Publications by authors named "Dong-Wan Kim"

434 Publications

Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study.

J Clin Oncol 2021 Aug 2:JCO2100662. Epub 2021 Aug 2.

Janssen R&D, Spring House, PA.

Purpose: Non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor () exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site.

Methods: CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included a population with Exon20ins NSCLC. The primary end points were dose-limiting toxicity and overall response rate. We report findings from the postplatinum Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5.

Results: In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively.

Conclusion: Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with Exon20ins mutations after progression on platinum-based chemotherapy.
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http://dx.doi.org/10.1200/JCO.21.00662DOI Listing
August 2021

Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors in Patients With De Novo EGFR-Mutant NSCLC.

J Thorac Oncol 2021 Jul 6. Epub 2021 Jul 6.

Seoul National University Cancer Research Institute, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

Introduction: EGFR mostly exists subclonally and is acquired as the most common mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs). Nevertheless, because de novo EGFR-mutant NSCLC is rare, little is known on acquired resistance mechanisms to third-generation EGFR TKIs.

Methods: Acquired resistance mechanisms were analyzed using tumor and plasma samples before and after third-generation EGFR TKI treatment in four patients with de novo EGFR-mutant NSCLC. Genetic alterations were analyzed by whole-exome sequencing, targeted sequencing, fluorescence in situ hybridization, and droplet digital PCR. MTOR, confirmed for oncogenicity using the Ba/F3 system, was reproduced in H1975 cell lines using CRISPR/Cas9-RNP.

Results: Of seven patients with NSCLC with de novo EGFR mutation, four (LC1-4) who received third-generation EGFR TKIs acquired resistance after achieving a partial response (median = 27 mo, range: 17-48 mo). Novel MTOR and EGFR mutations in cis, MET amplification, and EGFR mutation were identified as acquired resistance mechanisms to third-generation EGFR TKIs. The MTOR mutation was oncogenic in Ba/F3 models and revealed resistance to osimertinib through AKT signaling activation in NCI-H1975 cells harboring the MTOR mutation edited by CRISPR/Cas9 (half-maximal inhibitory concentration, 800 ± 67 nM). Osimertinib in combination with mTOR inhibitors abrogated acquired resistance to osimertinib.

Conclusions: Activation of bypass pathways and the EGFR or EGFR mutation were identified as acquired resistance mechanisms to third-generation EGFR TKIs in patients with NSCLC with de novo EGFR mutation. In addition, MTOR- and EGFR-mutant NSCLC cells were sensitive to osimertinib plus mTOR inhibitors.
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http://dx.doi.org/10.1016/j.jtho.2021.06.013DOI Listing
July 2021

A study on pyro-hydrometallurgical process for selective recovery of Pb, Sn and Sb from lead dross.

J Hazard Mater 2021 Sep 13;417:126071. Epub 2021 May 13.

Department of Energy and Resources Engineering, Chonnam National University, Gwangju, Republic of Korea. Electronic address:

This study is to propose a pyro-hydrometallurgical process for recovering Pb, Sn, and Sb from lead dross (LD), incorporating stages of roasting, leaching, and precipitation. The LD, containing 67.2% of Pb, 4.0% of Sn, and 1.4% of Sb, was first roasted at 750 °C for 2 h to oxidise the sulphide metals. Approximately 90% of Pb was oxidised from the first roasting. The LD was second roasted by mixing with 95% HSO for sulphatising at 300 °C for 3 h to break the complex oxide structure of the oxyplumboromeite (PbSbO). After the two-step roasting process, over 99% of Pb was oxidised and Sb was separated. The calcine obtained was desulphurised by 2 M NaCO solution for insoluble PbSO to PbCO for selective leaching. The residue was then leached in 2.5 M HNO at 50 °C for 3 h and over 99% of Pb dissolved into the solution while Sn and Sb remained in the solid residue. The Pb containing solution was neutralised at pH 8 using 2 M NaCO and over 99% Pb was precipitated as PbCO and Pb hydroxides. A residue containing Sn and Sb was leached in 7 M NaOH at 95 for 1 h and over 99% Sn was leached selectively. Sn in the solution was precipitated at pH 7 using 2 M HSO as SnO. Sb was recovered as SbO in solid reside from Sn leaching. The overall recovery rates of Pb, Sn, and Sb from the LD were 99.5%, 95.4%, and 86.3%, respectively. The proposed process is expected to contribute to recycling Pb and other metal values from LD by minimising hazardous waste emissions.
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http://dx.doi.org/10.1016/j.jhazmat.2021.126071DOI Listing
September 2021

Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study.

Lancet Oncol 2021 07 9;22(7):959-969. Epub 2021 Jun 9.

Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Oncogenic alterations in RET have been identified in multiple tumour types, including 1-2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC.

Methods: ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA). Patients aged 18 years or older with locally advanced or metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment) were enrolled. In phase 2, patients received 400 mg once-daily oral pralsetinib, and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. Phase 2 primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumours version 1·1 and assessed by blinded independent central review) and safety. Tumour response was assessed in patients with RET fusion-positive NSCLC and centrally adjudicated baseline measurable disease who had received platinum-based chemotherapy or were treatment-naive because they were ineligible for standard therapy. This ongoing study is registered with ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive RET fusion-positive NSCLC was ongoing at the time of this interim analysis.

Findings: Of 233 patients with RET fusion-positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Overall responses were recorded in 53 (61%; 95% CI 50-71) of 87 patients with previous platinum-based chemotherapy, including five (6%) patients with a complete response; and 19 (70%; 50-86) of 27 treatment-naive patients, including three (11%) with a complete response. In 233 patients with RET fusion-positive NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia (43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were no treatment-related deaths in this population.

Interpretation: Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC.

Funding: Blueprint Medicines.
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http://dx.doi.org/10.1016/S1470-2045(21)00247-3DOI Listing
July 2021

Five Year Survival Update From KEYNOTE-010: Pembrolizumab Versus Docetaxel for Previously Treated, Programmed Death-Ligand 1-Positive Advanced NSCLC.

J Thorac Oncol 2021 May 26. Epub 2021 May 26.

The Netherlands Cancer Institute, Amsterdam, the Netherlands.

Introduction: In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in patients with previously treated, advanced NSCLC with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50% and ≥1%. We report 5-year efficacy and safety follow-up for the KEYNOTE-010 study.

Methods: Patients were randomized to pembrolizumab 2 mg/kg or 10 mg/kg once every 3 weeks or docetaxel 75 mg/m once every 3 weeks for up to 35 cycles (2 y). Patients who completed pembrolizumab treatment and subsequently had recurrence could receive second-course pembrolizumab for up to 17 cycles (1 y). Pembrolizumab doses were pooled in this analysis.

Results: A total of 1034 patients were randomized (pembrolizumab, n = 691; docetaxel, n = 343). Median study follow-up was 67.4 months (range: 60.0‒77.9). The hazard ratio (95% confidence interval) for OS was 0.55 (0.44‒0.69) for patients with PD-L1 TPS ≥50% and 0.70 (0.61‒0.80) with PD-L1 TPS ≥1%. The 5-year OS rates for pembrolizumab versus docetaxel were 25.0% versus 8.2% in patients with PD-L1 TPS ≥50% and 15.6% versus 6.5% with PD-L1 TPS ≥1%. Among 79 patients who completed 35 cycles/2 years of pembrolizumab, the OS rate 3 years after completion (∼5 y from randomization) was 83.0%. A total of 21 patients received second-course pembrolizumab; 11 (52.4%) had an objective response after starting the second course and 15 (71.4%) were alive at data cutoff. Exploratory biomarker analysis revealed that higher tissue tumor mutational burden (≥175 mutations per exome) was associated with improved outcomes with pembrolizumab.

Conclusions: Pembrolizumab continued to provide long-term benefit than docetaxel in patients with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1%. Our findings confirm pembrolizumab as a standard-of-care treatment in the second-line or later setting.
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http://dx.doi.org/10.1016/j.jtho.2021.05.001DOI Listing
May 2021

Acquired Resistance Mechanism of EGFR Kinase Domain Duplication to EGFR TKIs in Non-Small Cell Lung Cancer.

Cancer Res Treat 2021 May 3. Epub 2021 May 3.

Cancer Research Institute, Seoul National University, Seoul, Korea.

Purpose: Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare and poorly understood oncogenic mutation in non-small cell lung cancer (NSCLC). We aimed to investigate the acquired resistance mechanism of EGFR-KDD against EGFR-TKIs.

Materials And Methods: We identified EGFR-KDD in tumor tissue obtained from a patient with stage IV lung adenocarcinoma and established the patient-derived cell line SNU-4784. We also established several EGFR-KDD Ba/F3 cell lines: EGFR-KDD wild type (EGFR-KDDWT), EGFR-KDD domain 1 T790M (EGFR-KDDD1T), EGFR-KDD domain 2 T790M (EGFR-KDDD2T), and EGFR-KDD both domain T790M (EGFR-KDDBDT). We treated the cells with EGFR tyrosine kinase inhibitors (TKIs) and performed cell viability assays, immunoblot assays, and ENU (N-Ethyl-N-nitrosourea) mutagenesis screening.

Results: In cell viability assays, SNU-4784 cells and EGFR-KDDWT Ba/F3 cells were sensitive to 2nd generation and 3rd generation EGFR TKIs. In contrast, the T790M-positive EGFR-KDD Ba/F3 cell lines (EGFR-KDDT790M) were only sensitive to 3rd generation EGFR TKIs. In ENU mutagenesis screening, we identified the C797S mutation in kinase domain 2 of EGFR-KDDBDT Ba/F3 cells. Based on this finding, we established an EGFR-KDD domain 1 T790M/domain 2 cis-T790M + C797S (EGFR-KDDT/T+C) Ba/F3 model, which was resistant to EGFR TKIs and anti-EGFR monoclonal antibody combined with EGFR TKIs.

Conclusion: Our study reveals that the T790M mutation in EGFR-KDD confers resistance to 1st and 2nd generation EGFR TKIs, but is sensitive to 3rd generation EGFR TKIs. In addition, we identified that the C797S mutation in kinase domain 2 of EGFR-KDDT790M mediates a resistance mechanism against 3rd generation EGFR TKIs.
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http://dx.doi.org/10.4143/crt.2021.385DOI Listing
May 2021

Progress and Prospects on the Fabrication of Graphene-Based Nanostructures for Energy Storage, Energy Conversion and Biomedical Applications.

Chem Asian J 2021 Jun 7;16(11):1365-1381. Epub 2021 May 7.

Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925 (98), Riyadh, 11461, Saudi Arabia.

Graphene, a two-dimensional (2D) layered material has attracted much attention from the scientific community due to its exceptional electrical, thermal, mechanical, biological and optical properties. Hence, numerous applications utilizing graphene-based materials could be conceived in next-generation electronics, chemical and biological sensing, energy conversion and storage, and beyond. The interaction between graphene surfaces with other materials plays a vital role in influencing its properties than other bulk materials. In this review, we outline the recent progress in the production of graphene and related 2D materials, and their uses in energy conversion (solar cells, fuel cells), energy storage (batteries, supercapacitors) and biomedical applications.
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http://dx.doi.org/10.1002/asia.202100216DOI Listing
June 2021

Repeated intratracheal instillation of zinc oxide nanoparticles induced pulmonary damage and a systemic inflammatory response in cynomolgus monkeys.

Nanotoxicology 2021 Jun 18;15(5):621-635. Epub 2021 Apr 18.

Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeongeup, Republic of Korea.

Recently, some researchers have demonstrated that inhaled zinc oxide nanoparticles (ZnONPs) induce an acute systemic inflammatory response in workers. Considering nonhuman primates are preferably considered an animal model for translational research due to their proven similarity with humans in terms of genetics and physiology, we intratracheally instilled ZnONPs to cynomolgus monkey for 14 days and identified the toxic mechanism and bioaccumulation. ZnONPs were rapidly ionized or aggregated in a simulated pulmonary fluid, and they attracted neutrophils to the lungs and increased the pulmonary level of inflammatory mediators. Additionally, thickened alveolar walls, fibrin clots, and hemorrhages were observed in the lungs of the monkeys instilled with the higher dose accompanied by cell debris in the alveolar ducts and alveoli. Dark-field microscopy images revealed translocation of ZnONPs into other tissues accompanied by an increase in the relative weight of livers to body weight. In addition, when instilled at the higher dose, the albumin/globulin ratio notably decreased compared to the control, whereas the C-reactive protein (CRP) level was significantly elevated. ZnONPs also clearly induced apoptotic cell death in a 24 h exposure to alveolar macrophages. Taken together, part of inhaled ZnONPs may be ionized in the lung, resulting in acute toxic effects, including cell death and tissue damage, and the rest may move to other tissues in the form of particles, causing a systemic inflammatory response. Based on the proven evidence among workers, we also suggest that the CRP level can be recommended as a biomarker for ZnONPs-induced adverse health effects.
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http://dx.doi.org/10.1080/17435390.2021.1905899DOI Listing
June 2021

A phase II study of brentuximab vedotin in patients with relapsed or refractory Epstein-Barr virus-positive and CD30-positive lymphomas.

Haematologica 2021 Aug 1;106(8):2277-2280. Epub 2021 Aug 1.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Seoul National University Cancer Research Institute, Seoul.

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http://dx.doi.org/10.3324/haematol.2021.278301DOI Listing
August 2021

Programmed death-ligand 1 expression level as a predictor of EGFR tyrosine kinase inhibitor efficacy in lung adenocarcinoma.

Transl Lung Cancer Res 2021 Feb;10(2):699-711

Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.

Background: The main objective of this study was to investigate the impact of programmed death-ligand 1 (PD-L1) expression on the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in patients with advanced non-small cell lung cancer (NSCLC).

Methods: This study analyzed 108 patients with NSCLC who had received EGFR-TKI as first-line systemic treatment at Seoul National University Bundang Hospital and Seoul National University Hospital between December 2012 and October 2018. The National Cancer Center Research Institute (NCCRI) and The Cancer Genome Atlas (TCGA) datasets were analyzed to investigate the mechanisms underlying EGFR-TKI-resistance in tumors with high PD-L1 expression.

Results: Among the 108 patients, 55, 37, and 16 had negative (PD-L1 Tumor proportion score <1%), weak (1-49%), and strong (≥50%) PD-L1 expression, respectively. Patients with strong PD-L1 expression had significantly shorter median progression-free survival (PFS; 7.07 months) than patients with weak (14.73 months, P<0.001) or negative (12.70 months, P=0.001) PD-L1 expression. After adjustment for covariates by Cox regression, PD-L1 expression remained a significant indicator of adverse prognosis. In EGFR-TKI-refractory patients, the frequency of T790M mutation and the PFS following treatment with third-generation EGFR-TKI and PD-1 antibody were similar in the three groups. TCGA and NCCRI database analysis showed that high PD-L1 expression in EGFR-mutated NSCLCs correlated with IL-6/JAK/STAT3 signaling and high mutation frequency.

Conclusions: Strong PD-L1 expression in tumors might be a surrogate indicator of poor response to first-line EGFR-TKIs in NSCLC patients with sensitizing EGFR mutations, and may reflect a resistance mechanism involving JAK-STAT signaling.
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http://dx.doi.org/10.21037/tlcr-20-893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947423PMC
February 2021

Real-World Clinical Outcomes and Prognostic Factors for Patients with Advanced Angiosarcoma who Received Systemic Treatment.

Cancer Res Treat 2021 Feb 1. Epub 2021 Feb 1.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Purpose: Angiosarcoma is a highly aggressive mesenchymal tumor. Although systemic chemotherapy is often considered for the inoperable or metastatic angiosarcoma, the outcome of such treatment is unsatisfactory and poorly delineated.

Materials And Methods: We reviewed electronic medical records of 75 patients with angiosarcoma who were treated with systemic chemotherapy for inoperable or metastatic disease. Patients were classified as having liver involvement if they had either primary or metastatic hepatic lesions.

Results: Among the patients evaluated, 51 patients were male (68%) and 24 patients (32%) had primary cutaneous angiosarcoma. Liver involvement was present in 28 patients (37.3%). A total of 59 patients received first-line weekly paclitaxel (wPac) and showed an objective response rate (ORR) of 23.7% (n=14), a median progression free survival (mPFS) of 4.0 months (95% confidence interval [CI] 3.0-6.1), and a median overall survival (mOS) of 10.2 months (95% CI 7.0-14.6). Among patients without liver involvement, patients receiving wPac (n=35) had significantly prolonged mPFS (5.8 vs. 3.2 months, respectively, p=0.014) with a tendency for prolonged mOS (13.8 vs. 11.6 months, respectively, p=0.13) than those receiving other regimens (n=12). A total of 24 patients received second- or later-line pazopanib monotherapy and showed an ORR of 16.7% (n=4), a mPFS of 2.4 months (95% CI 1.8-4.3) and a mOS of 5.4 months (95% CI 3.5-NA).

Conclusion: Treatment with first-line wPac and later-line pazopanib seems to provide survival benefit, especially for patients with advanced angiosarcoma without liver involvement.
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http://dx.doi.org/10.4143/crt.2020.1337DOI Listing
February 2021

Clinical pattern of failure after a durable response to immune check inhibitors in non-small cell lung cancer patients.

Sci Rep 2021 Jan 28;11(1):2514. Epub 2021 Jan 28.

Department of Internal Medicine, Bundang Hospital, Seoul National University College of Medicine, 82, Gumi-ro 173 beon-gil, Bundang-Gu, Seongnam, Gyeonggi-do, 13620, Republic of Korea.

Although immune checkpoint inhibitors (ICIs) can induce durable responses in non-small-cell lung cancer (NSCLC) patients, a significant proportion of responders still experience progressive disease after a period of response. Limited data are available on the clinical patterns of acquired resistance (AR) to ICIs. Clinical and radiologic data from 125 NSCLC patients treated with anti-PD-1 or PD-L1 antibodies between 2011 and 2018 at two tertiary academic institutions were retrospectively reviewed. Overall, 63 (50.4%) patients experienced AR after ICI treatment in a median of 10.7 months. Among the 13 patients with a partial response with ICI, 12 (32.4%) had only lymph node progression. Most patients (n = 52, 82.5%) had one or two sites with progression (oligo-progression). The median overall survival (OS) after progression was significantly longer in the extrathoracic group than in the thoracic and liver progression groups (30.2 months [95% confidence interval (CI), 13.4 to not reached (NR)], 11.7 months [95% CI, 9.5-21.1], and 5.4 months [95% CI, 2.6-NR], respectively, P < 0.001). Patients with oligo-progression had significantly longer OS after AR than did the multi-progression patients (18.9 months [95% CI, 10.6-NR] vs. 8.8 months [95% CI, 5.7-NR], P = 0.04). No significant difference in progression-free survival was observed between the subsequent chemotherapy and the ICI after AR groups (P = 0.723). Patients with AR after ICI treatment had a unique progression pattern with oligo-progression and high rates of progression only in the lymph nodes. Local treatment and/or continuation of ICIs beyond AR might be an effective option.
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http://dx.doi.org/10.1038/s41598-021-81666-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844257PMC
January 2021

Overcoming the impact of the COVID-19 pandemic on oncology early phase trials and drug development in Asia-Experiences and perspectives of the Asian Oncology Early Phase 1 Consortium.

Asia Pac J Clin Oncol 2021 Aug 27;17(4):388-395. Epub 2021 Jan 27.

Experimental Cancer Therapeutics Unit, Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

Aim: The significance and prioritization of early phase oncology trial continuation during a global pandemic is unknown. This study reported the outcomes, multiple challenges, and broad recommendations associated with the impact of the novel coronavirus disease 2019 (COVID-19) on oncology early phase 1 trials-and on drug development in Asia-based on the experiences and perspectives of Asian oncology phase 1 centers.

Methods: Between March and April 2020 during the initial period of outbreak, the impact of COVID-19 across oncology phase 1 sites in five Asian countries-China (Hong Kong), Japan, South Korea, Taiwan, and Singapore-was retrospectively analyzed.

Results: There was no trial termination or treatment discontinuation in all five countries. Although the most common impact was new patient enrollment being placed on hold, which was based on pharmaceutical sponsors' decision-making, the situation varied per site. Most sites had no restrictions in place that would limit their ability to fully comply with the requirements of conducting the early phase studies. The number of protocol deviations during the pandemic was largely dependent on domestic transportation status during the outbreak rather than the ability of the clinical trial centers.

Conclusion: Determining the risk to benefits ratio of patients with cancer who are enrolled in early phase 1 clinical trials under the unusual circumstances of a global pandemic is important. Specific guidance or guidelines on the conduct of early phase 1 clinical trials during public health emergencies that are based on the recent lessons learned is urgently required.
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http://dx.doi.org/10.1111/ajco.13510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014030PMC
August 2021

High prevalence of a gene cluster conferring resistance to streptomycin, sulfonamide, and tetracycline in Escherichia coli isolated from indigenous wild birds.

J Gen Appl Microbiol 2021 Jun 22;67(2):81-84. Epub 2021 Jan 22.

Animal and Plant Quarantine Agency.

A total of 116 Escherichia coli isolates from cecal contents of 81 indigenous wild birds in Korea were tested for antimicrobial susceptibility. Seventy-one isolates from sparrows (Passer montanus) and one isolate from doves (Columba livia) were resistant to three antimicrobials, including streptomycin, sulfonamide, and tetracycline (SSuT). PCR and subsequent sequence analysis revealed the SSuT gene cluster region (approximately 13 kb) harboring genes encoding resistance to streptomycin (strA and strB), sulfonamide (sul2), and tetracycline (tetB, tetC, tetD, and tetR). In particular, tetracycline resistance genes were located on the transposon Tn10-like element. The SSuT element-harboring E. coli can be an important source of the transmission of antimicrobial resistance to other pathogenic bacteria. Therefore, strict sanitary measures in human and animal environments are necessary to prevent the spread of resistant bacteria through fecal residues of wild birds.
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http://dx.doi.org/10.2323/jgam.2020.06.003DOI Listing
June 2021

Tumor LAG-3 and NY-ESO-1 expression predict durable clinical benefits of immune checkpoint inhibitors in advanced non-small cell lung cancer.

Thorac Cancer 2021 03 17;12(5):619-630. Epub 2021 Jan 17.

Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.

Background: Immune checkpoint inhibitors (ICIs) are an established treatment for non-small cell lung cancer (NSCLC) that have demonstrated durable clinical benefits (DCBs). Previous studies have suggested NY-ESO-1 and LAG-3 to be surrogate markers of ICI responses in NSCLC; therefore, we explored the predictive value of their expression in NSCLC.

Methods: We retrospectively reviewed the records of 38 patients with advanced NSCLC treated with anti-PD-1 monoclonal antibodies from 2013 to 2016 at Seoul National University Hospital and Seoul National University Bundang Hospital after failed platinum-based chemotherapy. Tumor tissues from each patient were subjected to immunohistochemical analysis to determine NY-ESO-1, LAG-3, and PD-L1 expression, whose ability to predict progression-free survival (PFS) and overall survival (OS) was then analyzed alongside their positive (PPV) and negative (NPV) predictive values.

Results: NY-ESO-1 or LAG-3 expression was detected in all tumor samples from patients with high PD-L1 expression and was significantly associated with favorable outcomes, unlike PD-L1 expression. Patients with both NY-ESO-1- and LAG-3-expressing tumors had a high DCB rate and those with triple-positive PD-L1, LAG-3, and NY-ESO expression had a superior median OS and PFS than those with triple-negative expression. Furthermore, LAG-3 and NY-ESO-1 co-expression was an independent predictor of both PFS and OS, while LAG-3 displayed a good NPV.

Conclusions: Patients with NSCLC who co-express NY-ESO-1 or LAG-3 with PD-L1 exhibit greater DCBs and improved long-term survival following anti-PD-1 therapy. Moreover, NY-ESO-1 and LAG-3 could be novel predictive biomarkers of survival and should be considered in the future use of ICIs.
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http://dx.doi.org/10.1111/1759-7714.13834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919166PMC
March 2021

Olmutinib in T790M-positive non-small cell lung cancer after failure of first-line epidermal growth factor receptor-tyrosine kinase inhibitor therapy: A global, phase 2 study.

Cancer 2021 May 12;127(9):1407-1416. Epub 2021 Jan 12.

Hanmi Pharmaceutical Company, Ltd, Seoul, Republic of Korea.

Background: In this open-label, international phase 2 study, the authors assessed the efficacy and safety of olmutinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had a confirmed T790M mutation and disease progression on previous epidermal growth factor receptor-tyrosine kinase inhibitor therapy.

Methods: Patients aged ≥20 years received once-daily oral olmutinib 800 mg continuously in 21-day cycles. The primary endpoint was the objective response rate (patients who had a confirmed best overall response of a complete or partial response), assessed by central review. Secondary endpoints included the disease control rate, the duration of objective response, progression-free survival, and overall survival. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03).

Results: Overall, 162 patients (median age, 63 years; women, >60%) were enrolled from 68 sites in 9 countries. At the time of database cutoff, 23.5% of enrolled patients remained on treatment. The median treatment duration was 6.5 months (range, 0.03-21.68 months). Overall, 46.3% of patients (95% CI, 38.4%-54.3%) had a confirmed objective response (all partial responses). The best overall response (the objective response rate regardless of confirmation) was 51.9% (84 patients; 95% CI, 43.9%-59.8%). The confirmed disease control rate for all patients was 86.4% (95% CI, 80.2%-91.3%). The median duration of objective response was 12.7 months (95% CI, 8.3-15.4 months). Estimated median progression-free survival was 9.4 months (95% CI, 6.9-12.3 months), and estimated median overall survival was 19.7 months (95% CI, 15.1 months to not reached). All patients experienced treatment-emergent adverse events, and 71.6% of patients had grade ≥3 treatment-emergent adverse events.

Conclusions: Olmutinib has meaningful clinical activity and a manageable safety profile in patients with T790M-positive non-small cell lung cancer who received previous epidermal growth factor receptor-tyrosine kinase inhibitor therapy.
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http://dx.doi.org/10.1002/cncr.33385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247868PMC
May 2021

Discovery of acquired molecular signature on immune checkpoint inhibitors in paired tumor tissues.

Cancer Immunol Immunother 2021 Jun 3;70(6):1755-1769. Epub 2021 Jan 3.

Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Republic of Korea.

Background: Immune checkpoint inhibitor (ICI) has an emerging role in several types of cancer. However, the mechanisms of acquired resistance (AR) to ICI have not been elucidated yet. To identify these mechanisms, we analyzed the pre- and post-ICI paired tumor samples in patients with AR.

Methods: Six patients with renal cell carcinoma, urothelial cell carcinoma, or head and neck cancer, who showed an initial response to ICI followed by progression and had available paired tissue samples, were retrospectively analyzed. Whole exome sequencing, RNA sequencing, and multiplex immunohistochemistry were performed on pre-treatment and resistant tumor samples.

Results: The median time to AR was 370 days (range, 210 to 739). Increased expression of alternative immune checkpoints including TIM3, LAG3, and PD-1 as well as increased CD8 tumor-infiltrating lymphocytes were observed in post-treatment tumor than in pre-treatment tumor of a renal cell carcinoma patient. In contrast, CD8 T cells and immunosuppressive markers were all decreased at AR in another patient with human papillomavirus-positive head and neck squamous cell carcinoma. This patient had an evident APOBEC-associated signature, and the tumor mutation burden increased at AR. Resistant tumor tissue of this patient harbored a missense mutation (E542K) in PIK3CA. No significant aberrations of antigen-presenting machinery or IFN-γ pathway were detected in any patient.

Conclusions: Our study findings suggest that the observed increase in immunosuppressive markers after ICI might contribute to AR. Moreover, APOBEC-mediated PIK3CA mutagenesis might be an AR mechanism. To validate these mechanisms of AR, further studies with enough sample size are required.
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http://dx.doi.org/10.1007/s00262-020-02799-yDOI Listing
June 2021

Outcomes According to ALK Status Determined by Central Immunohistochemistry or Fluorescence In Situ Hybridization in Patients With ALK-Positive NSCLC Enrolled in the Phase 3 ALEX Study.

J Thorac Oncol 2021 02 24;16(2):259-268. Epub 2020 Oct 24.

Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.

Introduction: We retrospectively examined progression-free survival (PFS) and response by ALK fluorescence in situ hybridization (FISH) status in patients with advanced ALK immunohistochemistry (IHC)-positive NSCLC in the ALEX study.

Methods: A total of 303 treatment-naive patients were randomized to receive twice-daily alectinib 600 mg or crizotinib 250 mg. ALK status was assessed centrally using Ventana ALK (D5F3) CDx IHC and Vysis ALK Break Apart FISH Probe Kit. Primary end point is investigator-assessed PFS. Secondary end points of interest are objective response rate and duration.

Results: Investigator-assessed PFS was significantly prolonged with alectinib versus crizotinib in ALK IHC-positive and FISH-positive tumors (n = 203, 67%) (hazard ratio [HR] = 0.37, 95% confidence interval [CI]: 0.25-0.56; p < 0.0001) and ALK IHC-positive and FISH-uninformative tumors (n = 61, 20%) (HR = 0.39, 95% CI: 0.20-0.78) but not in ALK IHC-positive and FISH-negative tumors (n = 39, 13%) (HR = 1.33, 95% CI: 0.6-3.2). Objective response rates were higher with alectinib versus crizotinib in ALK IHC-positive and FISH-positive tumors (90.6% versus 81.4%; stratified OR = 2.22, 95% CI: 0.97-5.07) and ALK IHC-positive and FISH-uninformative tumors (96.0% versus 75.0%; OR = 9.29, 95% CI: 1.05-81.88) but not in ALK IHC-positive and FISH-negative tumors (28.6% versus 44.4%; OR = 0.45, 95% CI: 0.12-1.74). Next-generation sequencing was performed in 35 of 39 patients with ALK IHC-positive and FISH-negative tumors; no ALK fusion was identified in 20 of 35 patients (57.1%) by next-generation sequencing, but 10 of 20 (50.0%) had partial response or stable disease.

Conclusions: Outcomes of patients with ALK IHC-positive and FISH-positive and ALK IHC-positive and FISH-uninformative NSCLC were similar to those of the overall ALEX population. These results suggest that Ventana ALK IHC is a standard testing method for selecting patients for treatment with alectinib.
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http://dx.doi.org/10.1016/j.jtho.2020.10.007DOI Listing
February 2021

Effect of PM10 on pulmonary immune response and fetus development.

Toxicol Lett 2021 Mar 7;339:1-11. Epub 2020 Dec 7.

Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, Republic of Korea; Department of Biomedical Science and technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul, Republic of Korea.

Despite numerous reports that ambient particulate matter is a key determinant for human health, toxicity data produced based on physicochemical properties of particulate matters is very lack, suggesting lack of scientific evidence for regulation. In this study, we sampled inhalable particulate matters (PM10) in northern Seoul, Korea. PM10 showed atypical- and fiber-type particles with the average size and the surface charge of 1,598.1 ± 128.7 nm and -27.5 ± 2.8, respectively, and various toxic elements were detected in the water extract. On day 90 after the first pulmonary exposure, total cell number dose-dependently increased in the lungs of both sexes of mice. PM10 induced Th1-dominant immune response with pathological changes in both sexes of mice. Meanwhile, composition of total cells and expression of proteins which functions in cell-to-cell communication showed different trends between sexes. Following, male and female mice were mated to identify effects of PM10 to the next generation. PM10 remained in the lung of dams until day 21 after birth, and the levels of IgA and IgE increased in the blood of dams exposed to the maximum dose compared to control. In addition, the interval between births of fetuses, the number of offspring, the neonatal survival rate (day 4 after birth) and the sex ratio seemed to be affected at the maximum dose, and particularly, all offspring from one dam were stillborn. In addition, expression of HIF-1α protein increased in the lung tissue of dams exposed to PM10, and level of hypoxia-related proteins was notably enhanced in PM10-exposed bronchial epithelial cells compared to control. Taken together, we suggest that inhaled PM10 may induce Th1-shifting immune response in the lung, and that it may affect reproduction (fetus development) by causing lung hypoxia. Additionally, we propose that further study is needed to identify particle-size-dependent effects on development of the next generation.
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http://dx.doi.org/10.1016/j.toxlet.2020.11.024DOI Listing
March 2021

Impact of Dermanyssus gallinae infestation on persistent outbreaks of fowl typhoid in commercial layer chicken farms.

Poult Sci 2020 Dec 25;99(12):6533-6541. Epub 2020 Sep 25.

Animal and Plant Quarantine Agency, Gimcheon-si, Gyeongsangbuk-do, Korea. Electronic address:

Although it has rapidly decreased since the early 2000s, fowl typhoid still occurs in commercial layer chickens, causing a significant economic loss in Korea. There is growing concern about the emergence of new pathogenic strains of the causative agent, Salmonella Gallinarum, which is able to overcome vaccine immunity. It has also been suspected that the poultry red mite, Dermanyssus gallinae, which is commonly found in layer chicken farms, may be an important cause of the recurrence of fowl typhoid in the farms. This study was conducted to examine changes in the virulence of recent isolates of S. Gallinarum obtained from layer farms and estimate the potential of the disease transmission of D. gallinae in the farms. Clinical and environmental samples and mites collected from layer farms affected by fowl typhoid between 2013 and 2018 were tested for S. Gallinarum. The isolates were characterized by genotypic analyses and in vitro virulence assays with chicken-derived cell lines. Vaccine protection against recent isolates was examined in the chickens. A total of 45 isolates of S. Gallinarum were collected and there was no evidence of changes in their virulence. It has also been demonstrated that the S. Gallinarum 9R vaccine strain widely used in Korea is still effective in controlling fowl typhoid if the susceptibility of birds to the disease is not increased by stress. Salmonella Gallinarum isolated from the outer and inner parts of D. gallinae, environmental dust, and dead birds of the same farm showed the same or closely related genotypes. Consequently, the present study indicated that the horizontal transmission and environmental persistence of S. Gallinarum and the increased disease susceptibility of chickens in layer farms could be mediated by D. gallinae, causing persistent outbreaks of fowl typhoid.
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http://dx.doi.org/10.1016/j.psj.2020.09.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705004PMC
December 2020

High prevalence and variable fitness of fluoroquinolone-resistant avian pathogenic isolated from chickens in Korea.

Avian Pathol 2021 Apr 3;50(2):151-160. Epub 2021 Feb 3.

Avian Disease Research Division, Animal and Plant Quarantine Agency, Gimcheon-si, Korea.

Colibacillosis caused by avian pathogenic (APEC) is the most common bacterial disease in poultry, resulting in significant economic losses. Resistance to fluoroquinolones has been found to be high in APEC worldwide, which has increased concerns about risks to human health as well as poultry production. In the present study, we determined the prevalence, genetic traits, and fitness traits of fluoroquinolone-resistant APEC isolated from chickens in Korea using a total of 286 APEC isolates collected between 2014 and 2017. The APEC isolates were highly resistant to nalidixic acid (86.0%), ampicillin (71.7%), tetracycline (69.6%), and sulfisoxazole (61.2%), and 132 (46.2%) of the isolates were resistant to both enrofloxacin and ciprofloxacin. These fluoroquinolone-resistant isolates showed eight mutation combinations including single- or double-point mutations in the , , or genes. The isolates with double mutations (codons 83 and 87) in and additional mutations in and showed high-level fluoroquinolone resistance (minimum inhibitory concentrations, 16-128 µg/ml). The isolates fell into four phylogenetic groups, and groups A (47/132, 35.6%) and B1 (47/132, 36.4%) were the most predominant. Nine isolates (6.8%) belonged to group B2 and included major lineages of extraintestinal pathogenic , sequence type (ST) 95 (= 3) and ST69 (= 2). The isolates varied in their virulence-associated gene content, biofilm formation, and intramacrophage survival. Overall, fluoroquinolone-resistant APEC in poultry poses a potential risk to public health and represents a highly diverse group of the resistant bacteria that varied in their genetic and fitness traits.
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http://dx.doi.org/10.1080/03079457.2020.1855322DOI Listing
April 2021

Toxicity of orally administered food-grade titanium dioxide nanoparticles.

J Appl Toxicol 2021 Jul 25;41(7):1127-1147. Epub 2020 Nov 25.

East-West Medical Science Research Institute, Kyung Hee University, Seoul, Republic of Korea.

This year, France banned the application of titanium dioxide nanoparticles as a food additive (hereafter, E171) based on the insufficient oral toxicity data. Here, we investigated the subchronic toxic responses of E171 (0, 10, 100, and 1,000 mg/kg) and tried to elucidate the possible toxic mechanism using AGS cells, a human stomach epithelial cell line. There were no dose-related changes in the Organisation for Economic Cooperation and Development test guideline-related endpoints. Meanwhile, E171 deeply penetrated cells lining the stomach tissues of rats, and the IgM and granulocyte-macrophage colony-stimulating factor levels were significantly lower in the blood from rats exposed to E171 compared with the control. The colonic antioxidant protein level decreased with increasing Ti accumulation. Additionally, after 24-h exposure, E171 located in the perinuclear region of AGS cells and affected expression of endoplasmic reticulum stress-related proteins. However, cell death was not observed up to the used maximum concentration. A gene profile analysis also showed that immune response-related microRNAs were most strongly affected by E171 exposure. Collectively, we concluded that the NOAEL of E171 for 90 days repeated oral administration is between 100 and 1,000 mg/kg for both male and female rats. Additionally, further study is needed to clarify the possible carcinogenesis following the chronic accumulation in the colon.
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http://dx.doi.org/10.1002/jat.4099DOI Listing
July 2021

2020 Clinical Practice Guideline for Percutaneous Transthoracic Needle Biopsy of Pulmonary Lesions: A Consensus Statement and Recommendations of the Korean Society of Thoracic Radiology.

Korean J Radiol 2021 02 19;22(2):263-280. Epub 2020 Nov 19.

Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Percutaneous transthoracic needle biopsy (PTNB) is one of the essential diagnostic procedures for pulmonary lesions. Its role is increasing in the era of CT screening for lung cancer and precision medicine. The Korean Society of Thoracic Radiology developed the first evidence-based clinical guideline for PTNB in Korea by adapting pre-existing guidelines. The guideline provides 39 recommendations for the following four main domains of 12 key questions: the indications for PTNB, pre-procedural evaluation, procedural technique of PTNB and its accuracy, and management of post-biopsy complications. We hope that these recommendations can improve the diagnostic accuracy and safety of PTNB in clinical practice and promote standardization of the procedure nationwide.
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http://dx.doi.org/10.3348/kjr.2020.0137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817630PMC
February 2021

Pan-cancer methylation analysis reveals an inverse correlation of tumor immunogenicity with methylation aberrancy.

Cancer Immunol Immunother 2021 Jun 24;70(6):1605-1617. Epub 2020 Nov 24.

Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Tumor immunogenicity is driven by various genomic and transcriptomic factors but the association with the overall status of methylation aberrancy is not well established. We analyzed The Cancer Genome Atlas pan-cancer database to investigate whether the overall methylation aberrancy links to the immune evasion of tumor. We created the definitions of hypermethylation burden, hypomethylation burden and methylation burden to establish the values that represent the degree of methylation aberrancy from human methylation 450 K array data. Both hypermethylation burden and hypomethylation burden significantly correlated with global methylation level as well as methylation subtypes defined in previous literatures. Then we evaluated whether methylation burden correlates with tumor immunogenicity and found that methylation burden showed a significant negative correlation with cytolytic activity score, which represent cytotoxic T cell activity, in pan-cancer (Spearman rho = - 0.37, p < 0.001) and 30 of 33 individual cancer types. Furthermore, this correlation was independent of mutation burden and chromosomal instability in multivariate regression analysis. We validated the findings in the external cohorts and outcomes of patients who were treated with immune checkpoint inhibitors, which showed that high methylation burden group had significantly poor progression-free survival (Hazard ratio 1.74, p = 0.038). Overall, the degree of methylation aberrancy negatively correlated with tumor immunogenicity. These findings emphasize the importance of methylation aberrancy for tumors to evade immune surveillance and warrant further development of methylation biomarker.
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http://dx.doi.org/10.1007/s00262-020-02796-1DOI Listing
June 2021

First-Line Lorlatinib or Crizotinib in Advanced -Positive Lung Cancer.

N Engl J Med 2020 11;383(21):2018-2029

From the Massachusetts General Hospital Cancer Center (A.T.S.) and Pfizer (G.P.) - both in Boston; Sarah Cannon Research Institute-Tennessee Oncology, Nashville (T.M.B.); European Institute of Oncology, IRCCS (F.M.), and Pfizer (A.P., A.M.C.) - both in Milan; Vall d'Hebron University Hospital and Institute of Oncology, International Oncology Bureau-Quirón, Barcelona (E.F.); National Cancer Center Hospital, Tokyo (Y.G.); Princess Margaret Cancer Centre, Toronto (G.L.); Toulouse University Hospital, Toulouse, France (J.M.); Seoul National University College of Medicine and Seoul National University Hospital, Seoul, South Korea (D.-W.K.); State Key Laboratory of Translational Oncology, Chinese University of Hong Kong, Hong Kong (T.M.); Pfizer, La Jolla, CA (H.T.); and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (B.J.S.).

Background: Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK), has antitumor activity in previously treated patients with -positive non-small-cell lung cancer (NSCLC). The efficacy of lorlatinib, as compared with that of crizotinib, as first-line treatment for advanced -positive NSCLC is unclear.

Methods: We conducted a global, randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced -positive NSCLC who had received no previous systemic treatment for metastatic disease. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included independently assessed objective response and intracranial response. An interim analysis of efficacy was planned after approximately 133 of 177 (75%) expected events of disease progression or death had occurred.

Results: The percentage of patients who were alive without disease progression at 12 months was 78% (95% confidence interval [CI], 70 to 84) in the lorlatinib group and 39% (95% CI, 30 to 48) in the crizotinib group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.19 to 0.41; P<0.001). An objective response occurred in 76% (95% CI, 68 to 83) of the patients in the lorlatinib group and 58% (95% CI, 49 to 66) of those in the crizotinib group; among those with measurable brain metastases, 82% (95% CI, 57 to 96) and 23% (95% CI, 5 to 54), respectively, had an intracranial response, and 71% of the patients who received lorlatinib had an intracranial complete response. The most common adverse events with lorlatinib were hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects. Lorlatinib was associated with more grade 3 or 4 adverse events (mainly altered lipid levels) than crizotinib (in 72% vs. 56%). Discontinuation of treatment because of adverse events occurred in 7% and 9% of the patients, respectively.

Conclusions: In an interim analysis of results among patients with previously untreated advanced -positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels. (Funded by Pfizer; CROWN ClinicalTrials.gov number, NCT03052608.).
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http://dx.doi.org/10.1056/NEJMoa2027187DOI Listing
November 2020

A randomised phase 2b study comparing the efficacy and safety of belotecan vs. topotecan as monotherapy for sensitive-relapsed small-cell lung cancer.

Br J Cancer 2021 02 16;124(4):713-720. Epub 2020 Nov 16.

National Cancer Center, Goyang, South Korea.

Background: This study compared the efficacy/safety of the camptothecin analogues belotecan and topotecan for sensitive-relapsed small-cell lung cancer (SCLC).

Methods: One-hundred-and-sixty-four patients were randomised (1:1) to receive five consecutive daily intravenous infusions of topotecan (1.5 mg/m) or belotecan (0.5 mg/m), every 3 weeks, for six cycles. Main outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), tolerability and toxicity. The study statistical plan was non-inferiority design with ORR as the endpoint.

Results: In the belotecan vs. topotecan groups, ORR (primary endpoint) was 33% vs. 21% (p = 0.09) and DCR was 85% vs. 70% (p = 0.030). PFS was not different between groups. Median OS was significantly longer with belotecan than with topotecan (13.2 vs. 8.2 months, HR = 0.69, 95% CI: 0.48-0.99), particularly in patients aged <65 years, with more advanced disease (i.e., extensive-stage disease, time to relapse: 3-6 months), or Eastern Cooperative Oncology Group performance status 1 or 2. More belotecan recipients completed all treatment cycles (53% vs. 35%; p = 0.022).

Conclusions: The efficacy/safety of belotecan warrants further evaluation in Phase 3 trials. Belotecan potentially offers an alternative to topotecan for sensitive-relapsed SCLC, particularly in patients aged <65 years, with more advanced disease, or poor performance.
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http://dx.doi.org/10.1038/s41416-020-01055-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884704PMC
February 2021

Organogermanium Nanowire Cathodes for Efficient Lithium-Oxygen Batteries.

ACS Nano 2020 Nov 11;14(11):15894-15903. Epub 2020 Nov 11.

School of Civil, Environmental, and Architectural Engineering, Korea University, Seoul 02841, South Korea.

We report a technique for effectively neutralizing the generation of harmful superoxide species, the source of parasitic reactions, in lithium-oxygen batteries to generate stable substances. In organic electrolytes, organogermanium (Propa-germanium, Ge-132) nanowires can suppress solvated superoxide and induce strong surface-adsorption reaction due to their high anti-superoxide disproportionation activity. Resultantly, the effect of organogermanium nanowires mitigate toxic oxidative stress to stabilize organic electrolytes and promote good LiO growth. These factors led to long duration of the electrolytes and impressive rechargeability of lithium-oxygen batteries.
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http://dx.doi.org/10.1021/acsnano.0c07262DOI Listing
November 2020

In Situ Conversion of Metal-Organic Frameworks into VO -V S Heterocatalyst Embedded Layered Porous Carbon as an "All-in-One" Host for Lithium-Sulfur Batteries.

Small 2020 Nov 2;16(47):e2004806. Epub 2020 Nov 2.

School of Civil, Environmental and Architectural Engineering, Korea University, Seoul, 02841, South Korea.

Although lithium-sulfur batteries exhibit a fivefold higher energy density than commercial lithium-ion batteries, their volume expansion and insulating nature, and intrinsic polysulfide shuttle have hindered their practical application. An alternative sulfur host is necessary to realize porous, conductive, and polar functions; however, there is a tradeoff among these three critical factors in material design. Here, the authors report a layered porous carbon (LPC) with VO /V S heterostructures using one-step carbonization-sulfidation of metal-organic framework templates as a sulfur host that meets all the criteria. In situ conversion of V-O ions into V S nuclei in the confined 2D space generated by dynamic formation of the LPC matrix creates {200}-facet-exposed V S nanosheets decorated with tiny VO nanoparticles. The VO /V S  @ LPC composite facilitates high sulfur loading (70 wt%), superior energy density (1022 mA h g at 0.2 C, 100 cycles), and long-term cyclability (665 mA h g at 1 C, 1000 cycles). The enhanced Li-S chemistry is attributed to the synergistic heterocatalytic behavior of polar VO and conductive V S in the soft porous LPC scaffold, which accelerates polysulfide adsorption, conversion, and charge-transfer ability simultaneously.
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http://dx.doi.org/10.1002/smll.202004806DOI Listing
November 2020

Phase II study of durvalumab and tremelimumab in pulmonary sarcomatoid carcinoma: KCSG-LU16-07.

Thorac Cancer 2020 12 7;11(12):3482-3489. Epub 2020 Oct 7.

Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.

Background: Pulmonary sarcomatoid carcinoma (PSC) is rare with a poor outcome and is resistant to conventional cytotoxic chemotherapy. The efficacy and safety of durvalumab and tremelimumab for treating recurrent or metastatic PSCs were assessed by a nonrandomized, open-label, phase II study.

Methods: A total of 18 patients with recurrent or metastatic PSC received 1500 mg of durvalumab and 75 mg of tremelimumab every four weeks, followed by 750 mg of durvalumab every two weeks until the disease progressed, or an unacceptable toxicity level was reached. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. Genomic profiling of PSC by next-generation sequencing (NGS) and determination of peripheral blood lymphocyte subsets using flow cytometry were performed for exploratory analysis.

Results: A total of 15 out of 18 patients were evaluated for the analysis of the primary endpoint. At the data cutoff point, the ORR of 26.7% (95% confidence interval [CI]: 7.8-55.1) was achieved with the median follow-up duration of 12.0 months (range, 8.4-16.1). Median PFS and OS were 5.9 months (95% CI: 1.1-11.9) and 15.4 months (95% CI: 11.1-not reached), respectively. Treatment-related adverse events (AEs) of any grade were reported in 16 patients; the most common AEs were pruritus (n = 5), pneumonitis (n = 4), and rash (n = 4). Treatment was discontinued in two patients due to AEs of grade ≥ 3.

Conclusions: Durvalumab and tremelimumab demonstrated clinical benefit with a prolonged survival and manageable toxicity profile in patients with recurrent or metastatic PSC.
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http://dx.doi.org/10.1111/1759-7714.13684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705626PMC
December 2020

A Phase 1 study of gefitinib combined with durvalumab in EGFR TKI-naive patients with EGFR mutation-positive locally advanced/metastatic non-small-cell lung cancer.

Br J Cancer 2021 01 5;124(2):383-390. Epub 2020 Oct 5.

Departments of Thoracic/Head and Neck Medical Oncology and Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.

Background: EGFR tyrosine kinase inhibitors (TKIs) induce cytolysis and release of tumour proteins, which can stimulate antigen-specific T cells. The safety and efficacy of durvalumab and gefitinib in combination for TKI-naive patients with advanced EGFRm NSCLC was evaluated.

Methods: This Phase 1 open-label, multicentre trial (NCT02088112) was conducted in 56 patients with NSCLC. Dose expansion permitted TKI-naive patients, primarily with activating L858R or Ex19del EGFRm. Arms 1 + 1a received concurrent therapy; Arm 2 received 4 weeks of gefitinib induction followed by concurrent therapy.

Results: From dose escalation, the recommended dose of durvalumab was 10 mg/kg Q2W with 250 mg QD gefitinib. Pharmacokinetics were as expected, consistent with inhibition of soluble PD-L1 and no treatment-emergent immunogenicity. In dose expansion, 35% of patients had elevated liver enzymes leading to drug discontinuation. In Arms 1 + 1a, objective response rate was 63.3% (95% CI: 43.9-80.1), median progression-free survival (PFS) was 10.1 months (95% CI: 5.5-15.2) and median response duration was 9.2 months (95% CI: 3.7-14.0).

Conclusions: Durvalumab and gefitinib in combination had higher toxicity than either agent alone. No significant increase in PFS was detected compared with historical controls. Therefore, concurrent PD-L1 inhibitors with gefitinib should be generally avoided in TKI-naive patients with EGFRm NSCLC.
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http://dx.doi.org/10.1038/s41416-020-01099-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852511PMC
January 2021
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