Concomitant genomic features stratify prognosis to patients with advanced EGFR mutant lung cancer.

This study aimed to explore the clinical significance of genomics features including tumor mutation burden (TMB) and copy number alteration (CNA) for advanced EGFR mutant lung cancer. We retrospectively identified 1378 patients with advanced EGFR mutant lung cancer and next-generation sequencing tests from three cohorts. Multiple co-occurring genomics alternations occurred in a large proportion (97%) of patients with advanced EGFR mutant lung cancers. Both TMB and CNA were predictive biomarkers for these patients. A joint analysis of TMB and CNA found that patients with high TMB and high CNA showed worse responses to EGFR-TKIs and predicted worse outcomes. TMBhighCNAhigh, as a high-risk genomic feature, showed predictive ability in most of the subgroups based on clinical characteristics. These patients had larger numbers of metastatic sites, and higher rates of EGFR copy number amplification, TP53 mutations, and cell-cycle gene alterations, which showed more potential survival gain from combination treatment. Furthermore, a nomogram based on genomic features and clinical features was developed to distinguish prognosis. Genomic features could stratify prognosis and guide clinical treatment for patients with advanced EGFR mutant lung cancer.

Paclitaxel liposome (Lipusu) based chemotherapy combined with immunotherapy for advanced non-small cell lung cancer: a multicenter, retrospective real-world study.

BACKGROUND: Paclitaxel liposome (Lipusu) is known to be effective in non-small cell lung cancer (NSCLC) as first-line treatment. This study aimed to evaluate the effectiveness and safety of paclitaxel liposome based chemotherapy plus PD-1/PD-L1 inhibitor in patients with advanced NSCLC. METHODS: In this multicenter, retrospective, real-world study, patients with advanced NSCLC who were administered paclitaxel liposome based chemotherapy plus PD-1/PD-L1 inhibitor in three centers (Peking University People's Hospital as the lead center) in China between 2016 and 2022 were included. Progression-free survival (PFS), overall survival (OS), objective response rate, disease control rate, and adverse events (AEs) were evaluated. RESULTS: A total of 49 patients were included, with 33 (67.3%) receiving paclitaxel liposome based chemotherapy plus PD-1/PD-L1 inhibitor as first-line treatment. There were 34 patients (69.4%) diagnosed with squamous cell carcinoma and 15 (30.6%) with adenocarcinoma. The median follow-up was 20.5 (range: 3.1-41.1) months. The median PFS and OS of all patients were 9.7 months (95% confidence interval [CI], 7.0-12.4) and 30.5 months (95% CI, not evaluable-not evaluable), respectively. Patients with squamous cell carcinoma and adenocarcinoma had median PFS of 11 months (95%CI, 6.5-15.5) and 9.3 months (95%CI, 7.0-12.4), respectively. The median PFS was 9.9 months (95%CI, 7.1-12.7) in patients who received the combined regimen as first-line treatment. Treatment-related AEs of any grade were observed in 25 (51.0%) patients, and AEs of grade 3 or worse were observed in nine patients (18.4%). The most common treatment-related AEs were myelosuppression (14.3%) and fever (10.2%). CONCLUSIONS: Paclitaxel liposome based chemotherapy plus PD-1/PD-L1 inhibitor prolonged the PFS in advanced NSCLC with acceptable safety, which was worthy of clinical application.

Pemetrexed induces ROS generation and cellular senescence by attenuating TS-mediated thymidylate metabolism to reverse gefitinib resistance in NSCLC.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are strongly recommended for non-small-cell lung cancer (NSCLC) patients harbouring active EGFR mutations, while drug resistance makes exploring resistance mechanisms and seeking effective therapeutic strategies urgent endeavours. Thymidylate synthetase (TYMS or TS) is a dominant enzyme in thymidylate nucleotide metabolism. In this study, we found a positive correlation between TS expression and overall survival (OS) and disease-free survival (DFS) in lung adenocarcinoma. The examination of gene sets from 140 NSCLC patients received EGFR-TKI therapy demonstrated a negative correlation between high TS expression and the efficacy of EGFR-TKI therapy. 24 tissue specimens from NSCLC patients exhibited upregulated TS mRNA expression in NSCLC patients resistant to gefitinib. The NSCLC cell PC9 and HCC827 sensitive to gefitinib and relatively resistant PC9/GR and HCC827/GR cells were used to demonstrate the knockdown of TS restored the sensitivity of resistant cells to gefitinib. Furthermore, pemetrexed effectively suppressed TS-mediated thymidylate metabolism and induced ROS generation, DNA damage and cellular senescence, thereby hampering cancer progression and restoring sensitivity to gefitinib. Our findings illuminate the potential mechanism of TS-triggered gefitinib resistance and indicate inhibition of TS by pemetrexed can potentiate the effect of gefitinib in NSCLC. Pemetrexed combined with gefitinib has potent anti-progression potential in gefitinib-resistant NSCLC. This study suggests that NSCLC patients with both high TS expression and EGFR-driving mutations might benefit more from a combination strategy of EGFR-TKI and pemetrexed-based chemotherapy than EGFR-TKI monotherapy, which has profound clinical implications and therapeutic value.

Safety, efficacy, and pharmacokinetics of SH-1028 in EGFR T790M-positive advanced non-small cell lung cancer patients: A dose-escalation phase 1 study.

BACKGROUND: SH-1028 is a new third-generation EGFR tyrosine kinase inhibitors (TKI) to benefit patients with EGFR T790M-mutated NSCLC. Here, the authors report its clinical safety, preliminary efficacy, and pharmacokinetic (PK) profile for the first time. METHODS: Patients with EGFR T790M mutation, locally advanced non-small cell lung cancer (NSCLC), or metastatic NSCLC who had progressed after previous EGFR TKI therapy were eligible. Patients received SH-1028 at five oral dose levels (60 mg, 100 mg, 200 mg, 300 mg, and 400 mg) once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary end points were the safety, dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and PK profile. Secondary end points included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), etc. RESULTS: Data cut off on December 31, 2020, a total of 20 patients were enrolled during the trial, two of three patients in 300 mg cohort experienced a DLT, and no DLT was observed in 240 mg cohort, 240 mg was determined to be the MTD of SH-1028. A total of 95.0% (19 of 20) of patients reported treatment-related adverse events (TRAEs), and the incidence of serious adverse events was 20.0% (4 of 20). The ORR and DCR of the 200 mg cohort were 75% (95% confidence interval [CI], 19.41-99.37) and 75.0% (95% CI, 19.41-99.37), respectively. The overall ORR was 40% (95% CI, 19.12-63.95), and DCR was 70.0% (95% CI, 45.72-88.11). According to the PK profile, the dosage regimen for future studies was determined as 200 mg once daily. CONCLUSIONS: SH-1028 showed a manageable safety and promising antitumor activity in patients with EGFR T790M mutation at the dose of 200 mg once daily. PLAIN LANGUAGE SUMMARY: Lung cancer has a high morbidity and mortality, with an estimated 1.8 million deaths in 2020. Non-small cell lung cancer accounts for approximately 85% of lung cancer. First- or second-generation EGFR TKIs' weak selectivity often led to the occurrence of treatment-related adverse events, such as interstitial lung disease, rash, diarrhea, etc., along with acquired drug resistance within approximately 1 year. A dose of 200 mg of SH-1028 once daily showed a preliminary antitumor activity with manageable safety in patients with EGFR T790M mutation.

Ferroptosis in cancer therapy: a novel approach to reversing drug resistance.

Ferroptosis is an intracellular iron-dependent form of cell death that is distinct from apoptosis, necrosis, and autophagy. Extensive studies suggest that ferroptosis plays a pivotal role in tumor suppression, thus providing new opportunities for cancer therapy. The development of resistance to cancer therapy remains a major challenge. A number of preclinical and clinical studies have focused on overcoming drug resistance. Intriguingly, ferroptosis has been correlated with cancer therapy resistance, and inducing ferroptosis has been demonstrated to reverse drug resistance. Herein, we provide a detailed description of the mechanisms of ferroptosis and the therapeutic role of regulating ferroptosis in reversing the resistance of cancer to common therapies, such as chemotherapy, targeted therapy and immunotherapy. We discuss the prospect and challenge of regulating ferroptosis as a therapeutic strategy for reversing cancer therapy resistance and expect that our review could provide some references for further studies.

On-treatment blood TMB as predictors for camrelizumab plus chemotherapy in advanced lung squamous cell carcinoma: biomarker analysis of a phase III trial.

BACKGROUND: Camrelizumab plus chemotherapy significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone as first-line treatment in advanced lung squamous cell carcinoma (LUSC) in the phase III trial (CameL-sq), which has become an option of standard-of-cares for Chinese patients with advanced LUSC. However, the predictive biomarkers remain unknown. METHODS: Tumor tissue samples at baseline, and peripheral blood samples at baseline (pretreatment) and after two cycles of treatment (on-treatment) were prospectively collected from 270 LUSC patients from the CameL-sq study. Blood tumor mutation burden (bTMB) and its dynamics were analyzed to explore their predictive values. RESULTS: Pretreatment bTMB was not associated with objective response, PFS and OS in camrelizumab or placebo plus chemotherapy groups. Low on-treatment bTMB was associated with significantly better objective response (73.8% vs 27.8%, P < 0.001), PFS (median, 9.1 vs 4.1 months; P < 0.001) and OS (median, not reached vs 8.0 months; P < 0.001) in camrelizumab plus chemotherapy group whereas it did not correlate with objective response and PFS in chemotherapy alone group. Importantly, on-treatment bTMB level could discriminate patients of initially radiological stable disease who would long-term benefit from camrelizumab plus chemotherapy (low vs high, median OS, 18.2 vs 7.8 months; P = 0.001). Combing on-treatment bTMB and its dynamics improved the ability for predicting the efficacy of camrelizumab plus chemotherapy. CONCLUSION: On-treatment bTMB together with its dynamics could serve as a predictive biomarker for camrelizumab plus chemotherapy in patients with advanced LUSC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03668496.

A two-phase comprehensive NSCLC prognostic study identifies lncRNAs with significant main effect and interaction.

Long noncoding RNA (lncRNA) are involved in regulating physiological behaviors for various malignant tumors, including non-small-cell lung cancer (NSCLC). However, few studies comprehensively evaluated both lncRNA-lncRNA interaction effects and main effects of lncRNA on overall survival of NSCLC. Hence, we performed a two-phase designed study of lncRNA expression in tumor tissues using 604 NSCLC patients from The Cancer Genome Atlas as the discovery phase and 839 patients from Gene Expression Omnibus as the validation phase. In the discovery phase, we adopted a two-step strategy, Screening before Testing, for dimension reduction and signal detection. These candidate lncRNAs first screened out by the weighted random forest (Ranger), were then tested through the Cox proportional hazards model adjusted for covariates. Significant lncRNAs with either type of effects aforementioned were carried forward into the validation phase to confirm their significances again. As a result, in the discovery phase, 19 lncRNAs were identified by Ranger, among which five lncRNAs and one pair of lncRNA-lncRNA interaction exhibited significant effects (FDR-q ≤ 0.05) main and interaction effects on NSCLC survival, respectively, through Cox model. After the independent validation, we finally observed that one lncRNA (ENSG00000227403.1) with main effect was robustly associated with NSCLC prognosis (HRdiscovery = 0.90, P = 1.20 × 10-3; HRvalidation = 0.94, P = 4.11 × 10-3) and one pair of lncRNAs (ENSG00000267121.4 and ENSG00000272369.1) had significant interaction effect on NSCLC survival (HRdiscovery = 1.12, P = 3.07 × 10-4; HRvalidation = 1.11, P = 0.0397). Our comprehensive NSCLC prognostic study of lncRNA provided population-level evidence for further functional study.

RNA methyltransferase METTL3 induces intrinsic resistance to gefitinib by combining with MET to regulate PI3K/AKT pathway in lung adenocarcinoma.

Clinical research data show that gefitinib greatly improves the progression-free survival of patients, so it is used in advanced non-small cell lung cancer patients with EGFR mutation. However, some patients with EGFR sensitive mutations do not have good effects on initial gefitinib treatment, and this mechanism is rarely studied. METTL3, a part of N6-adenosine-methyltransferase, has been reported to play an important role in a variety of tumours. In this study, we found that METTL3 is up-regulated in gefitinib-resistant tissues compared to gefitinib-sensitive tissues. Cell function experiments have proved that under the treatment of gefitinib, METTL3 knockdown promotes apoptosis and inhibits proliferation of lung cancer cells. Mechanistic studies have shown that METTL3 combines with MET and causes the PI3K/AKT signalling pathway to be manipulated, which affects the sensitivity of lung cancer cells to gefitinib. Therefore, our research shows that METTL3 can be used as a molecular marker to predict the efficacy of EGFR-TKI therapy in patients, and METTL3 may be a potential therapeutic target.

Efficacy and acquired resistance of EGFR-TKI combined with chemotherapy as first-line treatment for Chinese patients with advanced non-small cell lung cancer in a real-world setting.

BACKGROUND: To compare the benefits and explore the cause of acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and its combination with chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutation in a real-life setting. METHODS: This retrospective analysis included 117 advanced NSCLC patients with EGFR mutation who underwent next-generation sequencing (NGS) prior to treatment. The combination group included 50 patients who received the regimen of EGFR-TKI combined with chemotherapy, while the EGFR-TKI monotherapy group included 67 patients treated with TKI only. The primary endpoint of this study was progression-free survival (PFS); the secondary endpoints were overall survival (OS), response rate, and toxicity. RESULTS: The median PFS was significantly longer in the combination group than in the EGFR-TKI monotherapy group (19.00 months [95% CI, 14.67-23.33] vs. 11.70 months [95% CI, 10.81-12.59], p < 0.001). Subgroup analysis showed a similar trend of results. The median OS was not reached in the combination group and was 38.50 (95% CI, 35.30-41.70) months in the EGFR-TKI monotherapy group (p = 0.586). Patients in the combination group were more likely to experience adverse events, most of which showed the severity of grade 1 or 2. T790M mutation remains the main reason for acquired resistance, and the frequency of T790M mutation was similar between the two groups (p = 0.898). CONCLUSIONS: Compared with EGFR-TKI monotherapy, EGFR-TKI combined with chemotherapy significantly improved PFS in advanced NSCLC patients with EGFR mutation, with acceptable toxicity.

Metabolic disposition of [14 C]-abivertinib, an epidermal growth factor receptor tyrosine kinase inhibitor: Role of glutathione conjugation.

AIMS: To determine the absorption, distribution, metabolism and excretion of abivertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Seven patients with advanced NSCLC were given a single 200 mg/83 µCi oral suspension of [14 C]-abivertinib. Blood, urine and faeces were collected. Mass balance of radioactivity, the pharmacokinetics of abivertinib, and the total radioactivity were determined. Metabolite profiling and characterisation were performed. RESULTS: The mean recovery was 82.16%, with 2.38 and 79.78% of the radioactive dose excreted in urine and faeces, respectively. The unchanged abivertinib was the major radioactive component detected in plasma within the first 24 hours after dosing, accounting for 59.17% of the total drug-related radioactivity. Abivertinib in urine accounted for only 0.96% of the administered dose, whereas in faeces it accounted for 33.36%. Eight metabolites were detected and characterised in plasma, among which MII-7, a product of cysteine glycine conjugate, was the only circulating metabolite, accounting for approximate 10.6% of the total drug-related exposure. MII-2 (an abivertinib cysteine-glycine adduct) and M7 (a reduced product of abivertinib) were the 2 major metabolites in the excreta, accounting for 20.0 and 12.4%, respectively, of the drug-related radioactivity in faeces. CONCLUSION: Following a single oral administration, the unchanged abivertinib was the predominant drug-related material in plasma, urine and faeces. The drug-related materials were primarily eliminated via the faecal route. Direct glutathione conjugation of abivertinib played a significant role in the metabolic clearance and metabolite exposure of abivertinib.

A Novel Long Non-Coding RNA, SOX21-AS1, Indicates a Poor Prognosis and Promotes Lung Adenocarcinoma Proliferation.

BACKGROUND: In recent years, long non-coding RNAs (lncRNAs) have been shown to be a novel class of regulators of cancer biological processes. Although lncRNAs are dysregulated in numerous cancer types, limited data are available on the expression profiles and potential functions of lncRNAs in lung adenocarcinoma (LUAD). This study evaluated the expression and biological roles of lncRNA SOX21 antisense RNA 1 (SOX21-AS1) in LUAD. METHODS: Quantitative reverse transcription PCR (qRT-PCR) was performed to detect the expression levels of SOX21-AS1 in 68 pairs of LUAD tissues and corresponding non-tumor tissues. The effect of SOX21-AS1 on proliferation was evaluated by MTT, colony formation, EdU assays, flow-cytometric analysis and in vivo tumor formation assays. Real-time PCR, western-blot and immunohistochemistry were used to evaluate the mRNA and protein expression of p57. RESULTS: Higher expression levels of SOX21-AS1 positively correlated with tumor size and advanced tumor-node-metastasis (TNM) stage. Multivariate analyses indicated that SOX21-AS1 expression could serve as an independent prognostic factor for overall survival of LUAD. Furthermore, knockdown of SOX21-AS1 significantly inhibited LUAD cell proliferation both in vitro and in vivo and induced cell cycle phase arrest and cell apoptosis. Importantly, through qRT-PCR and western blot analysis, we found that inhibition of SOX21-AS1 remarkably induced p57 expression. CONCLUSIONS: Collectively, our study demonstrates that SOX21-AS1 is involved in the development and progression of LUAD and that SOX21-AS1 may be a potential diagnostic factor as well as a target for new therapies for patients with LUAD.

Low expression of long noncoding RNA CASC2 indicates a poor prognosis and regulates cell proliferation in non-small cell lung cancer.

Recently, long noncoding RNAs (lncRNAs) have been shown to have important regulatory roles in human cancer biology. The aim of this study was to evaluate the expression and biological role of lncRNA CASC2 in non-small cell lung cancer (NSCLC). By bioinformatics analysis, we found that CASC2 was significantly decreased in NSCLC. qRT-PCR was performed to investigate the expression of CASC2 in tumor tissues and corresponding non-tumor NSCLC tissues from 76 patients. The lower expression of CASC2 was remarkably correlated with advanced TNM stage and tumor size. Multivariate analyses found that CASC2 expression served as an independent predictor for overall survival of NSCLC. Moreover, overexpression of CASC2 significantly inhibited NSCLC cell proliferation both in vitro and in vivo. In conclusion, our study demonstrated that CASC2 is involved in the development and progression of NSCLC and shows that CASC2 may be a potential diagnostic and target for new therapies in patients with NSCLC.

Decreased expression of long noncoding RNA MEG3 affects cell proliferation and predicts a poor prognosis in patients with colorectal cancer.

Colorectal cancer (CRC) remains an important public health problem in the world. Long noncoding RNA (lncRNA) is an RNA molecular that is longer than 200 nucleotides and cannot be translated into a protein. Recent studies have shown that lncRNAs play important roles in carcinogenesis and cancer metastasis. The aim of this study was to evaluate the expression and biological role of lncRNA maternally expressed gene 3 (MEG3) in colorectal cancer. Quantitative real-time-PCR (qRT-PCR) was performed to investigate the expression of MEG3 in tumor tissues and corresponding nontumor colorectal tissues from 62 patients. The lower expression of MEG3 was remarkably correlated with low histological grade, deep tumor invasion, and advanced tumor node metastasis (TNM) stage. Multivariate analyses revealed that MEG3 expression served as an independent predictor for overall survival. Further experiments revealed that overexpressed MEG3 significantly inhibited CRC cell proliferation both in vitro and in vivo. In conclusion, our study demonstrated that MEG3 is involved in the development and progression of colorectal cancer by regulating cell proliferation and shows that MEG3 may be a potential diagnostic and prognostic target in patients with colorectal cancer.

Downregulation of MicroRNA-1 is Associated with Poor Prognosis in Hepatocellular Carcinoma.

BACKGROUND: The relationship between microRNA-1 (miR-1) expression and prognosis has not been reported in hepatocellular carcinoma (HCC). The present study aimed to explore the clinicopathological significance and the prognostic role of miR-1 in HCC. METHODS: The expression levels of miR-1 were quantified using real-time quantitative PCR (q-PCR) in 40 surgically resected HCC samples and matched adjacent non-cancerous tissues. RESULTS: MiR-1 expression was significantly downregulated in HCC compared with matched non-cancerous tissues. Aberrant miR-1 expression was significantly correlated with gender, expression of hepatitis B virus surface antigen (HBsAg), tumor differentiation, vein invasion, and TNM stage. Patients with low expression of miR-1 had significantly reduced overall survival compared with patients with high expression of miR-1 (p = 0.04).The multivariate Cox regression analysis indicated that miR-1 expression (HR = 2.79; p = 0.005), gender (HR = 0.087; p = 0.005), vein invasion (HR = 0.172; p = 0.007), and TNM stage (HR = 3.421; p = 0.001) were independent prognostic factors for overall survival. CONCLUSIONS: Low miR-1 expression is associated with shortened survival time. MiR-1 may act as a potential prognostic biomarker for HCC patients.

Correlation between the expression levels of miR-1 and PIK3CA in non-small-cell lung cancer and their relationship with clinical characteristics and prognosis.

AIMS: To examine the relationship between the expression levels of miR-1 and PIK3CA in resected non-small-cell lung cancer (NSCLC) tissues and clinical characteristics and prognosis. MATERIALS & METHODS: Levels of miR-1 and PIK3CA in cancerous and normal tissues obtained from 55 patients with NSCLC were measured by real-time PCR and western blot assays, and their associations with clinicopathological features were evaluated. RESULTS: A total of 69.1% of the NSCLC tissue samples showed low miR-1 expression (p < 0.05) and 70.9% showed high PIK3CA expression (p < 0.05). Patients with low miR-1 expression and those with high PIK3CA expression had significantly higher incidences of lymph node metastases and postoperative recurrences within 1 year after surgery than those with moderate miR-1 expression and moderate PIK3CA expression (p < 0.05 for both). CONCLUSION: Low expression of miR-1 and overexpression of PIK3CA in NSCLC tissues may be useful predictors of lymph node metastasis and postoperative recurrence in patients with NSCLC.

A Visual Analysis of the Research Dynamics in Resistance to EGFR Inhibitors for NSCLC.

Purpose: Activating mutations in epidermal growth factor receptor (EGFR) have been identified as key predictive biomarkers for the customized treatment with EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), aiding in improving patient response rates and survival. However, resistance challenges the efficacy of these treatments, with limited understanding of post-resistance therapeutic strategies. A deep understanding of the biology and resistance mechanisms of EGFR-mutant NSCLC is crucial for developing new treatment approaches. This study, through bibliometric analysis, summarizes the trends in research on resistance to EGFR-TKIs. Methods: Research papers on NSCLC with EGFR inhibitor resistance were collected from the Web of Science Core Collection (WoSCC). The analysis utilized bibliometric tools like CiteSpace, VOSviewer, and other platforms for comprehensive analysis and visualization of the outcomes. Results: The WoSCC database contains a total of 5866 documents on resistance to EGFR-TKIs treatment, including 4727 articles (93.48%) and 1139 reviews (6.52%), spanning 81 countries and regions, 4792 institutions, with the involvement of 23,594 authors. Since 2016, there has been a significant increase in publications in this field. China has the highest publication output, while the United States has the highest citation count for papers. Harvard University leads in terms of the number of publications. Among the top ten journals with the highest output, Clinical Cancer Research has the highest impact factor at 11.5, with 90% of the journals classified in Q1 or Q2. Rafael Rosell is one of the most influential authors in this field, ranking second in publication volume and fourth in citation count. Research on EGFR-TKIs resistance mainly focuses on genetic testing, resistance mechanisms, and post-resistance treatment strategies. Conclusion: This study provides researchers with a reliable basis and guidance for finding authoritative references, understanding research trends, and exploring potential directions.

Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS).

BACKGROUND: The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. METHODS: Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS). RESULTS: Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. CONCLUSIONS: These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03849768.

Carbonic Anhydrase IX Controls Vulnerability to Ferroptosis in Gefitinib-Resistant Lung Cancer.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI, such as gefitinib) in lung cancer continues to be a major problem. Recent studies have shown the promise of ferroptosis-inducing therapy in EGFR-TKI resistant cancer, but have not been translated into clinical benefits. Here, we identified carbonic anhydrase IX (CA9) was upregulated in gefitinib-resistant lung cancer. Then we measured the cell viability, intracellular reactive oxygen species (ROS) levels, and labile iron levels after the treatment of ferroptosis inducer erastin. We found that CA9 confers resistance to ferroptosis-inducing drugs. Mechanistically, CA9 is involved in the inhibition of transferrin endocytosis and the stabilization of ferritin, leading to resistance to ferroptosis. Targeting CA9 promotes iron uptake and release, thus triggering gefitinib-resistant cell ferroptosis. Notably, CA9 inhibitor enhances the ferroptosis-inducing effect of cisplatin on gefitinib-resistant cells, thus eliminating resistant cells in heterogeneous tumor tissues. Taken together, CA9-targeting therapy is a promising approach to improve the therapeutic effect of gefitinib-resistant lung cancer by inducing ferroptosis.

Low­dose anlotinib combined with EGFR­TKI can be used as an alternative for EGFR­TKI­resistant non­small cell lung cancer in elderly patients.

The current treatment options for epidermal growth factor receptor (EGFR) mutation-positive lung cancer in the elderly with tyrosine kinase inhibitor (TKI) resistance are limited. Although chemotherapy combined with vascular endothelial growth factor inhibitors significantly improves progression-free survival (PFS) in TKI-resistant patients, it often cannot be tolerated in elderly patients, leading to treatment failure. Anlotinib is a small molecule inhibitor made in China. The application of low-dose anlotinib in elderly patients with TKI-resistant lung cancer deserves further investigation. A total of 48 elderly patients with non-small cell lung cancer (NSCLC) were enrolled to evaluate the efficacy of anlotinib combined with continuous EGFR-TKI vs. anlotinib monotherapy in patients with acquired EGFR-TKI resistance. Anlotinib was administered at a dose of 6-8 mg per day, lower than the normal dose and known as a low dose, which is well tolerated in elderly patients. There were 25 cases in the combination group and 23 cases in the anlotinib monotherapy group. The primary endpoint of the present study was PFS, and the secondary endpoints were overall survival (OS), response rate and toxicity. The median PFS (mPFS) was significantly longer in the combination group than that in the anlotinib monotherapy group: 6.0 months [95% confidence interval (CI), 4.35-7.65] compared with 4.0 months (95% CI, 3.38-4.62) (P=0.002). Analysis of the subgroups showed similar trends in results. The median OS was 32 months (95% CI, 22.04-41.96) in the combination group and 28 months (95% CI, 27.13-28.87) in the anlotinib monotherapy group (P=0.217). According to stratification analysis, second-line treatment with anlotinib combined with EGFR-TKI resulted in a better mPFS than third-line treatment (7.5 vs. 3.7 months, HR=3.477; 95% CI, 1.117-10.820; P=0.031). In the combination group, patients with gradual/local progression after EGFR-TKI failure had a longer mPFS than those with dramatic progression (7.5 vs. 6.0 months, HR=5.875; 95% CI, 1.414-10.460; P=0.015). Multivariate analyses showed that continuous EGFR-TKI combined with anlotinib after EGFR-TKI resistance was associated with longer PFS (P=0.019), whereas dramatic progression (P=0.014) had a detrimental effect on follow-up treatment. Grade 2 adverse events (AEs) were reported in four patients (17.39%) in the anlotinib monotherapy group and eight patients (32.00%) in the combination group. Of these, the most common grade 2 AEs were hypertension, fatigue, diarrhea, paronychia, mucositis and transaminase elevation. There were no grade 3/4/5 AEs. In conclusion, the present study demonstrated that low-dose anlotinib combined with EGFR-TKI is superior to anlotinib alone following EGFR-TKI failure, making it the preferred regimen for elderly patients with acquired EGFR-TKI resistance.

Efficacy and safety of antiangiogenic agents or chemotherapy plus EGFR-TKIs in advanced non-small cell lung cancer: A systematic review and network meta-analysis.

BACKGROUND: The combination of antiangiogenic agents with epidermal growth factor receptor inhibitors (EGFR-TKIs) and chemotherapy with EGFR-TKIs are the most common combination treatment options in epidermal growth factor receptor (EGFR) positive non-small cell lung cancer (NSCLC). This network meta-analysis was performed to evaluate the differences between them. METHODS: We searched the PubMed, EMBASE and the Cochrane Controlled Trials Register up to August 2022. The primary outcomes were progression-free survival (PFS) and objective response rate (ORR). The secondary endpoints were overall survival (OS), disease control rate (DCR) and adverse events (AEs). The data of hazard ratio (HR) or risk ratio (RR) with their corresponding 95% confidence intervals (CIs) were extracted in the studies. A network meta-analysis (NMA) was used to indirectly compare the efficacy and safety of antiangiogenic agents plus EGFR-TKIs and chemotherapy plus EGFR-TKIs. RESULTS: Pooled data of included studies were demonstrated that chemotherapy plus EGFR-TKIs had a benefit in ORR compared to antiangiogenic agents plus EGFR-TKIs in patients with EGFR mutated NSCLC (RR = 1.1, 95% CI: 1.0-1.2). However, there were no significant differences in PFS, OS and DCR between in the two group (PFS: HR = 1.0, 95% CI: 0.74-1.6; OS: HR = 0.78, 95% CI: 0.45-1.5; DCR: RR = 1.0, 95% CI: 0.94-1.1). The common treatment-related AEs in the two groups were relatively manageable. CONCLUSION: Based on the efficacy and safety, the combination of chemotherapy with EGFR-TKIs is considered the best combination treatment options in advanced NSCLC with EGFR mutation.