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.

A clinical decision support system to predict the efficacy for EGFR-TKIs based on artificial neural network.

BACKGROUND: The efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) was affected by numerous factors. In the study, we developed and validated an artificial neural network (ANN) system based on clinical characteristics and next-generation sequencing (NGS) to support clinical decisions. METHODS: A multicenter retrospective non-interventional study was conducted. 240 patients from three hospitals with advanced non-small cell lung cancer (NSCLC) and EGFR mutation were tested by NGS before the first treatment. All patients received formal EGFR-TKIs treatment. Five different models were individually trained to predict the efficacy of EGFR-TKIs based on one medical center with 188 patients. Two independent cohorts from other medical centers were collected for external validation. RESULTS: Compared with logistic regression, four machine learning methods showed better predicting abilities for EGFR-TKIs. The inclusion of NGS tests improved the predictive power of models. ANN performed best on the dataset with mutations TP53, RB1, PIK3CA, EGFR mutation sites, and tumor mutation burden (TMB). The prediction accuracy, recall and AUC were 0.82, 0.82, and 0.82, respectively in our final model. In the external validation set, ANN still showed good performance and differentiated patients with poor outcomes. Finally, a clinical decision support software based on ANN was developed and provided a visualization interface for clinicians. CONCLUSION: This study provides an approach to assess the efficacy of NSCLC patients with first-line EGFR-TKI treatment. Software is developed to support clinical decisions.

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.

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.

B4GALT1 promotes immune escape by regulating the expression of PD-L1 at multiple levels in lung adenocarcinoma.

BACKGROUND: Invasive adenocarcinoma (IAC), which is typically preceded by minimally invasive adenocarcinoma (MIA), is the dominant pathological subtype of early-stage lung adenocarcinoma (LUAD). Identifying the molecular events underlying the progression from MIA to IAC may provide a crucial perspective and boost the exploration of novel strategies for early-stage LUAD diagnosis and treatment. METHODS: Transcriptome sequencing of four pairs of MIA and IAC tumours obtained from four multiple primary lung cancer patients was performed to screen out beta-1,4-galactosyltransferase1 (B4GALT1). Function and mechanism experiments in vitro and in vivo were performed to explore the regulatory mechanism of B4GALT1-mediated immune evasion by regulating programmed cell death ligand 1 (PD-L1). RESULTS: B4GALT1, a key gene involved in N-glycan biosynthesis, was highly expressed in IAC samples. Further experiments revealed that B4GALT1 regulated LUAD cell proliferation and invasion both in vitro and in vivo and was related to the impaired antitumour capacity of CD8 + T cells. Mechanistically, B4GALT1 directly mediates the N-linked glycosylation of PD-L1 protein, thus preventing PD-L1 degradation at the posttranscriptional level. In addition, B4GALT1 stabilized the TAZ protein via glycosylation, which activated CD274 at the transcriptional level. These factors lead to lung cancer immune escape. Importantly, inhibition of B4GALT1 increased CD8 + T-cell abundance and activity and enhanced the antitumour immunity of anti-PD-1 therapy in vivo. CONCLUSION: B4GALT1 is a critical molecule in the development of early-stage LUAD and may be a novel target for LUAD intervention and immunotherapy.

LncRNA LINC00969 promotes acquired gefitinib resistance by epigenetically suppressing of NLRP3 at transcriptional and posttranscriptional levels to inhibit pyroptosis in lung cancer.

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment prolongs the survival of lung cancer patients harbouring activating EGFR mutations. However, resistance to EGFR-TKIs is inevitable after long-term treatment. Molecular mechanistic research is of great importance in combatting resistance. A comprehensive investigation of the molecular mechanisms underlying resistance has important implications for overcoming resistance. An accumulating body of evidence shows that lncRNAs can contribute to tumorigenesis and treatment resistance. By bioinformatics analysis, we found that LINC00969 expression was elevated in lung cancer cells with acquired gefitinib resistance. LINC00969 regulated resistance to gefitinib in vitro and in vivo. Mechanistically, gain of H3K4me1 and H3K27Ac led to the activation of LINC00969 expression. LINC00969 interacts with EZH2 and METTL3, transcriptionally regulates the level of H3K27me3 in the NLRP3 promoter region, and posttranscriptionally modifies the m6A level of NLRP3 in an m6A-YTHDF2-dependent manner, thus epigenetically repressing NLRP3 expression to suppress the activation of the NLRP3/caspase-1/GSDMD-related classical pyroptosis signalling pathways, thereby endowing an antipyroptotic phenotype and promoting TKI resistance in lung cancer. Our findings provide a new mechanism for lncRNA-mediated TKI resistance from the new perspective of pyroptosis via simultaneous regulation of histone methylation and RNA methylation. The pivotal role of LINC00969 gives it the potential to be a novel biomarker and therapeutic target for overcoming EGFR-TKI resistance in lung cancer.

Befotertinib (D-0316) versus icotinib as first-line therapy for patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer: a multicentre, open-label, randomised phase 3 study.

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.

Efficacy and Safety of Anti-Programmed Death-Ligand 1 Monoclonal Antibody Socazolimab With Carboplatin and Etoposide for Extensive-Stage SCLC: Results From the Phase 1b Clinical Trial.

Introduction: The study (ClinicalTrials.gov, NCT04346914) is an open label, single-arm, phase 1b clinical trial investigating the safety, tolerability, and efficacy of the recombinant human anti-programmed death-ligand 1 monoclonal antibody socazolimab in combination with carboplatin and etoposide in the first-line treatment of extensive-stage SCLC. Good safety and efficacy were found in previous phase 1 clinical trials of other cancers, such as cervix cancer. Methods: Patients received socazolimab (5 mg/kg) every three weeks until disease progression or physician decision. Carboplatin (area under the curve: 5) was also administered every three weeks and etoposide (100 mg/m2) on days 1, 2, and 3 of the treatment cycle. The primary purpose of the study was safety measured by the Common Terminology Criteria for Adverse Events. Secondary purposes included objective response rate, progression-free survival, duration of response, and overall survival. Results: From April 15, 2020 (enrollment date), to December 30, 2021 (data cutoff), 20 patients with extensive-stage SCLC were administered with socazolimab, carboplatin, and etoposide. Objective response rate was 70.0% (95% confidence interval [CI]: 45.72%-88.11%). Median progression-free survival was 5.65 months (95% CI: 4.14-6.54), and the median duration of response was 4.29 months (95% CI: 2.76-5.85). Median overall survival was 14.88 months (95% CI: 10.09-not evaluated). The highest incidence of treatment-related adverse events included anemia (100%), decreased neutrophil count (95%), decreased platelet count (95%), and decreased white blood cell count (95%), which occurred during combination therapy. The most common grade 3 or 4 treatment-related adverse events were neutropenia (90%), decreased white blood cell count (65%), decreased platelet count (50%), and anemia (30%), which were also common adverse reactions of chemotherapy. No adverse events leading to death had occurred. Conclusions: Results revealed that the combination therapy of socazolimab, carboplatin, and etoposide had preliminarily confirmed the safety of socazolimab in the first-line treatment of SCLC combined with EC chemotherapy. Currently, a phase 3, randomized, placebo-controlled trial (ClinicalTrials.gov, NCT04878016) is being conducted with 498 patients.

Efficacy and safety of KL-A167 in previously treated recurrent or metastatic nasopharyngeal carcinoma: a multicenter, single-arm, phase 2 study.

Background: KL-A167 is a fully humanized monoclonal antibody targeting programmed cell death-ligand 1. This phase 2 study aimed to evaluate the efficacy and safety of KL-A167 in Chinese patients with previously treated recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). Methods: This was a multicentre, single-arm, phase 2 study of KL-A167 in R/M NPC (KL167-2-05-CTP) (NCT03848286), conducted at 42 hospitals across the People's Republic of China. Eligible patients had histologically confirmed non-keratinising R/M NPC, and had failed at least two lines of chemotherapy. Patients received KL-A167 900mg intravenously once every 2 weeks until confirmed disease progression, intolerable toxicity, or withdrawal of informed consent. The primary endpoint was objective response rate (ORR) assessed by the independent review committee (IRC) according to RECIST v1.1. Findings: Between Feb 26th, 2019 and Jan 13th, 2021, 153 patients were treated. Totally, 132 patients entered full analysis set (FAS) and were evaluated for the efficacy. As of data cutoff date on Jul 13th, 2021, the median follow-up time was 21.7 months (95%CI 19.8-22.5). For FAS population, the IRC-assessed ORR was 26.5% (95%CI 19.2-34.9%), and disease control rate (DCR) was 56.8% (95%CI 47.9-65.4%). Median progression-free survival (PFS) was 2.8 months (95%CI 1.5-4.1) . Median duration of response was 12.4 months (95%CI 6.8-16.5), and median overall survival (OS) was 16.2 months (95%CI 13.4-21.3). When using the cutoff of 1000 copies/ml, 5000 copies/ml and 10,000 copies/ml for plasma EBV DNA titer, baseline low plasma EBV DNA was consistently related with better DCR, PFS and OS. Dynamic change of plasma EBV DNA was significantly associated with ORR and PFS. Among 153 patients, treatment related-adverse events (TRAEs) occurred in 73.2% of patients, and grade ≥3 TRAEs were in 15.0% of patients. No TRAE leading to death was reported. Conclusion: In this study, KL-A167 showed promising efficacy and an acceptable safety profile in patients with previously treated R/M NPC. Baseline plasma EBV DNA copy number might be a potentially useful prognostic biomarker for KL-A167 treatment, and post-treatment EBV DNA decrease might be correlated with better response to KL-A167. Funding: Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd., China National Major Project for New Drug Innovation (2017ZX09304015).

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.

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.

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.

Clinical implications of ctDNA for EGFR-TKIs as first-line treatment in NSCLC.

PURPOSE: This study aimed to explore the clinical implications of ctDNA for epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) as the first-line treatment in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) in real-world settings. METHODS: A total of 122 patients with NSCLC who underwent tissue and liquid next generation sequencing (NGS) tests were included. 66 patients with detected EGFR mutation in both tumor-tissue and plasma were included into the EGFRt+, p+ group, and 56 patients with EGFR mutation detected only in tumor-tissue were included into the EGFRt+, p- group. The differences in clinical characteristics, concomitant mutations and prognosis between the two groups were compared. RESULTS: The detection rate of the EGFRt+, p+ group was 54.1% (66/122). EGFRt+, p+ in the NGS test was particularly relevant to the size of tumors, liver metastasis, bone metastasis and TP53 mutation. In patients with TP53 mutation in ctDNA, the detection rate of EGFR mutation in ctDNA was up to 91.3%. EGFRt+, p+ could be an independent prognostic factor for first-line EGFR-TKIs treatment. Combination therapy seems to be a promising approach to improve the outcome for EGFRt+, p+ (P = 0.017, HR 0.509 [95% CI 0.288-0.897]). Moreover, the combination of TP53 mutated status and EGFRm status in plasma showed a better completion of risk stratification for PFS (Log-rank P < 0.001). CONCLUSIONS: Co-detection of EGFR mutation in tumor tissue and plasma is an independent prognostic factor for first-line EGFR-TKIs treatment. Moreover, combination therapy could be a promising approach to improve the outcome for these patients.

Rechallenge of immune checkpoint inhibitors in a case with adverse events inducing myasthenia gravis.

The mechanism(s) of immune checkpoint inhibitor (ICI)-induced myasthenia gravis (MG), an immune-related adverse event (irAE) that is fatal and limits subsequent ICI use, remain unexplored. Here, through comparative genomic analysis, we identified a pathogenic p.S467C germline variant in SLC22A5 in a thymoma case with ICI-induced MG, which was found to be associated with fatty acid oxidation through its regulation on L-carnitine levels. Remarkably, ICI rechallenge with L-carnitine pretreatment led to durable response without MG-related symptoms. Thus, we provide the first clinical evidence of genetic test-directed irAE management, which integrates individualized ICI treatment into the evolving paradigm of cancer management.

MNX1-AS1 Promotes Phase Separation of IGF2BP1 to Drive c-Myc-Mediated Cell-Cycle Progression and Proliferation in Lung Cancer.

c-Myc and E2F1 play critical roles in many human cancers. As long noncoding RNAs (lncRNA) are known to regulate various tumorigenic processes, elucidation of mechanisms of cross-talk between lncRNAs and c-Myc/E2F1-related signaling pathways could provide important insights into cancer biology. In this study, we used integrated bioinformatic analyses and found that the lncRNA MNX1-AS1 is upregulated in non-small cell lung cancer (NSCLC) via copy-number gain and c-Myc-mediated transcriptional activation. High levels of MNX1-AS1 were associated with poor clinical outcomes in patients with lung cancer. MNX1-AS1 promoted cell proliferation and colony formation in vitro and tumor growth in vivo. MNX1-AS1 bound and drove phase separation of IGF2BP1, which increased the interaction of IGF2BP1 with the 3'-UTR (untranslated region) of c-Myc and E2F1 mRNA to promote their stability. The c-Myc/MNX1-AS1/IGF2BP1 positive feedback loop accelerated cell-cycle progression and promoted continuous proliferation of lung cancer cells. In a lung cancer patient-derived xenograft model, inhibition of MNX1-AS1 suppressed cancer cell proliferation and tumor growth. These findings offer new insights into the regulation and function of c-Myc and E2F1 signaling in NSCLC tumorigenesis and suggest that the MNX1-AS1/IGF2BP1 axis may serve as a potential biomarker and therapeutic target in NSCLC. SIGNIFICANCE: MNX1-AS1 drives phase separation of IGF2BP1 to increase c-Myc and E2F1 signaling and to activate cell-cycle progression to promote proliferation in NSCLC.

Molecular subtypes based on cuproptosis-related genes and immune profiles in lung adenocarcinoma.

Background: Recent studies have identified several molecular subtypes of lung adenocarcinoma (LUAD) that have different prognoses to help predict the efficacy of immunotherapy. However, the prognostic prediction is less than satisfactory. Alterations in intracellular copper levels may affect the tumor immune microenvironment and are linked to cancer progression. Previous studies have identified some genes related to cuproptosis. The characteristics of the cuproptosis molecular subtypes have not been thoroughly studied in LUAD. Methods: The transcriptomic data and clinical information of 632 LUAD patients were used to investigate the LUAD molecular subtypes that are associated with the cuproptosis-related genes (CRGs), the tumor immune microenvironment, and stemness. The cuproptosis score was constructed using univariate Cox regression and the minor absolute shrinkage and selection operator (LASSO) to quantify the prognostic characteristics. Results: Three different molecular subtypes related to cuproptosis, with different prognoses, were identified in LUAD. Cluster A had the highest cuproptosis score and the worst prognosis. Patients in the high cuproptosis score group had a higher somatic mutation frequency and stemness scores. Patients in the low cuproptosis score group had more immune infiltration and better prognosis. Conclusion: Molecular subtypes of LUAD based on CRGs reflect the differences in LUAD patients. The cuproptosis score can be used as a promising biomarker, which is of great significance to distinguish the relationship between cuproptosis and the immune microenvironment. The cuproptosis signature based on the cuproptosis score and clinical characteristics of individual patients will be useful for guiding immunotherapy in LUAD.

Efficacy and safety of camrelizumab plus apatinib in previously treated patients with advanced non-small cell lung cancer harboring EGFR or ALK genetic aberration.

Background: Camrelizumab plus apatinib shows encouraging antitumor activity and acceptable toxicity in chemotherapy-pretreated patients with advanced non-small cell lung cancer (NSCLC); however, clinical benefits from this combination regimen in NSCLC patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) have not been reported. We assessed the efficacy and safety of this combined regimen in pretreated patients with advanced NSCLC and defined EGFR/ALK status (EGFR+/ALK+) in a phase 1b/2 trial. Methods: Previously treated patients with advanced EGFR+/ALK+ NSCLC were enrolled and given camrelizumab 200 mg intravenously every 2 weeks plus apatinib at the recommended dose of 250 mg orally once daily. Patients harboring sensitive EGFR mutations or ALK fusion genes had received at least one EGFR/ALK TKI and a platinum-based chemotherapy regimen before the enrollment. The primary endpoint was objective response rate (ORR). Results: All 43 enrolled patients comprised the efficacy and safety analysis population. The confirmed ORR was 18.6% (95% CI: 8.4-33.4%) and the clinical benefit response rate was 27.9% (95% CI: 15.3-43.7%). Median progression-free survival (PFS) was 2.8 months (95% CI: 1.9-5.5 months) and median overall survival was not reached (95% CI: 7.3 months-not reached), with a median follow-up period of 15.7 months (range, 0.5-24.4 months). The most common grade ≥3 treatment-related adverse events (TRAEs) were hypertension (16.3%), proteinuria (11.6%) and palmar-plantar erythrodysaesthesia syndrome (9.3%). No unexpected adverse events were recorded. Conclusions: Camrelizumab plus apatinib showed moderate antitumor activity and acceptable safety profile in previously treated patients with advanced NSCLC and EGFR or ALK genetic aberrations, which warranted further validation. Trial Registration: ClinicalTrials.gov identifier: NCT03083041. Registered March 17, 2017.

Genome-wide CRISPR/Cas9 screening for therapeutic targets in NSCLC carrying wild-type TP53 and receptor tyrosine kinase genes.

BACKGROUND: Targeted drugs have greatly improved the therapeutic outcome of non-small cell lung cancer (NSCLC) patients compared with conventional chemotherapy, whereas about one-third of patients are so far not suitable for targeted therapy due to lack of known driver oncogenes such as a mutated receptor tyrosine kinase (RTK) genes. In this study, we aimed to identify therapeutic targets for this subgroup of NSCLC patients. METHODS: We performed genome-wide CRISPR/Cas9 screens in two NSCLC cell lines carrying wild-type TP53 and receptor tyrosine kinase (wtTP53-RTK) genes using a GeCKO v2.0 lentiviral library (containing 123411 sgRNAs and targeting 19050 genes). MAGeCKFlute was used to analyse and identify candidate genes. Genetic perturbation and pharmacological inhibition were used to validate the result in vitro and in vivo. RESULTS: The Genome-wide CRISPR/Cas9 screening identified MDM2 as a potential therapeutic target for wtTP53-RTK NSCLC. Genetic and pharmacological inhibition of MDM2 reduced cell proliferation and impaired tumour growth in the xenograft model, thus confirming the finding of the CRISPR/Cas9 screening. Moreover, treatment by a selective MDM2 inhibitor RG7388 triggered both cell cycle arrest and apoptosis in several NSCLC cell lines. Additionally, RG7388 and pemetrexed synergistically blocked the cell proliferation and growth of wtTP53-RTK tumours but had limited effects for other genotypes. CONCLUSIONS: We identified MDM2 as an essential gene and a potential therapeutic target in wtTP53-RTK NSCLC via a genome-wide CRISPR/Cas9 screening. For this subgroup, treatment by RG7388 alone or by its combination with pemetrexed resulted in significant tumour inhibition.

Efficacy and Safety of Befotertinib (D-0316) in Patients With EGFR T790M-Mutated NSCLC That Had Progressed After Prior EGFR Tyrosine Kinase Inhibitor Therapy: A Phase 2, Multicenter, Single-Arm, Open-Label Study.

INTRODUCTION: Befotertinib (D-0316) is a novel, third-generation EGFR tyrosine kinase inhibitor (TKI). This study evaluated befotertinib in patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy. METHODS: This was a single-arm, open-label, phase 2 study at 49 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC harboring EGFR T790M mutations with disease progression after prior first- or second-generation EGFR TKI therapy received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee in intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT03861156. RESULTS: A total of 176 patients and 290 patients were included in cohorts A (50 mg) and B (75-100 mg), respectively. At data cutoff (August 15, 2021), independent review committee-assessed ORR was 67.6% (95% confidence interval [CI]: 61.9%-72.9%) in cohort B. The investigator-assessed ORR was 54.0% (95% CI: 46.3%-61.5%) in cohort A and 65.9% (95% CI: 60.1%-71.3%) in cohort B. The median investigator-assessed progression-free survival was 11.0 (95% CI: 9.6-12.5) months in cohort A and 12.5 (95% CI: 11.1-13.8) months in cohort B. The median independent review committee-assessed progression-free survival in cohort B was 16.6 (95% CI: 15.0-not evaluable [NE]) months. The intracranial ORR was 26.7% (95% CI: 7.8%-55.1%) in cohort A by investigator assessment, while 57.1% (95% CI: 34.0%-78.2%) and 55.9% (95% CI: 37.9%-72.8%) in cohort B by investigator and independent review committee assessment, respectively. The median investigator-assessed intracranial progression-free survival was 16.5 (95% CI: 8.6-NE) months in cohort A, while the median intracranial progression-free survival was not evaluable in cohort B due to immature data regardless of investigator or independent review committee assessment. and NE (95% CI: 13.8-NE) in cohort B. The overall survival was immature. Grade 3 or higher treatment-related adverse events and treatment-related serious adverse events occurred in 20.5% and 11.4% of patients in cohort A and in 29.3% and 10.0% of patients in cohort B, respectively. CONCLUSIONS: Befotertinib of 75 to 100 mg has satisfying efficacy and manageable toxicity in patients with locally advanced or metastatic NSCLC harboring T790M mutation with resistance to first- or second-generation EGFR TKIs. A phase 3 randomized trial is underway (NCT04206072).

AENEAS: A Randomized Phase III Trial of Aumolertinib Versus Gefitinib as First-Line Therapy for Locally Advanced or MetastaticNon-Small-Cell Lung Cancer With EGFR Exon 19 Deletion or L858R Mutations.

PURPOSE: Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor approved in China. This double-blind phase III trial evaluated the efficacy and safety of aumolertinib compared with gefitinib as a first-line treatment for locally advanced or metastatic EGFR-mutated non-small-cell lung cancer (NSCLC; ClinicalTrials.gov identifier: NCT03849768). METHODS: Patients at 53 sites in China were randomly assigned 1:1 to receive either aumolertinib (110 mg) or gefitinib (250 mg) once daily. The primary end point was progression-free survival (PFS) per investigator assessment. RESULTS: A total of 429 patients who were naïve to treatment for locally advanced or metastatic NSCLC were enrolled. PFS was significantly longer with aumolertinib compared with gefitinib (hazard ratio, 0.46; 95% CI, 0.36 to 0.60; P < .0001). The median PFS with aumolertinib was 19.3 months (95% CI, 17.8 to 20.8) versus 9.9 months with gefitinib (95% CI, 8.3 to 12.6). Objective response rate and disease control rate were similar in the aumolertinib and gefitinib groups (objective response rate, 73.8% and 72.1%, respectively; disease control rate, 93.0% and 96.7%, respectively). The median duration of response was 18.1 months (95% CI, 15.2 to not applicable) with aumolertinib versus 8.3 months (95% CI, 6.9 to 11.1) with gefitinib. Adverse events of grade ≥ 3 severity (any cause) were observed in 36.4% and 35.8% of patients in the aumolertinib and gefitinib groups, respectively. Rash and diarrhea (any grade) were observed in 23.4% and 16.4% of patients who received aumolertinib compared with 41.4% and 35.8% of those who received gefitinib, respectively. CONCLUSION: Aumolertinib is a well-tolerated third-generation epidermal growth factor receptor tyrosine kinase inhibitor that could serve as a treatment option for EGFR-mutant NSCLC in the first-line setting.