Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC). Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected ALK-positive NSCLC are lacking. METHODS: We conducted a global, phase 3, open-label, randomized trial in which patients with completely resected, ALK-positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA (as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control) were randomly assigned in a 1:1 ratio to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was disease-free survival, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat population. Other end points included central nervous system (CNS) disease-free survival, overall survival, and safety. RESULTS: In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (hazard ratio, 0.24; 95% CI, 0.13 to 0.43; P<0.001). Alectinib was associated with a clinically meaningful benefit with respect to CNS disease-free survival as compared with chemotherapy (hazard ratio for CNS disease recurrence or death, 0.22; 95% CI, 0.08 to 0.58). Data for overall survival were immature. No unexpected safety findings were observed. CONCLUSIONS: Among patients with resected ALK-positive NSCLC of stage IB, II, or IIIA, adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. (Funded by F. Hoffmann-La Roche; ALINA ClinicalTrials.gov number, NCT03456076.).

Expert consensus on indocyanine green fluorescence imaging for thoracoscopic lung resection (The Version 2022).

The use of the white-light thoracoscopy is hampered by the low contrast between oncologic margins and surrounding normal parenchyma. As a result, many patients with in situ or micro-infiltrating adenocarcinoma have to undergo lobectomy due to a lack of tactile and visual feedback in the resection of solitary pulmonary nodules. Near-infrared (NIR) guided indocyanine green (ICG) fluorescence imaging technique has been widely investigated due to its unique capability in addressing the current challenges; however, there is no special consensus on the evidence and recommendations for its preoperative and intraoperative applications. This manuscript will describe the development process of a consensus on ICG fluorescence-guided thoracoscopic resection of pulmonary lesions and make recommendations that can be applied in a greater number of centers. Specifically, an expert panel of thoracic surgeons and radiographers was formed. Based on the quality of evidence and strength of recommendations, the consensus was developed in conjunction with the Chinese Guidelines on Video-assisted Thoracoscopy, and the National Comprehensive Cancer Network (NCCN) guidelines on the management of pulmonary lesions. Each of the statements was discussed and agreed upon with a unanimous consensus amongst the panel. A total of 6 consensus statements were developed. Fluorescence-guided thoracoscopy has unique advantages in the visualization of pulmonary nodules, and recognition and resection of the anterior plane of the pulmonary segment. The expert panel agrees that fluorescence-guided thoracoscopic surgery has the potential to become a routine operation for the treatment of pulmonary lesions.

NIR-responsive polydopamine-based calcium carbonate hybrid nanoparticles delivering artesunate for cancer chemo-photothermal therapy.

Artesunate (AS), the first-line treatment of malaria with a satisfactory safety profile, has been repurposed as a potential anticancer candidate as it mainly generates reactive oxygen species (ROS) through its intrinsic endoperoxide bridge reacting with ferrous-based catalysts to suppress cancer cell growth. However, further clinical translation of AS is hindered by the attenuated anticancer efficacy due to insufficient ROS generation. Herein, we rationally integrated hydrophobic-modified AS (hAS) with biomimetic polydopamine (PDA) and biomineral calcium carbonate to fabricate high AS-loaded nanomedicine (Ca-PDA/hAS@PEG) for cancer chemo-photothermal therapy, which exerted anticancer effects in the following ways: (1) the heat was generated when PDA was irradiated by near-infrared (NIR) light for photothermal therapy. Meanwhile, the increased temperature accelerated the production of ROS from hAS, thus enhancing the anticancer efficacy of hAS-based chemotherapy; (2) hAS-mediated chemotherapy boosted the cancer inhibition effect of photothermal therapy by arousing the intracellular ROS levels in the presence of endogenous ferrous ions and sensitizing cancer cells to thermal ablation; (3) the integration of calcium carbonate into the nanoparticle facilitated the pH-responsive drug release for precise treatment. Such hybrid nanoparticles exhibited a combinational antitumor effect of photothermal therapy and chemotherapy in vivo with no systemic toxicity. Taken together, our work presents a facile strategy to improve the anticancer efficacy of AS by combining chemical modification and photothermal therapy-assisted endoperoxide bridge cleavage, which may offer opportunities to pave the way for clinical translation of AS-based nanomedicines. STATEMENT OF SIGNIFICANCE: The clinical translation of artesunate (AS) is hindered by the attenuated anticancer efficacy due to insufficient ROS generation. Herein, we rationally integrated hydrophobic-modified AS (hAS) with biomimetic polydopamine (PDA) and biomineral calcium carbonate to fabricate high AS-loaded nanomedicine (Ca-PDA/hAS@PEG) for improved cancer chemo-photothermal therapy. The heat generated from PDA in response to near-infrared light irradiation could locally ablate tumor as well as accelerate the production of ROS by hAS, thus enhancing the anticancer efficacy of hAS-based chemotherapy. On the other hand, hAS-based chemotherapy amplified the intracellular oxidative stress, sensitizing cancer cells to thermal ablation. Our work presents a facile strategy to improve the anticancer efficacy of AS by combining chemical modification and photothermal therapy-assisted endoperoxide bridge cleavage.

Genomic characteristics and drug screening among organoids derived from non-small cell lung cancer patients.

BACKGROUND: Patient-derived organoid (PDO) models are highly valuable and have potentially widespread clinical applications. However, limited information is available regarding organoid models of non-small cell lung cancer (NSCLC). This study aimed to characterize the consistency between primary tumors in NSCLC and PDOs and to explore the applications of PDOs as preclinical models to understand and predict treatment response during lung cancer. METHODS: Fresh tumor samples were harvested for organoid culture. Primary tumor samples and PDOs were analyzed via whole-exome sequencing. Paired samples were subjected to immunohistochemical analysis. There were 26 antineoplastic drugs tested in the PDOs. Cell viability was assessed using the Cell Titer Glo assay 7-10 days after drug treatment. A heatmap of log-transformed values of the half-maximal inhibitory concentrations was generated on the basis of drug responses of PDOs through nonlinear regression (curve fit). A total of 12 patients (stages I-III) were enrolled, and 7 paired surgical tumors and PDOs were analyzed. RESULTS: PDOs retained the histological and genetic characteristics of the primary tumors. The concordance between tumors and PDOs in mutations in the top 20 NSCLC-related genes was >80% in five patients. Sample purity was significantly and positively associated with variant allele frequency (Pearson r = 0.82, P = 0.0005) and chromosome stability. The in vitro response to drug screening with PDOs revealed high correlation with the mutation profiles in the primary tumors. CONCLUSIONS: PDOs are highly credible models for detecting NSCLC and for prospective prediction of the treatment response for personalized precision medicine. KEY POINTS: Lung cancer organoid models could save precious time of drug testing on patients, and accurately select anticancer drugs according to the drug sensitivity results, so as to provide a powerful supplement and verification for the gene sequencing.

Neoadjuvant and adjuvant epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy for lung cancer.

The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis and the meta-analysis of individual participant data reported by non-small cell lung cancer (NSCLC) Meta-analysis Collaborative Group in neo-adjuvant setting validated respectively that adjuvant and neoadjuvant chemotherapy would significantly improve overall survival (OS) and recurrence-free survival for resectable NSCLC. However, chemotherapy has reached a therapeutic plateau. It has been confirmed that epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) targeting therapy provides a dramatic response to patients with advanced EGFR-mutation positive NSCLC. Researchers have paid more attention to exploring applications of TKIs to early resectable NSCLCs. Several studies on adjuvant TKI treatment concluded its safety and feasibility. But there existed certain limitations of these studies as inference factors to interpret data accurately: the BR19 study recruited patients among which almost 52% had stage IB and only 15 (3.0%, 15/503) had been confirmed with EGFR-mutant type; retrospective studies performed at Memorial Sloan Kettering Cancer Center (MSKCC) selected EGFR mutant-type NSCLC patients but couldn't avoid inherent defects inside retrospective researches; the RADIANT study revised endpoints from targeting at EGFR immunohistochemistry (IHC)+ and/or fluorescence in situ hybridization (FISH)+ mutation to only EGFR IHC+ mutation, leading to selective bias; despite that the SELECT study validated efficacy of adjuvant TKI and second round of TKI after resistance occurred, a single-arm clinical trial is not that persuasive in the absence of comparison with chemotherapy. Taking all these limitations into account, CTONG1104 in China and IMPACT in Japan have been conducted and recruiting patients to offer higher level of evidences to explore efficacy of preoperative TKI therapy for early resectable EGFR mutation positive NSCLC patients (confirmed by pathological results of tumor tissue or lymph node biopsy). On the other hand, case reports and several phase II clinical trials with small sample size tried to elbow their way on respect of preoperative TKI treatment and advised that TKI tended to improve response rate. However, no data on survival rate was present. The first phase II study of biomarker-guided neoadjuvant therapy for stage IIIA-N2 NSCLC patients stratified by EGFR mutation status, sponsored by CSLC0702, showed erlotinib tended to improve response rate, but failed to show benefits of disease-free survival (DFS) or OS. Subsequently, CTONG1103 was designed to investigate efficacy of erlotinib vs. combination of gemcitabine/cisplatin (GC) as neoadjuvant treatment in stage IIIA-N2 NSCLC with sensitizing EGFR mutation in exon 19 or 21. All these ongoing trials should be worthy of our expect to provide convincing evidences for customized therapy for patients with resectable NSCLC.