and most of the adverse events were well managed. INTERPRETATION: The results show that garsorasib has a high response rate, long duration of response, and an acceptable and manageable safety profile in patients with previously treated KRASG12C-mutated NSCLC. Garsorasib potentially provides a promising treatment option for this patient population. FUNDING: InventisBio.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Mutation , Proto-Oncogene Proteins p21(ras) , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Male , Female , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Middle Aged , Aged , Proto-Oncogene Proteins p21(ras)/genetics , China , Treatment Outcome , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effectsABSTRACT
PURPOSE: Taletrectinib, a highly potent, CNS-active, ROS1 tyrosine kinase inhibitor (TKI), has demonstrated high and durable response rates, high intracranial objective response rate (ORR), prolonged progression-free survival (PFS), and activity against G2032R with a favorable safety profile. We report outcomes from the pivotal TRUST-I study (ClinicalTrials.gov identifier: NCT04395677) of taletrectinib for ROS1+ non-small cell lung cancer in China. METHODS: TRUST-I evaluated TKI-naÑve and crizotinib-pretreated patients. The primary end point was confirmed ORR (cORR) by independent review committee; key secondary end points included duration of response (DOR), PFS, and safety. RESULTS: As of November 2023, 173 patients were enrolled (median age, 55 years; 58% female; 73% never smoked; TKI naÑve: n = 106; crizotinib pretreated: n = 67). In TKI-naÑve patients, cORR and intracranial cORR were 91% and 88%, respectively, and 52% and 73% in crizotinib-pretreated patients. In TKI-naÑve patients, median DOR and median PFS were not reached (NR) with 22.1-month and 23.5-month follow-up, respectively. In crizotinib-pretreated patients, the median DOR was 10.6 months (95% CI, 6.3 months to NR; 8.4-month follow-up), and the median PFS was 7.6 months (95% CI, 5.5 to 12.0 months; 9.7-month follow-up). Eight of 12 patients (67%) with G2032R mutations responded. The most frequent treatment-emergent adverse events (TEAEs) were increased AST (76%), diarrhea (70%), and increased ALT (68%), most of which were grade 1-2. Incidences of neurologic TEAEs were low (dizziness: 23%; dysgeusia: 10%) and mostly grade 1. Discontinuations (5%) and dose reductions (19%) due to TEAEs were low. CONCLUSION: Taletrectinib continues to show high and durable overall responses, prolonged PFS, robust activity against intracranial lesions and acquired resistance mutations including G2032R, and a favorable safety profile with a low incidence of neurologic TEAEs.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Protein-Tyrosine Kinases , Proto-Oncogene Proteins , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Female , Male , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Middle Aged , Adult , Aged , Proto-Oncogene Proteins/genetics , Protein-Tyrosine Kinases/antagonists & inhibitors , China , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Progression-Free Survival , Crizotinib/therapeutic use , Crizotinib/adverse effects , Young Adult , East Asian PeopleABSTRACT
OBJECTIVE: To explore the efficacy of serplulimab plus chemotherapy in esophageal squamous cell carcinoma (ESCC) patients with liver metastases. METHODS: A post hoc exploratory analysis of ASTRUM-007 study was performed, focusing on the association between the liver metastases status and the clinical outcomes. A systematic literature search of electronic databases was conducted to identify eligible randomized controlled trials for the meta-analysis. Study-level pooled analyses of hazard ratios (HRs) for PFS according to liver metastases were performed. RESULTS: The post hoc analysis of ASTRUM-007 showed that although patients with liver metastases had a worse prognosis comparing with the non-liver metastases patients in both treatment arms (serplulimab plus chemotherapy arm: median PFS, 5.7 vs. 6.6 months, HR 1.57 [95% CI, 1.15-2.13]; median OS, 13.7 vs. 15.3 months, HR 1.48 [95% CI, 1.09-1.98]; placebo plus chemotherapy arm: median PFS, 4.3 vs. 5.5 months, HR 1.58 [95% CI, 1.01-2.39]; median OS, 10.3 vs. 11.2 months, HR 1.32 [95% CI, 0.84-2.00]), OS and PFS benefits derived from serplulimab plus chemotherapy versus placebo plus chemotherapy in this study were observed in both patients with liver metastases (HR of PFS: 0.60; 95% CI, 0.37-0.97; HR of OS: 0.68; 95% CI, 0.43-1.11) and the non-liver metastases patients (HR of PFS: 0.62; 95% CI, 0.49-0.80; HR of OS: 0.69; 95% CI, 0.55-0.87) with similar magnitude. Three randomized controlled trials were included in the meta-analysis. Pooled HRs demonstrated that the addition of anti-PD-1 antibodies significantly improved PFS compared to chemotherapy alone regardless of liver metastases status. CONCLUSIONS: This study reveals that the presence of liver metastases is a poor prognostic factor but does not affect the improvements in both PFS and OS brought by adding PD-1 blockade to chemotherapy in ESCC patients. Predictive biomarkers for survival in these patients warrant further investigation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Liver Neoplasms , Humans , Liver Neoplasms/secondary , Liver Neoplasms/drug therapy , Liver Neoplasms/mortality , Esophageal Squamous Cell Carcinoma/drug therapy , Esophageal Squamous Cell Carcinoma/secondary , Esophageal Squamous Cell Carcinoma/mortality , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/pathology , Esophageal Neoplasms/mortality , Male , Immune Checkpoint Inhibitors/therapeutic use , Female , Middle Aged , Randomized Controlled Trials as Topic , Aged , Treatment Outcome , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosageABSTRACT
INTRODUCTION: KRAS glycine-to-cysteine substitution at codon 12 (G12C) mutation is a well-recognized and increasingly promising therapeutic target with huge unmet clinical needs in NSCLC patients. IBI351 is a potent covalent and irreversible inhibitor of KRAS G12C. Here, we present the efficacy and safety of IBI351 from an open-label, single-arm, phase 2 pivotal study. METHODS: Eligible patients with NSCLC with KRAS G12C who failed standard therapy were enrolled. IBI351 was orally administered at a dose of 600 mg twice daily. The primary endpoint was confirmed objective response rate assessed by an independent radiological review committee (IRRC) as per Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints were safety, IRRC-confirmed disease control rate, duration of response, progression-free survival (PFS), and overall survival. RESULTS: As of December 13, 2023, 116 patients were enrolled (Eastern Cooperative Oncology Group Performance Status 1: 91.4%; brain metastasis: 30.2%; prior treatments with both anti-PD-1 or anti-PD-L1 inhibitors and platinum-based chemotherapy: 84.5%). As per the IRRC assessment, the confirmed objective response rate was 49.1% (95% confidence interval [CI]: 39.7-58.6), and the disease control rate was 90.5% (95% CI: 83.7-95.2). The median duration of response was not reached whereas disease progression or death events occurred in 22 patients (38.6%), and the median PFS was 9.7 months (95% CI: 5.6-11.0). overall survival data was immature. Treatment-related adverse events (TRAEs) occurred in 107 patients (92.2%) whereas 48 patients (41.4%) had equal to or higher than grade three TRAEs. Common TRAEs were anemia (44.8%), increased alanine aminotransferase (28.4%), increased aspartate aminotransferase (27.6%), asthenia (26.7%) and presence of protein in urine (25.0%). TRAEs leading to treatment discontinuation occurred in nine patients (7.8%). In biomarker evaluable patients (n = 95), all patients had positive KRAS G12C in tissue whereas 72 patients were blood-positive and 23 were blood-negative for KRAS G12C. Patients with KRAS G12C in both blood and tissue had higher tumor burden at baseline (p < 0.05) and worse PFS (p < 0.05). Tumor mutation profiling identified tumor protein p53 (45.3%), serine/threonine kinase 11 (STK11) (30.5%), and kelch-like ECH-associated protein 1 (21.1%) as the most common genes co-mutated with KRAS G12C. Among 13 genes with mutation frequency equal to or higher than 5%, mutations of six genes (STK11, kelch-like ECH-associated protein 1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma, DNA polymerase epsilon, SMAD family member 4, and BMP/retinoic acid-inducible neural-specific protein 3) were significantly associated with worse PFS (p < 0.05). Mutation in STK11 was also found to have a significant association with higher tumor burden at baseline and lower response rate (p < 0.05). CONCLUSIONS: IBI351 monotherapy demonstrated promising and sustained efficacy with manageable safety, supporting its potential as a new treatment option for KRAS G12C-mutant NSCLC.
ABSTRACT
Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC ('EC alone'; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607 .
ABSTRACT
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.
ABSTRACT
BACKGROUND: The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib-refractory, anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study. METHODS: In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by KaplanâMeier methods with two-sided 95% confidence intervals (CIs). Next-generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management. RESULTS: At the data cut-off date (August 31, 2022), with a median follow-up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3-53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 (TP53) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks. CONCLUSION: Ensartinib led to a favorable OS in patients with advanced, crizotinib-resistant, and ALK-positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Circulating Tumor DNA , Lung Neoplasms , Protein Kinase Inhibitors , Humans , Anaplastic Lymphoma Kinase/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Circulating Tumor DNA/blood , Circulating Tumor DNA/genetics , Crizotinib , Lung Neoplasms/genetics , Neoplasm Proteins , Piperazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyridazines/therapeutic use , Drug Resistance, Neoplasm/geneticsABSTRACT
OBJECTIVE: To compare the efficacy and toxicity of chemotherapy under the guidance of molecular markers and with vinorelbine in elderly patients with epidermal growth factor receptor (EGFR) wild-type advanced non-small cell lung cancer (NSCLC). METHODS: A total of 86 elderly patients with pathologically-confirmed advanced NSCLC with EGFR wild-type were recruited between June 2010 to October 2012. There were 69 males and 17 females, aging from 70 to 83 years. They were divided randomly into 2 groups according to the proportion of 1: 1 by SPSS 16.0 software. The study group received chemotherapy (cisplatin, gemcitabine, paclitaxel, and pemetrexed ) under the guidance of molecular markers (excision repair cross-complementing 1 ERCC1, ribonucleotide reductase M1 RRM1, Class III beta-tubulin, thymidylate synthetase TS). The control group received vinorelbine 25 mg/m(2) days 1 and 8 with 21 days as a cycle. RESULTS: The progression-free survival (PFS) of the study group and the control group was 4.0 months (95%CI: 3.1-4.9) and 3.0 months (95% CI: 2.4-3.6 ) respectively, the difference being statistically significant (χ(2) = 4.750, P = 0.029). The objective response rate (ORR) was 23% (10/43) and 19% (8/43) (χ(2) = 0.281, P = 0.596), the disease control rate (DCR) was 79% (34/43) and 77% (33/43) (χ(2) = 0.068, P = 0.795), and the median overall survival (OS) was 8.3 months and 7.5 months (χ(2) = 0.756, P = 0.385), respectively; the differences being not significant. Adverse effects were similar between the study group and the control group. The most commonly seen adverse events were hematological toxicity, nausea, vomiting, fatigue, alopecia, joint and muscle pain. Most of the toxicity was of grade I and grade II. There was no treatment-related death. CONCLUSIONS: The PFS was prolonged in elderly patients with EGFR wild-type advanced NSCLC under the guidance of molecular markers, but there was no improvement in ORR, DCR and OS. Further studies are needed to evaluate the clinical significance of this treatment modality.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Female , Humans , Lung Neoplasms/genetics , Male , Vinblastine/administration & dosage , Vinblastine/analogs & derivatives , VinorelbineABSTRACT
BACKGROUND: This study aimed to evaluate the efficacy and safety of KN046, a novel recombinant humanised antibody targeting PD-L1 and CTLA-4 in advanced non-small cell lung cancer (NSCLC) patients after failure or intolerance to platinum-based chemotherapy. METHODS: In this multi-centre, open-label phase II clinical trial, patients were enroled after failure or intolerance to platinum-based chemotherapy. KN046 at 3 mg/kg or 5 mg/kg was administered intravenously every 2weeks. The primary end-point was objective response rate (ORR) evaluated by a blinded independent review committee (BIRC). RESULTS: A total of 30 and 34 patients were included in the 3 mg/kg (cohort A) and 5 mg/kg (cohort B) cohorts. On 31st August 2021, the median follow-up duration was 24.08 months (interquartile [IQR], 22.28, 24.84) and 19.35months (IQR, 17.25, 20.90) in the 3 mg/kg and 5 mg/kg cohorts, respectively. BIRC-assessed ORRs were 13.3% and 14.7% in the 3 mg/kg and 5 mg/kg cohorts, respectively. Median progression-free survival was 3.68 (95% confidence interval [CI] 3.22-7.29) and 3.68 (95%CI 1.81-7.39) months, while overall survival was 19.70 (95.5%CI 15.44-not estimated [NE]) and 13.04 (95.5%CI 9.86-NE) months, respectively. The most common treatment-related adverse events (TRAEs) were anaemia (28.1%), hyperglycaemia (26.7%), and infusion-related reactions (26.7%). The incidence rates of grade ≥ 3 TRAEs and TRAEs leading to treatment discontinuation were 42.2% and 14.1%, respectively. CONCLUSIONS: Both 3 mg/kg and 5 mg/kg KN046 showed promising efficacy and favourable safety profile for advanced NSCLC after failure or intolerance to previous platinum-based chemotherapy. TRIAL REGISTRATION NUMBER: NCT03838848.