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AbstractObjectiveTo compare the efficacy and safety of sacituzumab tirumotecan (sac-TMT) with docetaxel in patients with locally advanced or metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after previous treatment failure with EGFR-tyrosine kinase inhibitors and platinum based chemotherapy.DesignMulticentre, open label, randomised controlled trial.Setting48 centres in China, 1 September 2023 to 31 December 2024.Participants137 adults (aged 18-75 years) with EGFR-mutated advanced or metastatic NSCLC after previous treatment failure with EGFR-tyrosine kinase inhibitors and platinum based chemotherapy.InterventionPatients were randomly assigned (2:1) to receive sac-TMT (5 mg/kg) on days 1 and 15 of each four week cycle, or docetaxel (75 mg/m2) on day 1 of each three week cycle. Patients in the docetaxel group were permitted to crossover to sac-TMT treatment on disease progression.Main outcome measuresThe primary endpoint was objective response rate as assessed by a blinded independent review committee (BIRC). The secondary endpoints included objective response rate assessed by the investigator; disease control rate, progression-free survival, time to response, and duration of response assessed by BIRC and the investigator; overall survival; and safety.Results137 patients were randomised to receive sac-TMT (n=91) or docetaxel (n=46). Median follow-up was 12.2 months at the data cut-off for efficacy (31 December 2024). BIRC assessed objective response rate was significantly higher in the sac-TMT group (45% (41/91)) v docetaxel (16% (7/45)), with a difference of 29% (95% confidence interval (CI) 15% to 43%; one sided P<0.001). Median progression-free survival was longer with sac-TMT than with docetaxel assessed by BIRC (6.9 v 2.8 months; hazard ratio 0.30, 95% CI 0.20 to 0.46; one sided P<0.001) and the investigator (7.9 v 2.8 months; hazard ratio 0.23, 0.15 to 0.36; one sided P<0.001). The 12 month overall survival rate was 73% with sac-TMT and 54% with docetaxel (hazard ratio 0.49, 0.27 to 0.88; one sided P=0.007). After adjustment for crossover using the rank-preserving structural failure time model, sac-TMT also showed improved overall survival (hazard ratio 0.36, 0.20 to 0.66). Grade ≥3 treatment related adverse events were less frequent with sac-TMT than with docetaxel (56% v 72%), with no new safety signals identified.ConclusionsSac-TMT showed statistically significant and clinically meaningful improvements in objective response rate, progression-free survival, and overall survival compared with docetaxel, with a manageable safety profile in patients with EGFR-mutated locally advanced or metastatic NSCLC.Trial registrationClinicalTrials.gov NCT05631262.

Chemoresistance constitutes a prevalent factor that significantly impacts thesurvival of patients undergoing treatment for smal-cell lung cancer (SCLC). Chemotherapy resistance in SCLC patients is generally classified as primary or acquired resistance, each governedby distinct mechanisms that remain inadequately researched. In this study, we performed transcriptome screening of peripheral blood plasma obtainedfrom 17 patients before and after receiving combined etoposide and platinum treatment. We firs testimated pseudo-single-cell analysis using xCell and ESTIMATE and identified differentially expressed genes (DEGs), then performed network analysis to discover key hub genes involved in chemotherapy resistance. Our analysis showed a significant increase in class-switched memory B cell scores acrossboth chemotherapy resistance patterns, indicating their potential crucial role in mediatingresistance. Moreover, network analysis identifed , , and as potential contributors to primary resistance, with , and emerging assignificant factors in acquired resistance, providing valuable insights into chemotherapy resistancein SCLC. These findings offer valuable insights for understanding chemotherapy resistance and related gene signatures in SCLC, which could help further biological validation studies.

Background Comprehensive genomic analysis and optimal treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor ( EGFR ) G719X + S768I co-mutations remain limited. This study aimed to elucidate the genetic landscape and the clinical effectiveness of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in this subset. Methods A total of 645 EGFR -mutant NSCLC patients were retrospectively screened, with 142 patients harbored EGFR G719X + S768I co-mutations. Among these patients, next-generation sequencing was performed in 126 patients, and the efficacy of first-line EGFR-TKIs was evaluated in 96 patients with stage IV disease. Impacts of variant allele frequency (VAF) and concurrent TP53 mutations were also analyzed. Results Among G719X variants, G719C was most prevalent (69.8%), followed by G719A (19.0%) and G719S (8.7%). The most common co-existing mutation was TP53 (38.0%), followed by ALK and PIK3CA (6.3% each). For first-line EGFR-TKIs, the overall objective response rate (ORR) reached 68.8%, with a median progression-free survival (mPFS) of 21.4 months (95% CI: 18.2–24.6). Afatinib showed a significantly better response compared to both first- and third-generation EGFR-TKIs (1st vs. 2nd vs. 3rd generations, ORR: 35.7% vs. 76.8% vs. 61.5%, P  = 0.01; mPFS: 17.2 vs. 23.4 vs. 17.4 months, P  = 0.008). VAF and TP53 mutation status did not affect outcomes ( P  > 0.05), but patients with metastases in the brain and liver experienced notably shorter mPFS. Brain metastases patients had an ORR of 70.5% without additional benefit from third-generation TKIs. Conclusions This study delineates the genomic profile of EGFR G719X + S768I co-mutated NSCLC and highlights the superior effectiveness of second-generation EGFR-TKIs, particularly afatinib. These findings provided valuable insights to guide clinical decision-making and facilitate the development of tailored therapeutic strategies for this subset.

Oncolytic viruses (OVs) hold promise for cancer treatment. However, the antitumor efficacy is limited. Microbiota plays a pivotal role in cancer treatment and its impact on oncolytic virotherapy is unknown. Here, we show that VSVΔ51 has higher antitumor efficacy for hepatocellular carcinoma in the absence of microbiota in female mouse models. VSVΔ51 infection causes microbiota dysbiosis, increasing most of the gut bacteria abundance, while decreasing the commensal Lactobacillus . VSVΔ51 reduced intestinal expression of SLC20A1 that binds to Lactobacillus acidophilus ( L. acidophilus ) CdpA cell wall protein through IL6-JAK-STAT3 signaling, thereby attenuating attachment and colonization of L. acidophilus . L. acidophilus supplementation confers sensitivity to VSVΔ51 through restoring gut barrier integrity and microbiota homeostasis destroyed by VSVΔ51. In this work, we show that targeting microbiota homostasis holds substantial potential in improving therapeutic outcomes of oncolytic virotherapy. Here, the authors show that Lactobacillus acidophilus supplementation enhances oncolytic virus VSVΔ51 effect through restoring gut barrier integrity and microbiota homeostasis in mice.

Immune checkpoint inhibitors (ICIs) are approved as the first-line drug for treating many cancers and has shown significant survival benefits; however, it also causes immune-related adverse events (irAEs) while activating the immune system, involving multiple organs. Among them, cardiovascular immune-related adverse events (CV-irAE) are rare, but common causes of death in ICIs treated cancer patients, which manifest as myocardial, pericardial, vascular and other cardiovascular toxicities. Therefore, it is important that irAEs, especially CV-irAE should be carefully recognized and monitored during the whole ICIs treatment because early detection and treatment of CV-irAE can significantly reduce the mortality of such patients. Consequently, it is urgent to fully understand the mechanism and management strategies of CV-irAE. The effects of ICIs are multifaceted and the exact mechanism of CV-irAE is still elusive. Generally, T cells identify tumor cell antigens as well as antigen in cardiomyocytes that are the same as or homologous to those on tumor cells, thus causing myocardial damage. In addition, ICIs promote formation of cardiac troponin I (cTnI) that induces cardiac dysfunction and myocardial dilatation; moreover, ICIs also increase the production of cytokines, which promote infiltration of inflammation-linked molecules into off-target tissues. Currently, the management and treatment of cardiovascular toxicity are largely dependent on glucocorticoids, more strategies for prevention and treatment of CV-irAE, such as predictive markers are being explored. This review discusses risk factors, potential pathophysiological mechanisms, clinical manifestations, and management and treatment of CV-irAE, guiding the development of more effective prevention, treatment and management strategies in the future.

Continuous de novo fatty acid synthesis is required for the biosynthetic demands of tumor. FBXW7 is a highly mutated gene in CRC, but its biological functions in cancer are not fully characterized. Here, we report that FBXW7β, a FBXW7 isoform located in the cytoplasm and frequently mutated in CRC, is an E3 ligase of fatty acid synthase (FASN). Cancer-specific FBXW7β mutations that could not degrade FASN can lead to sustained lipogenesis in CRC. COP9 signalosome subunit 6 (CSN6), an oncogenic marker of CRC, increases lipogenesis via interacting with and stabilizing FASN. Mechanistic studies show that CSN6 associates with both FBXW7β and FASN, and antagonizes FBXW7β’s activity by enhancing FBXW7β autoubiquitination and degradation, which in turn prevents FBXW7β-mediated FASN ubiquitination and degradation, thereby regulating lipogenesis positively. Both CSN6 and FASN are positively correlated in CRC, and CSN6-FASN axis, regulated by EGF, is responsible for poor prognosis of CRC. The EGF-CSN6-FASN axis promotes tumor growth and implies a treatment strategy of combination of orlistat and cetuximab. Patient-derived xenograft experiments prove the effectiveness of employing orlistat and cetuximab combination in suppressing tumor growth for CSN6/FASN-high CRC. Thus, CSN6-FASN axis reprograms lipogenesis to promote tumor growth and is a target for cancer intervening strategy in CRC.

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.

Weight loss and cachexia are common problems in colorectal cancer patients; thus, parenteral and enteral nutrition support play important roles in cancer care. However, the impact of nonessential amino acid components of nutritional intake on cancer progression has not been fully studied. In this study, we discovered that gastrointestinal cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival ( P  < 0.001) than those who did not. Cystine indeed robustly promotes colon cancer cell growth in vitro and in immunodeficient mice, predominately by inhibiting SESN2 transcription via the GCN2-ATF4 axis, resulting in mTORC1 activation. mTORC1 inhibitors Rapamycin and Everolimus block cystine-induced cancer cell proliferation. In addition, cystine confers resistance to oxaliplatin and irinotecan chemotherapy by quenching chemotherapy-induced reactive oxygen species via synthesizing glutathione. We demonstrated that dietary deprivation of cystine suppressed colon cancer xenograft growth without weight loss in mice and boosted the antitumor effect of oxaliplatin. These findings indicate that cyst(e)ine, as part of supplemental nutrition, plays an important role in colorectal cancer and manipulation of cyst(e)ine content in nutritional formulations may optimize colorectal cancer patient survival.

Although cancer patients (CPs) are increasingly likely to visit emergency department (ED), no population-based study has compared the characteristics of CPs and non-cancer patients (NCPs) who visit the ED and examined factors associated with hospitalization via the ED. In this study, we (1) compared characteristics and diagnoses between CPs and NCPs who visited the ED in a cancer center or general hospital; (2) compared characteristics and diagnoses between CPs and NCPs who were hospitalized via the ED in a cancer center or general hospital; and (3) investigated important factors associated with such hospitalization. We analyzed patient characteristic and diagnosis [based on International Classification of Diseases-9 (ICD-9) codes] data from the ED of a comprehensive cancer center (MDACC), 24 general EDs in Harris County, Texas (HCED), and the National Hospital Ambulatory Medical Care Survey (NHAMCS) from 1/1/2007-12/31/2009. Approximately 3.4 million ED visits were analyzed: 47,245, 3,248,973, and 104,566 visits for MDACC, HCED, and NHAMCS, respectively, of which 44,143 (93.4%), 44,583 (1.4%), and 632 (0.6%) were CP visits. CPs were older than NCPs and stayed longer in EDs. Lung, gastrointestinal (excluding colorectal), and genitourinary (excluding prostate) cancers were the three most common diagnoses related to ED visits at general EDs. CPs visiting MDACC were more likely than CPs visiting HCED to be privately insured. CPs were more likely than NCPs to be hospitalized. Pneumonia and influenza, fluid and electrolyte disorders, and fever were important predictive factors for CP hospitalization; coronary artery disease, cerebrovascular disease, and heart failure were important factors for NCP hospitalization. CPs consumed more ED resources than NCPs and had a higher hospitalization rate. Given the differences in characteristics and diagnoses between CPs and NCPs, ED physicians must pay special attention to CPs and be familiar with their unique set of oncologic emergencies.

The present study was conducted to evaluate the efficacy and tolerability of using an immune checkpoint inhibitor (ICI; programmed cell death protein 1/ligand 1 [PD-1/PD-L1] inhibitor or cytotoxic T-lymphocyte antigen [CTLA]-4 inhibitor) combined with chemotherapy in the first-line treatment of small cell lung cancer. Potential articles and studies were identified using Web of Science, Cochrane Library, and ClinicalTrials.gov. The end points included overall survival, progression-free survival, objective response rate, and adverse events. Significant heterogeneity was represented by a P value (Ph) of <0.05 or an I2 value of ≥50%, and the random-effects model was applied for pooled analysis. Otherwise, the fixed-effects model was used. Subgroup analysis was performed based on the type of ICI. Potential publication bias was evaluated via funnel plot and the Egger test. Five eligible articles were included. Both overall survival (hazard ratio [HR] = 0.83; 95% CI, 0.75–0.91; P < 0.001) and progression-free survival (HR = 0.80; 95% CI, 0.73–0.86; P < 0.001) were significantly prolonged by joint ICI + chemotherapy treatment. Additionally, the rates of tolerable grade ≥3 adverse events were similar between the ICI combination regimens and conventional chemotherapy (relative risk = 1.05; 95% CI, 0.98–1.12; P = 0.17). Subanalysis demonstrated that patient survival and objective response rate were more efficiently improved with a combination of anti–PD-1/PD-L1, but not anti–CTLA-4, + chemotherapy. Based on data from the available literature, clinical efficacy (as measured by patient survival and objective response rate) was improved with a combination of anti–PD-1/PD-L1 + chemotherapy as first-line treatment compared with chemotherapy alone in patients with small cell lung cancer. •SCLC is a highly aggressive neuroendocrine tumor with limited response to chemotherapy.•Addition of anti-PD-1/PD-L1 to chemotherapy greatly improved survival of SCLC patients.•Anti-PD-1/PD-L1 has been recommended as first-line therapy for patients with ES-SCLC.