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Abstract Immune checkpoint inhibitor (ICI) rechallenge in non‐small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD‐1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option.

Abstract Immune checkpoint inhibitors (PD‐1/PD‐L1 and CTLA‐4 blockade) have revolutionized the treatment landscape in non‐small cell lung cancer (NSCLC). Secondary resistance to immunotherapy (IO), which poses a substantial challenge in clinical settings, occurs in several initial responders. Currently, new treatment approaches have been extensively evaluated in investigational studies for these patients to tackle this difficult problem; however, the lack of consistency in clinical definition, uniform criteria for enrollment in clinical trials, and interpretation of results remain significant hurdles to progress. Thus, our expert panel comprehensively synthesized data from current studies to propose a practical clinical definition of secondary resistance to immunotherapy in NSCLC in metastatic and neoadjuvant settings. In addition to patients who received IO alone (including IO‐IO combinations), we also generated a definition for patients treated with chemotherapy plus IO. This consensus aimed to provide guidance for clinical trial design and facilitate future discussions with investigators. It should be noted that additional updates in this consensus are required when new data is available.

Abstract Background Iruplinalkib (WX-0593) is an anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor. Here we reported the single-arm, phase II study (INTELLECT) results of the efficacy and safety of iruplinalkib for ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC) patients. Methods ALK-positive crizotinib-resistant advanced NSCLC patients aged ≥18 years, with Eastern Cooperative Oncology Group performance status of 0–2 were eligible. Patients received iruplinalkib 180 mg orally once daily for a 21-day cycle with a 7-day lead-in phase at 60 mg orally once daily. The primary endpoint was the independent review committee (IRC)-assessed objective response rate (ORR). Results From August 7, 2019, to October 30, 2020, 146 patients were included. As of the data cut-off date on November 30, 2021, the median follow-up time was 18.2 months (95% confidence interval [CI] 16.8–18.8). IRC-assessed ORR and disease control rate (DCR) were 69.9% (95% CI 61.7–77.2%) and 96.6% (95% CI 92.2–98.9%), respectively. Investigator-assessed ORR and DCR were 63.0% (95% CI 54.6–70.8%) and 94.5% (95% CI 89.5–97.6%), respectively. Investigator-assessed median duration of response and progression-free survival (the same as median time to progression) were 13.2 months (95% CI 10.4–17.7) and 14.5 months (95% CI 11.7–20.0), respectively. Corresponding IRC-assessed results were 14.4 months (95% CI 13.1–not evaluable [NE]), 19.8 months (95% CI 14.5–NE), and NE (95% CI 14.5–NE), respectively. Investigator-assessed intracranial ORRs were 46% (41/90, 95% CI 35–56%) in patients with central nervous system metastases and 64% (27/42, 95% CI 48–78%) in patients with measurable intracranial lesions. Overall survival data were immature. Treatment-related adverse events (TRAEs) occurred in 136/146 (93.2%) patients. The most common TRAEs were aspartate aminotransferase increased (63 [43.2%]), alanine aminotransferase increased (54 [37.0%]), and blood creatine phosphokinase increased (51 [34.9%]). Dose interruption, reduction, and discontinuation due to TRAEs occurred in 21 (14.4%), 16 (11.0%), and four (2.7%) patients, respectively. Conclusions In this study, iruplinalkib (WX-0593) demonstrated favorable efficacy and manageable safety profiles in patients with ALK-positive crizotinib-resistant advanced NSCLC. Iruplinalkib could be a new treatment option for this patient population. Trial registration Center for Drug Evaluation of National Medical Products Administration of China: CTR20190789, registered on April 28, 2019; ClinicalTrials.gov: NCT04641754, registered on November 24, 2020.

Abstract Risk factors vary in terms of the pattern of lung cancer metastasis and specific metastatic organs. In this study, we retrospectively analyzed the clinical risk factors of tumor metastasis in lung cancer patients and used second‐generation gene sequencing to characterize relevant gene mutations. The risk factors of different metastatic sites of real‐world lung cancer were explored to find the differentially expressed genes and risk factors in different metastatic organs, which laid a foundation for further study on the metastasis patterns and mechanisms of lung cancer. The clinical risk factors of tumor metastasis in 137 lung cancer patients who attended our department from May 2017 to March 2019 were retrospectively analyzed and grouped based on bone metastasis, brain metastasis, other distant metastasis, and no metastasis. Single‐ or multi‐factor logistic regression analysis was performed to analyze the effect of neutrophil/lymphocyte ratio/platelet/lymphocyte ratio/lymphocyte to monocyte ratio on platelets (PLTs) and bone metastasis by combining PLT values, age, pathology type, gender, and smoking history. Based on the presence or absence of bone metastasis, distal metastasis, and PLT values of lung cancer, 39 tissue specimens of primary lung cancer were taken for 773 gene grouping and gene mutation characterization. The tumor mutation load, gene copy number instability, microsatellite instability, and tumor heterogeneity among different groups were analyzed. Age and PLT level were independent risk factors for bone metastasis and distal metastasis, but not for brain metastasis. The RB1 gene was mutated during bone metastasis, and tumor heterogeneity was less in the elevated PLT group. PLT values were an independent risk factor for distant metastases from lung cancer other than the brain. Age has a significant effect on bone metastasis formation. RB1 gene mutation was significantly associated with bone metastasis.

Abstract WX-0593 (Iruplinalkib) is a novel, highly selective oral ALK and ROS1 tyrosine kinase inhibitor (TKI). In this study, the safety, antitumor activity, and pharmacokinetics of WX-0593 were evaluated in advanced non-small cell lung cancer (NSCLC) patients with ALK or ROS1 rearrangement. In the dose-escalation phase and dose-expansion phase, patients were treated with WX-0593 until disease progression, unacceptable toxicity, or subject withdrawal. In the dose-escalation phase, the primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety assessed by investigators. In the dose-expansion phase, the primary endpoint was objective response rate (ORR) assessed by investigators. Between September 25, 2017 and October 15, 2018, a total of 153 patients received WX-0593 treatment. Two dose-limiting toxicities (DLTs) including one grade 3 QT interval prolonged and one grade 2 chronic heart failure were reported at the dose of 300 mg in one patient. MTD was not reached. Overall, 140 of the 152 (92%) patients experienced treatment-related adverse events (TRAEs) and 35 of the 152 (23%) patients had TRAEs ≥grade 3. The overall ORR was 59.3% (32 of 54) for the dose-escalation phase and 56.6% (56 of 99) for the dose-expansion phase. For patients who were ALK-rearranged and ALK TKI naive, the ORR were 81.0% (17 of 21) in the dose-escalation phase and 76.3% (29 of 38) in the dose-expansion phase, and for patients who previously received crizotinib as the only ALK TKI, the ORR were 38.1% (8 of 21) and 45.7% (21 of 46) for the two phases, respectively. For patients who were ROS1-rearranged, the ORR were 30.0% (3 of 10) in the dose-escalation phase and 44.4% (4 of 9) in the dose-expansion phase. WX-0593 showed favorable safety and promising antitumor activity in advanced NSCLC patients with ALK or ROS1 rearrangement.

BackgroundExpanding the druggable novel anaplastic lymphoma kinase (ALK) fusions list is crucial to the precise treatment of patients with cancer with positive ALK fusions. The intergenic-ALK fusions accounted for a substantial proportion of ALK fusions. However, they were typically considered of limited clinical significance due to the obscure functional partners. In this case report, a patient carrying intergenic-ALK fusion presents an excellent outcome after taking the new second-generation tyrosine kinase inhibitor (TKI) candidate, WX-0593.Case PresentationA 47-year-old Chinese female patient diagnosed with IVB lung adenocarcinoma was admitted to the hospital with large dimension lesions in the left lobe of the lung. After 1 week of first line chemotherapy, no response was found. A novel ALK rearrangement generated by a fusion of the intergenic region between SLC8A1 and PKDCC to the intron 19 of ALK was presented after next-generation sequencing and was further confirmed by Sanger’s sequencing. High expression of ALK was revealed by immunohistochemistry. The patient was directed to engage in phase III clinical trial (NCT04632758) and received an orally active second-generation ALK inhibitor WX-0593. Over the course of 17 months, the partial response was obtained without significant side effects.ConclusionIn summary, a patient with non–small cell lung cancer harboring a novel intergenic-ALK fusion, whose intergenic breakpoint was located between SLC8A1 and PKDCC, benefited from a potent ALK TKI candidate WX-0593. This finding extended the scope of targetable ALK fusions. More importantly, it highlighted the advantages of next-generation sequencing in identifying rare but functional ALK fusions, which eventually benefit patients.

Abstract Background To explore the efficacy and safety of Transcatheter rectal arterial chemoembolization with oxaliplatin and S-1 concurrent chemoradiotherapy as neoadjuvant therapy for locally advanced rectal cancer. Methods This s a prospective, monocentric, non-randomized clinical study, a total of 95 patients were enrolled and assigned to two groups: an investigational group (n = 50) receiving transcatheter rectal arterial chemoembolization (TRACE) with oxaliplatin and preoperative radiotherapy plus S-1 concurrent chemotherapy (NATRACE-CRT), followed by surgery, a control group (n = 45) receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy plus capecitabine based chemotherapy (NA-CRT), followed by surgery. The primary endpoint was postoperative pathological regression rate which evaluated by tumor regression grade (TRG) according to the 7th edition of the American Joint Committee on Cancer (AJCC) standard, and the secondary endpoints included objective response rate (ORR) and toxicity, as well as surgical complications, and postoperative tumor downstaging. Results Compared with NA-CRT group (17.78% (95% confidence interval (CI): 6.2–29.4)), the TRG0 was 30% (95% CI 16.8–43.2) in the NATRACE-CRT group (P = 0.231). The TRG0 + 1 rate was 60% (95% CI: 45.9–74.1) and 33.33% (95% CI: 19–47.7) in NATRACE-CRT group and NA-CRT group, respectively (P = 0.013). The ORR of the NATRACE-CRT group was 84% and that of the NA-CRT group was 66.67% (p = 0.058). Incidence of preoperative toxic side effects and surgical complications was similar between the two groups. Conclusion TRACE with oxaliplatin plus concurrent S-1 chemoradiotherapy as a neoadjuvant therapy provided better pathological remission rate versus standard treatment with a similar safety profile. Trial registration NCT03601156 .

Abstract Background Epithelial‐to‐mesenchymal transition (EMT) plays a pivotal role in resistance to EGFR tyrosine kinase inhibitors (TKIs) in non‐small‐cell lung cancer (NSCLC). Our previous study revealed that in osteosarcoma, human apurinic/apyrimidinic endonuclease 1 (APE1) regulates transforming growth factor‐β (TGF‐β), an important player in EMT. We therefore hypothesized a link between APE1 and EGFR‐TKI responsiveness in NSCLC. Methods The protein levels of APE1 were analyzed in tumors of NSCLC patients receiving EGFR‐TKI treatment. The correlation between APE1 expression and progression‐free survival (PFS), overall survival (OS), or response rate were analyzed. The impact of APE1 on the response to EGFR‐TKIs was measured by exogenous manipulation of APE1 in EGFR‐TKI‐sensitive and EGFR‐TKI‐resistant cells. Results We indicate that low expression of APE1 in tumors is associated with a significantly longer PFS (20.8 months vs 8.4 months, P = 0.008) and a preferential OS (39.0 months vs 17.0 months, P = 0.001), with no difference in initial response rate to EGFR‐TKIs. We observed that APE1 protein level was significantly increased in EGFR‐TKI‐resistant cells and was associated with downregulated E‐cadherin and upregulated vimentin. The EMT phenotype, as well as the levels of TGF‐β, was suppressed in APE1 knockdown HCC827/IR and PC‐9/ER cells, while the EMT phenotype was promoted in APE1‐overexpressed HCC827 and PC‐9 cells. Furthermore, a specific APE1 redox inhibitor (ie, E3330) effectively reversed the EMT phenotype and further sensitized the cells to EGFR‐TKIs. Conclusion This study revealed a significant role of APE1 in EGFR‐TKI resistance via novel regulatory effects on the EMT phenotype in NSCLC.

Background and objective Antiangiogenesis has become the fourth module of cancer therapy nowadays. However, its clinical effect varies from cancer to cancer. The aim of this study is to compare the clinical efficacy of rh-endostatin (YH-16, Endostar) on retreated non-small cell lung cancer and colorectal cancer. Methods The patients including 17 cases of retreated non-small cell lung cancer (NSCLC) and 15 cases of retreated colorectal cancer were confirmed by histopathology or cytopathology. All the cases were administrated with rh-endostatin combining chemotherapy and radiotherapy. 7.5 mg/m2 rhendostatin solved in 500 mL of normal saline was slow intravenously dropped from day 1 to day 14. The efficacy was evaluated strictly according to RECIST criteria and the quality of life (QOL) was based on the Karnofsky performance (KPS). Results The response rate (RR) of 17 cases of retreated NSCLC was 11.8% (2/17), and the disease control rate (DCR) was 41.2% (7/17). However, the RR and DCR of the 15 cases of retreated colorectal cancer were up to 40% (6/15) and 86.6% (13/15). There was significant difference between these two tumors (P < 0.05). Moreover, significant difference was also found on the QOL of these two tumors [The improving and stable QOL was 41.2% (7/17) and 86.6% (13/15), respectively (P < 0.05)]. Conclusion The clinical efficacy of rh-endostatin on retreated colorectal cancer was better than on retreated non-small cell lung cancer, which suggested that it was necessary to perform more clinical observations on the digestive tumors.

BackgroundTimely identification of drug-induced Parkinson-like events is essential to improve clinical management and enhance patients’ quality of life. However, there is a significant lack of studies addressing these events in real-world settings.MethodsTo bridge this gap, we analyzed adverse event (AE) reports related to Parkinson-like events from the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the first quarter of 2024. Our objective was to summarize a list of potential drugs at high risk for Parkinson-like events and their corresponding proportions of AE reports.ResultsAs a result, a total of 54,639 AE reports linked to Parkinson-like events involving 1,224 drugs were identified. Among these, carbidopa/levodopa exhibited the highest number of reports, followed by baclofen and pimavanserin. The most frequently reported drug class was antiparkinsonian drugs and psycholeptics, followed by psychoanaleptics. Using two disproportionate analysis methods, the reporting odds ratio and proportional reporting ratio, we found that 136 drugs exhibited positive results in both methods, while 1,063 drugs did not show any positive signals.ConclusionThis study provides a comprehensive pharmacovigilance analysis of drugs associated with Parkinson-like events, aiming to promote rational drug use and inform clinical practice.

Nedaplatin (NDP) has been extensively used to treat patients with non-small cell lung cancer (NSCLC) in the last decade. The present study compared the survival benefits of NDP and cisplatin (DDP) in the treatment of NSCLC. Patients (n=392) with NSCLC were treated with at least two cycles of platinum-based chemotherapy. Among these patients, 202 received DDP-based chemotherapy, and 190 received NDP-based chemotherapy. The overall survival time of the two groups and the toxicity of drugs were analyzed. The results showed that only the chemotherapy cycle duration was found to be statistically different between DDP and NDP groups in all the characteristics. The mean chemotherapy duration was 3.3 cycles in the DDP group, and 4.1 cycles in the NDP group (χ²=20.206, P<0.001). Additionally, the chemotherapy cycle number was also an independent predictive factor for the overall survival time in the multivariate analysis (HR=0.539, P<0.001). The median survival time (MST) was 15 months in the DDP group, and 20 months in the NDP group (χ²=5.189, P=0.023). The 1-, 2- and 3-year overall survival rates were 62.4, 25.7 and 15.8%, and 78.9, 38.9, and 16.8% in the DPP and NDP groups, respectively. The incidence of grade 3-4 nausea/vomiting, anorexia and weight loss was higher in the DDP compared to the NDP group (36.1 vs. 8.4%, 17.3 vs. 5.8%, and 9.9 vs. 1%, respectively). In conclusion, NDP-based chemotherapy had a survival benefit compared to DDP-based chemotherapy for NSCLC patients, due to the lower toxicity of NDP, which renders this drug more tolerable, thus allowing patients to undergo more cycles of chemotherapy. [ABSTRACT FROM AUTHOR]