Publications by authors named "Hyun Ae Jung"

65 Publications

Extrapulmonary tuberculosis in patients with RET fusion-positive non-small cell lung cancer treated with pralsetinib: A Korean single-centre compassionate use experience.

Eur J Cancer 2021 Nov 6;159:167-173. Epub 2021 Nov 6.

Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Republic of Korea. Electronic address:

Background: Pralsetinib, an RET inhibitor, has shown a dramatic response in patients with RET fusion- or mutation-positive tumours in previous studies. As a novel target agent, however, the safety of pralsetinib remains to be determined. Herein, we present two cases of extrapulmonary tuberculosis (TB) that developed during pralsetinib therapy.

Methods: From April 2020, we administered pralsetinib to a total of 10 patients with RET fusion-positive non-small cell lung cancer under the compassionate use program. We retrospectively analysed the clinical efficacy of and adverse events related to pralsetinib therapy.

Results: Of the nine patients with measurable lesions, seven achieved a partial response. Additionally, one patient without measurable lesions also showed a clinical response. As of January 8, 2021, nine patients were still receiving pralsetinib therapy, while only one had discontinued pralsetinib therapy. Most adverse events were mild and manageable. However, two patients experienced extrapulmonary TB shortly after starting pralsetinib. The disease was well controlled with anti-TB medication, and the cancer lesions were managed through ongoing pralsetinib therapy.

Conclusion: The development of TB during pralsetinib therapy is worth noting, although further large studies are required to demonstrate definitive relationship between causality and underlying mechanism.
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http://dx.doi.org/10.1016/j.ejca.2021.09.037DOI Listing
November 2021

A Single-Arm, Prospective, Phase II Study of Cisplatin Plus Weekly Docetaxel as First-Line Therapy in Patients with Metastatic or Recurrent Salivary Gland Cancer.

Cancer Res Treat 2021 Nov 1. Epub 2021 Nov 1.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Purpose: Salivary gland cancers (SGCs) are relatively rare but comprise various histologic subtypes, which complicates design of prospective trials. Systemic chemotherapy plays a limited role in treatment of SGCs, but cisplatin and docetaxel showed efficacy in a previous preclinical study. Here, we conduct a prospective, phase II study to evaluate the efficacy and toxicities of cisplatin plus weekly docetaxel in patients with metastatic or recurrent SGC.

Materials And Methods: We included patients with histologically confirmed SGCs of the following subtypes: mucoepidermoid carcinoma, adenocarcinoma, ductal carcinoma, or adenoid cystic carcinoma. Patients had no prior systemic chemotherapy for metastatic or recurrent tumors and at least one measurable lesion. Patients were treated with docetaxel 35mg/m2 (D1, 8) and cisplatin 70mg/m2 (D1) every 21 days.

Results: Forty-one patients were enrolled between April 2014 and October 2020. The median age was 58 years (range, 32-73). The most common histologic subtype was adenoid cystic carcinoma (63.4%), followed by ductal carcinoma (24.4%). The most common metastatic site was the lung (75.6%). The median treatment cycle was 5.5 (range, 3-8), and the objective response rate was 46.3%, with three complete responses. The median duration of response was 6.8 months (IQR, 4.0-10.2). The progression-free survival and overall survival were 9.4 months (95% CI, 8.4-10.5) and 28.2 months (95% CI, 22.7-33.6), respectively. There were no treatment-related deaths. The most common grade 3/4 adverse events were neutropenia (4.9%) and fatigue (4.9%).

Conclusion: Cisplatin plus weekly docetaxel is effective and tolerable with manageable toxicity as first-line therapy in patients with metastatic or recurrent SGC.
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http://dx.doi.org/10.4143/crt.2021.1019DOI Listing
November 2021

Sequential afatinib and osimertinib in patients with EGFR mutation-positive NSCLC and acquired T790M: A global non-interventional study (UpSwinG).

Lung Cancer 2021 Sep 21;162:9-15. Epub 2021 Sep 21.

Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan. Electronic address:

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard of care for EGFR mutation-positive non-small cell lung cancer (NSCLC). However, optimal sequence of treatment has yet to be defined. Overall survival (OS) is influenced by the availability/use of subsequent therapy after first-line treatment. Emergence of T790M is the main mechanism of resistance to afatinib and second-line osimertinib could be a treatment option in this instance.

Methods: In this non-interventional, global study (NCT04179890), existing medical/electronic records were identified for consecutive EGFR TKI-naïve patients with EGFR mutation-positive NSCLC (Del19 or L858R) treated with first-line afatinib and second-line osimertinib in regular clinical practice (n = 191; all T790M-positive). The primary objective was time to treatment failure (TTF). Key secondary objectives were OS and objective response rate (ORR).

Results: At the start of afatinib treatment, median age (range) was 62 years (34-88). Fifty-five percent of patients were female and 67% were Asian. ECOG PS (0/1/≥2) was 31%/57%/12%. Fourteen percent of patients had brain metastases. At the start of osimertinib treatment, ECOG PS (0/1/≥2) was 25%/61%/14% and 14% had brain metastases (rising to 29% at the end of osimertinib treatment). The source of biopsy material (solid/liquid) was 86%/3% at the start of afatinib and 54%/33% at start of osimertinib. Mutations were mainly detected with PCR methods. Overall, median TTF was 27.7 months (95% CI: 24.0-30.2) and median OS was 36.5 months (95% CI: 32.9-41.8). ORR with afatinib and osimertinib was 74% and 45%. TTF, OS and ORR were generally consistent across subgroups.

Conclusion: Sequential afatinib and osimertinib demonstrated encouraging activity in patients with EGFR mutation-positive NSCLC and acquired T790M. Activity was observed across all subgroups, including patients with poor ECOG PS or brain metastases. ECOG PS and incidence of brain metastases remained stable prior to, and after, afatinib treatment.
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http://dx.doi.org/10.1016/j.lungcan.2021.09.009DOI Listing
September 2021

Treatment and Outcomes of Metastatic Pancreatic Cancer in Elderly Patients.

Chemotherapy 2021 4;66(4):107-112. Epub 2021 Aug 4.

Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Hwaseong-si, Republic of Korea.

Background And Aims: Although pancreatic cancers are common in older age-groups, the prognosis remains poor due to limited studies on treatment approaches and outcomes in a given population. We aimed to examine treatment patterns and their outcomes in older patients with metastatic pancreatic cancer in a real-world context.

Materials And Methods: We conducted a retrospective study including 167 patients with metastatic pancreatic cancer (aged ≥70 years and male/female: 78/89) between January 2010 and July 2015. Patients' retrieved data from medical records were analyzed according to treatment types, followed by a review of clinicopathologic variables and treatment outcomes.

Results: Of the 167 eligible patients for the study, only 21.6% (n = 36) received palliative chemotherapy. The median age of the chemotherapy group was 74.0 years and 78.6 years for the supportive care group. The median survival of the chemotherapy group was 9.2 months (range: 1.0-24.9 months), compared with that of the supportive care group, which was 2.3 months (range: 0.1-31.8 months). Among the patients in the chemotherapy group, 50% (n = 18) received gemcitabine-based double therapy, and 30% patients (n = 9) received second-line chemotherapy.

Conclusions: Our results showed that older patients with metastatic pancreatic cancer were less likely to receive chemotherapy. However, the survival benefit from chemotherapy was comparable to that of younger patients' counterpart. Thus, further study involving identification of older patients who would benefit from cytotoxic chemotherapy is needed.
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http://dx.doi.org/10.1159/000517245DOI Listing
November 2021

Long-Term Survival in Non-Small Cell Lung Cancer Patients with Metachronous Brain-Only Oligorecurrence Who Underwent Definitive Treatment.

Cancer Res Treat 2021 May 6. Epub 2021 May 6.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Purpose: Metachronous brain-only oligorecurrence in patients with non-small cell lung cancer (NSCLC) is a rare event with favorable prognosis, but the clinical outcome has not been fully determined. We retrospectively analyzed clinical outcomes and prognostic factors in metachronous brain-only oligorecurrence in patients with NSCLC who underwent definitive treatment.

Materials And Methods: We reviewed 4,437 NSCLC patients without oncogenic driver mutations who underwent definitive treatment between 2008 and 2018. Among them, we identified 327 patients who developed 1 to 5 brain metastases with or without systemic metastasis. Of the 327 patients, 71 had metachronous brain-only oligorecurrence without extracranial progression and were treated with local therapy to the brain. Overall survival (OS), progression-free survival (PFS), and prognostic factors affecting OS were analyzed.

Results: The median OS was 38.9 months (95% CI, 21.8 to 56.1 months) in 71 patients. The 2-year OS rate was 67.8% and the 5-year OS rate was 33.1%. The median PFS was 25.5 months (95% CI, 12.2 to 14.4 months). The longest surviving patient had a survival period of 115 months. Through multivariate analysis, ECOG ≥ 1 (HR: 5.33, p=0.005) was associated with poor survival. There was no significant difference in OS between patients with local therapy and those with local plus systemic therapy (18.5 vs. 34.7 months, p=0.82).

Conclusion: Metachronous brain-only oligorecurrence NSCLC patients who underwent definitive treatment experienced long-term survival with local therapy, highlighting the unique patient population. The role of systemic chemotherapy in this patient population requires further investigation.
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http://dx.doi.org/10.4143/crt.2021.306DOI Listing
May 2021

Prognostic Value of the Neutrophil-to-Lymphocyte Ratio before and after Radiotherapy for Anaplastic Thyroid Carcinoma.

Cancers (Basel) 2021 Apr 15;13(8). Epub 2021 Apr 15.

Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.

The neutrophil-lymphocyte ratio (NLR) is a marker of systemic inflammation, and its elevation has recently been associated with poor survival in many solid cancers. Leukocyte elevation and lymphocyte reduction are associated with a poor response to radiotherapy (RT). This study aimed to assess the prognostic value of NLR before and after RT for anaplastic thyroid carcinoma (ATC). This retrospective study analyzed 40 patients with ATC who received RT with available complete blood cell count data from November 1995 through May 2020 at Samsung Medical Center (Seoul, Korea). Patients were classified into two groups according to the NLR before and after RT. The median overall survival (OS) was 8.9 months (range, 3.5-18.2) in the low NLR group (<3.47) and 5.2 months (range, 2.7-7.5) months in the high NLR group (≥3.47). The association between NLR and OS was also observed in multivariable Cox regression analysis (hazard ratio, 3.18; 95% confidence interval, 1.15-8.85; = 0.026). The OS curves differed significantly according to post-RT NLR ( = 0.036). A high NLR before and after RT may be significantly associated with poor OS in patients with ATC who receive RT.
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http://dx.doi.org/10.3390/cancers13081913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071431PMC
April 2021

Multimodal treatments and outcomes for anaplastic thyroid cancer before and after tyrosine kinase inhibitor therapy: a real-world experience.

Eur J Endocrinol 2021 May 6;184(6):837-845. Epub 2021 May 6.

Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background: Anaplastic thyroid cancer (ATC) has dismal prognosis and there is no effective treatment. We aimed to evaluate the efficacy of tyrosine kinase inhibitor (TKI) therapy in real-world clinic and to suggest the most effective treatment modality according to the combination of treatments.

Methods: This retrospective study evaluated clinical outcomes and cause of death with multimodal treatments in patients with ATC at Samsung Medical Center.

Results: A total of 120 patients received anti-cancer treatment for ATC. Seventy-seven (64.2%) patients underwent surgery, 64 (53.3%) received radiotherapy, 29 (24.2%) received cytotoxic chemotherapy, and 19 (15.8%) received TKI therapy. In the TKI therapy group, eight achieved partial response (three with lenvatinib and five with dabrafenib plus trametinib), and two patients with lenvatinib showed stable disease. Median progression-free survival (PFS) of the TKI therapy group was 2.7 months (range: 0.1-12.7) and their median overall survival (OS) was 12.4 months (range: 1.7-47.7). Patients who received surgery or radiotherapy for local control showed superior OS than those who did not. In a multivariate analysis, surgery, TKI therapy, younger age, and no distant metastasis were associated with favorable OS. The combination of surgery, radiotherapy, and TKI therapy (median OS: 34.3 months, 6-month survival rates: 77.8%) was the most effective. Compared to the era without TKI therapy, distant metastasis has recently become the major cause of death in ATC over airway problems.

Conclusions: Multimodality treatment including TKI therapy demonstrated prolonged survival with dabrafenib plus trametinib as the most effective therapeutic option demonstrated for BRAF mutant ATC patients.
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http://dx.doi.org/10.1530/EJE-20-1482DOI Listing
May 2021

High concordance of actionable genomic alterations identified between circulating tumor DNA-based and tissue-based next-generation sequencing testing in advanced non-small cell lung cancer: The Korean Lung Liquid Versus Invasive Biopsy Program.

Cancer 2021 Aug 7;127(16):3019-3028. Epub 2021 Apr 7.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Background: Because of the growing number of actionable biomarkers in non-small cell lung cancer (NSCLC), sufficient tissue availability for testing is becoming a greater challenge. Liquid biopsy offers a potential solution by complementing standard tissue-based methods. In this study, the authors analyzed the concordance of actionable genomic alterations sequenced from circulating tumor DNA (ctDNA; Guardant360) and tissue (Oncomine Focus Assay).

Methods: From September 2015 to May 2018, 421 paired plasma and tissue samples from patients with advanced NSCLC who had previously undergone tissue testing by standard methods were collected. Both types of samples were available for 287 patients (262 in cohort 1 [treatment-naive] and 25 in cohort 2 [treatment failure]), and only 1 sample type was available for 134 patients (50 in cohort 3 [plasma only] and 84 in cohort 4 [tissue only]).

Results: In cohort 1, 198 samples (77.6%) showed concordance between tissue and plasma next-generation sequencing (NGS). Among the discordant cases, plasma testing detected additional genomic alterations in 11 patients (4.2%). In 50 patients without tissue-based NGS results (cohort 3), the ctDNA-based test detected genomic alterations in 20 samples (40.0%). The median allele frequency (AF) of mutations identified with ctDNA-based NGS (0.74%) was lower than that identified with the tissue-based NGS test (13.90%). Clinical responses to matched targeted therapy occurred, regardless of the ctDNA AF. Upfront ctDNA-based testing identified 60.4% of patients with genomic alterations. In addition, ctDNA-based testing uncovered 12.0% more actionable alterations when it was performed after tissue-based NGS testing.

Conclusions: The results indicate that a ctDNA-based test identifies additional patients with actionable genomic alterations and could, therefore, be used to complement traditional tissue-based testing for NSCLC.

Lay Summary: Circulating tumor DNA (ctDNA)-based next-generation sequencing (NGS) testing is becoming essential as the number of actionable genomic biomarker increases for the treatment selection of non-small cell lung cancer. This study demonstrates the additive value of ctDNA-based testing in addition to tissue-based NGS and standard of care-based biomarker testing for detecting additional patients with actionable genomic alterations. Clinical responses have also been observed in patients with a low allele frequency detected by ctDNA-based NGS testing.
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http://dx.doi.org/10.1002/cncr.33571DOI Listing
August 2021

Comprehensive evaluation of the clinical utility of plasma EGFR test in non-small cell lung cancer patients with acquired resistance to first-line EGFR inhibitors.

Transl Lung Cancer Res 2021 Feb;10(2):878-888

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Background: Plasma epidermal growth factor receptor (EGFR) mutation tests are widely used when non-small cell lung cancer (NSCLC) patients acquire resistance to EGFR inhibitors. We comprehensively evaluated the clinical utility of plasma EGFR test.

Methods: We screened NSCLC patients who had a plasma EGFR test upon acquiring resistance to first- or second-generation EGFR inhibitors. Plasma EGFR tests were performed with the EGFR mutation test.

Results: A total of 355 patients were tested for plasma EGFR mutations, and T790M was detected in 83 patients (23%). Of 79 patients who were tested multiple times, T790M was newly detected in 13 subsequent plasma tests. When initial plasma tests did not detect any EGFR mutation types, the detection rate of T790M in subsequent tests was very low (9%, 5/56), while detection rates of T790M in subsequent tests increased (35%, 8/23) in those individuals in whom sensitizing mutations had been detected in the initial plasma test (P=0.005). Paired plasma and tissue EGFR test results were available for 235 patients. Sensitivity and specificity of the plasma tests for T790M were 14% and 87%, respectively. Among 235 patients, 140 patients had tissue EGFR tests performed after T790M-negative plasma results were reported. The subsequent tissue test detected T790M in 61% (44/72) of these patients when any EGFR mutations were not detected in prior plasma tests, while the detection rate of T790M in subsequent tissue tests was 37% (25/68) when sensitizing mutations were detected in prior plasma tests (P=0.004).

Conclusions: Because the sensitivity of plasma EGFR test for T790M is low, follow-up tissue or plasma tests are necessary. Presence or absence of a sensitizing mutation in the initial plasma tests can be used to determine which samples (tissue or plasma) should be submitted for further testing.
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http://dx.doi.org/10.21037/tlcr-20-1128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947405PMC
February 2021

Immune Checkpoint Inhibitors for Non-Small-Cell Lung Cancer with Brain Metastasis : The Role of Gamma Knife Radiosurgery.

J Korean Neurosurg Soc 2021 Mar 4;64(2):271-281. Epub 2020 Dec 4.

Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Objective: Immune checkpoint inhibitors (ICIs) are approved for treating non-small-cell lung cancer (NSCLC); however, the safety and efficacy of combined ICI and Gamma Knife radiosurgery (GKS) treatment remain undefined. In this study, we retrospectively analyzed patients treated with ICIs with or without GKS at our institute to manage patients with brain metastases from NSCLC.

Methods: We retrospectively reviewed medical records of patients with brain metastases from NSCLC treated with ICIs between January 2015 and December 2017. Of 134 patients, 77 were assessable for brain responses and categorized into three groups as follows : group A, ICI alone (n=26); group B, ICI with concurrent GKS within 14 days (n=24); and group C, ICI with non-concurrent GKS (n=27).

Results: The median follow-up duration after brain metastasis diagnosis was 19.1 months (range, 1-77). At the last follow-up, 53 patients (68.8%) died, 20 were alive, and four were lost to follow-up. The estimated median overall survival (OS) of all patients from the date of brain metastasis diagnosis was 20.0 months (95% confidence interval, 12.5-27.7) (10.0, 22.5, and 42.1 months in groups A, B, and C, respectively). The OS was shorter in group A than in group C (p=0.001). The intracranial disease progression-free survival (p=0.569), local progression-free survival (p=0.457), and complication rates did not significantly differ among the groups. Twelve patients showed leptomeningeal seeding (LMS) during follow-up. The 1-year LMS-free rate in treated with ICI alone group (69.1%) was significantly lower than that in treated with GKS before ICI treatment or within 14 days group (93.2%) (p=0.004).

Conclusion: GKS with ICI showed no favorable OS outcome in treating brain metastasis from NSCLC. However, GKS with ICI did not increase the risk of complications. Furthermore, compared with ICI alone, GKS with ICI may be associated with a reduced incidence of LMS. Further understanding of the mechanism, which remains unknown, may help improve the quality of life of patients with brain metastasis.
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http://dx.doi.org/10.3340/jkns.2020.0135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969051PMC
March 2021

The different central nervous system efficacy among gefitinib, erlotinib and afatinib in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer.

Transl Lung Cancer Res 2020 Oct;9(5):1749-1758

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background: Brain metastasis is common in non-small cell lung cancer (NSCLC) and has an even higher incidence in epidermal growth factor receptor (EGFR)-mutant cancers. Although EGFR tyrosine kinase inhibitors (TKIs) are effective against brain metastases, it is unknown which first- or second-generation EGFR TKI is most effective.

Methods: Patients treated with first-line gefitinib, erlotinib, or afatinib for advanced EGFR-mutant NSCLC were included. The efficacy against brain metastasis was evaluated by comparing the response rates of measurable and non-irradiated brain metastases, central nervous system progression-free survival (CNS-PFS), and the cumulative incidence of CNS failure.

Results: Among the 559 patients who received EGFR-TKIs (gefitinib, n=299; erlotinib, n=93; afatinib, n=167), 198 had initial brain metastasis before starting EGFR-TKIs. The CNS response rates of gefitinib, erlotinib, and afatinib were 64.7%, 68.2%, and 72.9%, respectively (P=0.78). In the overall study population, irrespective of initial CNS metastasis, the median CNS-PFS was 17.3 months for gefitinib, 12.4 months for erlotinib, and 23.3 months for afatinib (P<0.001). In multivariate analysis for CNS-PFS, the hazard ratio (HR) of afatinib was 0.63 (95% CI, 0.47-0.83) compared with gefitinib or erlotinib. In the competing risk analysis for cumulative incidence of CNS failure, afatinib showed a lower cumulative incidence of CNS failure compared with gefitinib or erlotinib after adjusting for both EGFR mutation type and preexisting CNS metastases (HR 0.51, 95% CI, 0.34-0.75, P=0.0007).

Conclusions: Through there are some limitation as a retrospective study, afatinib showed similar CNS response rates, superior CNS-PFS and cumulative incidence of CNS failure, compared with gefitinib or erlotinib.
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http://dx.doi.org/10.21037/tlcr-20-379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653133PMC
October 2020

Nivolumab for esophageal squamous cell carcinoma and the predictive role of PD-L1 or CD8 expression in its therapeutic effect.

Cancer Immunol Immunother 2021 May 29;70(5):1203-1211. Epub 2020 Oct 29.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.

Introduction: Nivolumab, a programmed death 1 (PD-1) inhibitor, has recently demonstrated efficacy as second-line therapy for esophageal squamous cell carcinoma (ESCC) patients in a phase III trial. We report real-world clinical outcomes of nivolumab therapy for ESCC patients.

Methods: ESCC patients refractory/intolerant to at least one line of chemotherapy and who received nivolumab as a subsequent line of therapy were included. The efficacy and safety of nivolumab and the predictive role of PD-L1 and CD8 expression were analyzed.

Results: Fifty-eight patients were analyzed for safety and survival outcomes, while 57 were analyzed for objective response rates (ORR) excluding one with no measurable lesions. Eleven patients achieved a partial response, leading to an ORR of 19.3%. The median response duration was 6.5 months (range 4.1-22.4). The median progression-free survival (PFS) and overall survival were 2.1 (95% confidence interval [CI] 1.8-2.3) and 7.4 (95% CI 4.8-10.0) months, respectively. Among patients with adequate samples, 56.9% (29/51), 27.5% (14/51), and 17.6% (9/51) expressed a combined positive score (CPS) ≥ 1, ≥ 10, and ≥ 20, respectively, while 24.4% (11/45) and 57.5% (23/40) were positive for intratumoral and peritumoral CD8 + T cell infiltration, respectively. A significantly longer PFS was observed in patients with a CPS ≥ 20 (7.5 [95% CI 1.8-13.1] vs. 1.9 [1.4-2.3] months, P = 0.05), and a trend towards better survival was seen in those with CPS ≥ 10 or intratumoral CD8 + T cell infiltration.

Conclusions: Nivolumab is a valuable option at subsequent treatment lines for patients with advanced ESCC.
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http://dx.doi.org/10.1007/s00262-020-02766-7DOI Listing
May 2021

Mutations in genes affecting DNA methylation enhances responses to decitabine in patients with myelodysplastic syndrome.

Korean J Intern Med 2021 03 23;36(2):413-423. Epub 2020 Oct 23.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background/aims: In this study, we tested whether mutations in the methylation pathway genes ten-eleven-translocation 2 (TET2) and DNA methyltransferase gene 3A (DNMT3A) improve the responses of patients with myelodysplastic syndrome (MDS) to decitabine.

Methods: We retrospectively sequenced the TET2 and DNMT3A genes from 70 patients diagnosed with de novo MDS between June 2008 and December 2011 and treated with a 5-day regimen of decitabine (290 cycles). We then analyzed treatment outcomes.

Results: Patients with hematological improvement survived longer than those without hematological improvement (22.9 months vs. 10.9 months, p = 0.006). Among the 70 patients, 12 (17.1%) carried TET2 or DNMT3A mutations. The baseline characteristics of patients with wild type or mutated genes were similar. Patients with mutations in TET2 or DNMT3A had a higher overall response rate than those with the wild type genes (82.3% vs. 46.6%, p = 0.023). Multivariate analysis demonstrated that the TET2 or DMNT3A mutation status was associated with improved treatment responses and better overall survival among patients receiving decitabine.

Conclusion: These results demonstrate that TET2 mutations enhance the treatment response of MDS patients to hypomethylating agents like decitabine.
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http://dx.doi.org/10.3904/kjim.2019.385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969079PMC
March 2021

Clinical advantage of targeted sequencing for unbiased tumor mutational burden estimation in samples with low tumor purity.

J Immunother Cancer 2020 10;8(2)

Samsung Genome Institute, Samsung Medical Center, Seoul, Korea

Background: Tumor mutational burden (TMB) measurement is limited by low tumor purity of samples, which can influence prediction of the immunotherapy response, particularly when using whole-exome sequencing-based TMB (wTMB). This issue could be overcome by targeted panel sequencing-based TMB (pTMB) with higher depth of coverage, which remains unexplored.

Methods: We comprehensively reanalyzed four public datasets of immune checkpoint inhibitor (ICI)-treated cohorts (adopting pTMB or wTMB) to test each biomarker's predictive ability for low purity samples (cut-off: 30%). For validation, paired genomic profiling with the same tumor specimens was performed to directly compare wTMB and pTMB in patients with breast cancer (paired-BRCA, n=165) and ICI-treated patients with advanced non-small-cell lung cancer (paired-NSCLC, n=156).

Results: Low tumor purity was common (range 30%-45%) in real-world samples from ICI-treated patients. In the survival analyzes of public cohorts, wTMB could not predict the clinical benefit of immunotherapy when tumor purity was low (log-rank p=0.874), whereas pTMB could effectively stratify the survival outcome (log-rank p=0.020). In the paired-BRCA and paired-NSCLC cohorts, pTMB was less affected by tumor purity, with significantly more somatic variants identified at low allele frequency (p<0.001). We found that wTMB was significantly underestimated in low purity samples with a large proportion of clonal variants undetected by whole-exome sequencing. Interestingly, pTMB more accurately predicted progression-free survival (PFS) after immunotherapy than wTMB owing to its superior performance in the low tumor purity subgroup (p=0.054 vs p=0.358). Multivariate analysis revealed pTMB (p=0.016), but not wTMB (p=0.32), as an independent predictor of PFS even in low-purity samples. The net reclassification index using pTMB was 21.7% in the low-purity subgroup (p=0.016).

Conclusions: Our data suggest that TMB characterization with targeted deep sequencing might have potential strength in predicting ICI responsiveness due to its enhanced sensitivity for hard-to-detect variants at low-allele fraction. Therefore, pTMB could act as an invaluable biomarker in the setting of both clinical trials and practice outside of trials based on its reliable performance in mitigating the purity-related bias.
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http://dx.doi.org/10.1136/jitc-2020-001199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574938PMC
October 2020

Treatment and Outcomes of Metastatic Non-Small-Cell Lung Cancer Harboring Uncommon Mutations: Are They Different from Those with Common Mutations?

Biology (Basel) 2020 Oct 7;9(10). Epub 2020 Oct 7.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.

Approximately 10% of the epidermal growth factor receptor () mutations in non-small-cell lung cancer (NSCLC) are uncommon mutations. Although the efficacy of second (2G) or third generation (3G) tyrosine kinase inhibitors (EGFR-TKIs) in the patients with uncommon mutation has been proven, further studies are warranted to define the optimal treatment approach for uncommon mutation-positive NSCLC. This study retrospectively investigated the treatment patterns and outcomes of patients with uncommon mutation-positive NSCLC from January 2011 to December 2019 at the Samsung Medical Center, Seoul, Korea. During the study, 2121 patients with mutation-positive NSCLC received first-generation (1G, gefitinib or erlotinib) or 2G EGFR-TKI (afatinib) as the first-line (1L) systemic therapy. Of this, 135 (6.4%) patients harbored uncommon mutations. Of 135, 54 (40%, 54/135) patients had overlapping mutations with major mutations. The objective response rate (ORR) for the 1L EGFR-TKI was 63.3%. The median progression-free survivals (PFSs) were 8.6 months (95% CI: 3.8-13.5), 11.7 months (95% CI: 6.6-16.7), 7.7 months (95% CI: 4.9-17.4), and 5.0 months (95% CI: 3.7-6.1) for major uncommon mutation (G719X, L861Q), compound mutation with major mutation (Del 19 or exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The median overall survivals (OSs) were 25.6 months (16.9-34.2), 28.8 (95% CI: 24.4-33.4), 13.5 months (95% CI: 7.4-27.8), and 9.4 months (95% CI: 3.4-10.5) for major uncommon mutation (G719X), compound mutation with major mutation (Del 19 or exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The response rate, median PFS, and OS were 63.3%, 16.3 months (95% CI: 15.6-16.9), and 37.5 months (95% CI: 35.4-39.6) for common mutation-positive NSCLC. After failing 1L -TKI, repeated tissue or liquid biopsy were carried out on 44.9% (35/78) of patients with T790M detected in 10/35 (28.6%) patients. With subsequent 3G -TKI after failing the first-line -TKI, the ORR and PFS for 3G -TKI were 80% and 8.9 months (95% CI: 8.0-9.8). These patients showed a median OS of 34.6 months (95% CI: 29.8-39.4). The ORR, PFS and OS were poorer in patients with uncommon (especially other compound and other uncommon mutation) than those with common mutations. T790M was detected in 28.6% of the uncommon mutation-positive patients for whom prior 1G/2G -TKIs failed and underwent repeat biopsy at the time of progression.
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http://dx.doi.org/10.3390/biology9100326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600176PMC
October 2020

Clinical outcomes of immune checkpoint inhibitors for patients with recurrent or metastatic head and neck cancer: real-world data in Korea.

BMC Cancer 2020 Aug 5;20(1):727. Epub 2020 Aug 5.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.

Background: Anti-PD1 inhibitors have been approved for the treatment of recurrent or metastatic head and neck cancer (HNC), as a result of Global Phase III trials. However, the clinical outcomes of immune checkpoint inhibitors in patients who are not eligible for clinical trials or have various medical conditions have not been fully elucidated.

Methods: We retrospectively reviewed 46 patients with recurrent or metastatic HNC who received pembrolizumab or nivolumab between June 2016 and June 2019.

Results: Thirty-five patients had head and neck squamous cell carcinoma (HNSCC) affecting the oropharynx, oral cavity, hypopharynx, larynx, nasal cavity, or paranasal sinuses, and eleven patients had nasopharyngeal cancer (NPC). The median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 6.8 months, respectively, for patients with HNSCC, and 4.3 months and 11.8 months, respectively, for patients with NPC. The objective response rate (ORR) in all patients was 21%. Of 30 patients with HNSCC, 5 patients achieved complete response and 2 achieved partial response (ORR 23%); 1 of 8 NPC patients achieved partial response (13%). Patients who previously underwent radiotherapy had better OS than those who did not (median OS, 7.6 months vs. 2.3 months, p = 0.006). OS was longer in patients treated with pembrolizumab than in those treated with nivolumab (median OS, 11.8 months vs. 6.8 months, p = 0.017).

Conclusion: Consistent with previous reports, immune checkpoint inhibitors showed promising efficacy in patients with previously treated recurrent or metastatic HNC in a real-world setting.
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http://dx.doi.org/10.1186/s12885-020-07214-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405432PMC
August 2020

Evaluating entrectinib as a treatment option for non-small cell lung cancer.

Expert Opin Pharmacother 2020 Nov 31;21(16):1935-1942. Epub 2020 Jul 31.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul, Korea.

Introduction: Entrectinib, an oral pan-TRK, ALK, and ROS1 inhibitor is approved as a first-line treatment for NTRK-rearranged solid tumors and ROS1-rearranged non-small cell lung cancer (NSCLC). It has demonstrated clinical efficacy for patients harboring the relevant gene rearrangement in both systemic and intracranial disease, regardless of the tumor type.

Areas Covered: In this review, the authors analyzed data from preclinical and clinical studies, the characteristics of entrectinib compared to those of other relevant inhibitors (currently available and/or under investigation), and the emerging resistance mechanisms. The authors then provide the readers with their future perspectives.

Expert Opinion: Entrectinib has been well studied across many tumor types, including NSCLC with ALK, ROS1, and NTRK rearrangements. The drug has demonstrated favorable properties with oral administration, prolonged response duration, high intracranial efficacy, and a favorable toxicity profile. However, with acquisition of resistance and the development of newer generation TKIs, the optimal place for entrectinib in the landscape of targeted therapies for NSCLC warrants further validation.
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http://dx.doi.org/10.1080/14656566.2020.1798932DOI Listing
November 2020

Osimertinib Improves Overall Survival in Patients With EGFR-Mutated NSCLC With Leptomeningeal Metastases Regardless of T790M Mutational Status.

J Thorac Oncol 2020 11 9;15(11):1758-1766. Epub 2020 Jul 9.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address:

Introduction: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, efficiently penetrates the blood-brain barrier. This study explored whether treatment with osimertinib leads to improved overall survival (OS) for patients with EGFR-mutated NSCLC with leptomeningeal metastases (LM) compared with those not treated with osimertinib.

Methods: From October 2008 to October 2019, patients with EGFR-mutated NSCLC and cytologically confirmed LM were retrospectively analyzed for OS according to osimertinib treatment and T790M mutational status. The OS was defined as the time from the diagnosis of LM to death.

Results: For the 351 patients with LM included in the analysis, the median OS (mOS) was 8.1 months (95% confidence interval [CI]: 7.2-9.0). T790M mutation was detected in 88 of 197 patients tested, and a total of 110 patients were treated with osimertinib after LM. No difference in mOS according to T790M mutational status (10.1 mo [95% CI: 4.31-15.82] versus 9.0 [95% CI: 6.81-11.21], p = 0.936) was found. Nevertheless, patients treated with osimertinib had a superior OS of 17.0 months (95% CI: 15.13-18.94) compared with those not treated with osimertinib who had a mOS of 5.5 months (95% CI: 4.34-6.63), regardless of T790M mutational status (hazard ratio: 0.36 [95% CI: 0.28-0.47], p < 0.001). This was also considerably longer even than the mOS of 8.7 months (95% CI: 7.01-10.39) of those who were never treated with osimertinib but had first- or second-generation EGFR tyrosine kinase inhibitors.

Conclusions: Osimertinib is a promising treatment option for EGFR-mutated NSCLC with LM regardless of T790M mutational status.
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http://dx.doi.org/10.1016/j.jtho.2020.06.018DOI Listing
November 2020

EGFR C797S as a Resistance Mechanism of Lazertinib in Non-small Cell Lung Cancer with EGFR T790M Mutation.

Cancer Res Treat 2020 Oct 22;52(4):1288-1290. Epub 2020 Jun 22.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

The non-small cell lung cancer with activating epidermal growth factor receptor (EGFR) mutation eventually acquires resistant to either first or second-generation EGFR tyrosine kinase inhibitor (TKI). As the following option, targeting EGFR T790M with third-generation EGFR TKI is now established as a standard treatment option. In this study, we are reporting the first case of resistance mechanism to the novel third-generation EGFR TKI, lazertinib, which showed promising clinical efficacy in phase 1-2 study. The patients showed resistance to the treatment by acquiring the additional EGFR C797S mutation in cis which is also confirmed from the patient-derived cell lines.
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http://dx.doi.org/10.4143/crt.2020.278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577810PMC
October 2020

Biomarker-driven phase 2 umbrella trial study for patients with recurrent small cell lung cancer failing platinum-based chemotherapy.

Cancer 2020 09 25;126(17):4002-4012. Epub 2020 Jun 25.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Background: A high percentage of small cell lung cancer (SCLC) cases harbor cell cycle-related gene mutations and RICTOR amplification. Based on underlying somatic mutations, the authors have conducted a phase 2 biomarker-driven, multiarm umbrella study.

Methods: The SCLC Umbrella Korea StudiES (SUKSES) is an adaptive platform trial that undergoes continual modification according to the observed outcomes. This study included 286 patients with SCLC who failed platinum therapy and who had known genomic profiles based on a predesigned screening trial. Patients with MYC amplification or CDKN2A and TP53 co-alterations were allocated to adavosertib (SUKSES protocol C [SUKSES-C]; 7 patients) and those with RICTOR amplification were allocated to vistusertib (SUKSES-D; 4 patients). Alternatively, patients who were without any predefined biomarkers were assigned to a non-biomarker-selected arm: adavosertib (SUKSES-N1; 21 patients) or AZD2811NP (SUKSES-N3; 15 patients).

Results: Patients in the SUKSES-C and SUKSES-N1 arms demonstrated no objective response. Three patients presented with stable disease (SD) in SUKSES-C and 6 patients in SUKSES-N1. The median progression-free survival (PFS) was 1.3 months (95% confidence interval, 0.9 months to not available) for SUKSES-C and 1.2 months (95% CI, 1.1-1.4 months) for SUKSES-N1. Patients in the SUKSES-D arm demonstrated no objective response and no SD, with a PFS of 1.2 months (95% CI, 1.0 months to not available). The SUKSES-N3 arm had 5 patients with SD and a PFS of 1.6 months (95% CI, 0.9-1.7 months), without an objective response. Grade≥3 adverse events (graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]) were observed as follows: 3.2% in the SUKSES-C and SUKSES-N1 arms and 50.0% in the SUKSES-D arm. Target-related neutropenia (grade≥3) was observed in approximately 60.0% of patients in the AZD2811NP arm using the current dosing schedule.

Conclusions: To the best of the authors' knowledge, the current study is the first biomarker-driven umbrella study conducted in patients with recurrent SCLC. Although the current study demonstrated the limited clinical efficacy of monotherapy, novel biomarker approaches using other cell cycle inhibitor(s) or combinations warrant further investigation.
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http://dx.doi.org/10.1002/cncr.33048DOI Listing
September 2020

Ten-year patient journey of stage III non-small cell lung cancer patients: A single-center, observational, retrospective study in Korea (Realtime autOmatically updated data warehOuse in healTh care; UNIVERSE-ROOT study).

Lung Cancer 2020 08 31;146:112-119. Epub 2020 May 31.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address:

Introduction: Until the recent approval of immunotherapy after completing concurrent chemoradiotherapy (CCRT), there has been little progress in treating unresectable stage III non-small cell lung cancer (NSCLC). This prompted us to search real-world data (RWD) to better understand diagnosis and treatment patterns, and outcomes.

Methods: This non-interventional observational study used a unique, novel algorithm for big data analysis to collect and assess anonymized patient electronic medical records from a clinical data warehouse (CDW) over a 10-year period to capture real-world patterns of diagnosis, treatment, and outcomes of stage III NSCLC patients. We describe real-world patterns of diagnosis and treatment of patients with newly-diagnosed stage III NSCLC, and patients' characteristics, and assessment of treatment outcomes.

Results: We analyzed clinical variables from 23,735 NSCLC patients. Stage III patients (N = 4138, 18.2 %) were diagnosed as IIIA (N = 2,547, 11.2 %) or IIIB (N = 1,591. 7.0 %). Treated stage III patients (N = 2530, 61.1 %) had a median age of 64.2 years, were mostly male (78.5 %) and had an ECOG performance status of 1 (65.2 %). Treatment comprised curative-intent surgery (N = 1,254, 49.6 %) with 705 receiving neoadjuvant therapy; definitive CRT (N = 648, 25.6 %); palliative CT (N = 270, 10.7 %), or thoracic RT (N = 170, 6.7 %). Median OS (range) for neoadjuvant, surgery, CRT, palliative chemotherapy, lung RT alone, and supportive care was 49.2 (42.0-56.5), 52.5 (43.1-61.9), 30.3 (26.6-34.0), 14.7 (13.0-16.4), 8.8 (6.2-11.3), and 2.0 (1.0-3.0) months, respectively.

Conclusions: This unique in-house algorithm enabled a rapid and comprehensive analysis of big data through a CDW, with daily automatic updates that documented real-world PFS and OS consistent with the published literature, and real-world treatment patterns and clinical outcomes in stage III NSCLC patients.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.033DOI Listing
August 2020

Real world data of durvalumab consolidation after chemoradiotherapy in stage III non-small-cell lung cancer.

Lung Cancer 2020 08 31;146:23-29. Epub 2020 May 31.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address:

Objectives: The PACIFIC study demonstrated the benefits of durvalumab consolidation on progression-free survival (PFS) and overall survival (OS) among patients with unresectable locally advanced non-small-cell lung cancer (LA-NSCLC). However, in real-world practice, patients with unresectable LA-NSCLC are heterogeneous with diverse tumor burdens and clinical factors; thus, it is important to examine the effectiveness and side effects of durvalumab when used in real clinical practice.

Materials And Methods: We investigated the efficacy of durvalumab consolidation and the incidence of radiation pneumonitis in patients who received concurrent chemo-radiotherapy (CCRT) for unresectable LA-NSCLC in a single institute.

Results: Overall, 55.3 % of patients did not meet the criteria of the PACIFIC study; however, they still received consolidation durvalumab in real-world practice. Durvalumab consolidation was associated with favorable PFS in the total population as well as in the subgroup of patients who did not meet the criteria of the PACIFIC study. However, radiation pneumonitis occurred more frequently in the durvalumab group, especially within 3-6 months after CCRT. The incidence of grade 3 radiation pneumonitis was 14.3 % in the durvalumab group versus 2.5 % in the observation group.

Conclusions: Durvalumab consolidation was associated with favorable PFS in patients with LA-NSCLC in clinical practice. However, careful selection of candidates for durvalumab treatment and active surveillance and appropriate management for radiation pneumonitis are needed.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.035DOI Listing
August 2020

Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma.

Nat Commun 2020 05 8;11(1):2285. Epub 2020 May 8.

Samsung Genome Institute, Samsung Medical Center, Seoul, 06351, Korea.

Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell transcriptome profiling of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions.
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http://dx.doi.org/10.1038/s41467-020-16164-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210975PMC
May 2020

Outstanding clinical efficacy of PD-1/PD-L1 inhibitors for pulmonary pleomorphic carcinoma.

Eur J Cancer 2020 06 1;132:150-158. Epub 2020 May 1.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address:

Background: We evaluated programmed death ligand 1 (PD-L1) expression and efficacy of PD-1/PD-L1 inhibitors in patients with pulmonary pleomorphic carcinoma (PC).

Methods: We created two cohorts of patients diagnosed with pulmonary PC from 2016 to 2019, PD-L1 expression and programmed death 1 (PD-1)/PD-L1 inhibitor efficacy cohorts. The PD-L1 expression cohort included all patients evaluated for PD-L1 expression, irrespective of PD-1/PD-L1 inhibitor therapy. High PD-L1 expression was defined as ≥50% positive tumour cells (TC) for 22C3, ≥25% for SP263 or ≥10%/5% TC/immune cell (IC) for SP142. The PD-1/PD-L1 efficacy cohort included patients treated with PD-1/PD-L1 inhibitors, irrespective of PD-L1 tests.

Results: One hundred twenty-five of 175 patients diagnosed with pulmonary PCs were included in the PD-L1 expression cohort. Among them, 112 patients (89.6%) had PD-L1-positive (≥1%) tumours and 100 (80.0%) had tumours with high PD-L1 expression. A total of 49 patients were included in the efficacy cohort: 40 received pembrolizumab, 7 nivolumab and 2 atezolizumab. The objective response rate was 49.0%, with a median progression-free survival (PFS) of 7.2 months and a median overall survival of 22.2 months. In the efficacy cohort, high PD-L1 expression (n = 41) was associated with longer PFS (median: 7.2 versus 1.5 months, hazard ratio [HR]: 0.53 [0.22-1.29], p = 0.16) and overall survival (median: 22.2 versus 3.5, HR: 0.21 [0.08-0.57], p = 0.001) than low/negative/unknown PD-L1 expression (n = 8).

Conclusion: PD-1/PD-L1 inhibitors show outstanding efficacy for pulmonary PCs, and this is possibly attributable to high PD-L1 expression in these tumours.
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http://dx.doi.org/10.1016/j.ejca.2020.03.029DOI Listing
June 2020

Characteristics and Clinical Outcomes of Non-small Cell Lung Cancer Patients in Korea With Exon 14 Skipping.

In Vivo 2020 May-Jun;34(3):1399-1406

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

Background/aim: MET exon 14 skipping occurs in 3-4% of patients with lung adenocarcinomas. In this study, we performed a comprehensive analysis of clinical data from Korean non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping.

Patients And Methods: Overall, 1,020 patients diagnosed with NSCLC between January 2015 and July 2017 were analyzed by next-generation sequencing.

Results: MET exon 14 skipping was identified in 20 NSCLC patients (1.9%). The median age was 69 years (range=39-86 years), 60.0% were male, and most (55.0%) were ever-smokers. For first-line chemotherapy, the median overall survival was 9.5 months and progression-free survival was 4.0 months, respectively. Twelve patients received pemetrexed-based chemotherapy and the overall response rate was 33.3% (4/12). Among four crizotinib-treated patients, one continued therapy for 8 months with the best response being disease stability.

Conclusion: Given the poor clinical outcome and response to therapy for NSCLC, and the availability of promising anti-tumor MET inhibitors, screening for the MET exon 14 skip mutation should be incorporated into clinical practice.
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http://dx.doi.org/10.21873/invivo.11920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279794PMC
February 2021

PD-1 inhibitors for non-small cell lung cancer patients with special issues: Real-world evidence.

Cancer Med 2020 04 6;9(7):2352-2362. Epub 2020 Feb 6.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background: Immune checkpoint inhibitors (ICIs) have provided new therapeutic options for non-small cell lung cancer(NSCLC) patients. However, due to concerning increases in immune-related adverse events, clinical trials usually exclude patients with special issues such as viral hepatitis, tuberculosis (Tbc), interstitial lung disease (ILD) and autoimmune disease.

Methods: We retrospectively reviewed the medical records of NSCLC patients who received ICIs, and analyzed the clinical outcomes of patients with special issues.

Results: Between January 2015 and October 2018, 237 patients received ICIs. Of these patients, 26% (61/237) had special issues: 32 had hepatitis B viral (HBV) infections, 20 Tbc, six ILD, one HIV infection, one Behçet's disease and a past HBV infection, and one rheumatoid arthritis. The incidence of hepatitis tended to be higher in patients with HBV infections than in those without (18.8% vs 8.91%, P = .082). Severe hepatitis (grade 3 or higher) was more common in HBV-infected patients (12.5% vs 1.9%, P = .0021), but the AEs were well-managed. During ICI treatment, three of the 20 patients with a history of pulmonary Tbc developed active pulmonary Tbc, considered reactivations. No aggravation of ILD was noted. One RA patient experienced a disease flare and was treated with a low-dose steroid. There was no significant difference in the overall response rate or progression-free survival between patients with and without special issues.

Conclusion: Given the relatively low incidence of immune-related AEs and the comparability of clinical outcomes, ICIs can be treatment option of NSCLC patients with special issues.
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http://dx.doi.org/10.1002/cam4.2868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7131857PMC
April 2020

Markedly increased ocular side effect causing severe vision deterioration after chemotherapy using new or investigational epidermal or fibroblast growth factor receptor inhibitors.

BMC Ophthalmol 2020 Jan 9;20(1):19. Epub 2020 Jan 9.

Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Background: We sought to describe corneal epithelial changes after using epidermal (EGFR) or fibroblast growth factor receptor (FGFR) inhibitors as chemotherapy and to clarify incidence and prognosis.

Materials: Retrospective chart review.

Results: Among 6871 patients and 17 EGFR or FGFR inhibitors, 1161 patients (16.9%) referred for ophthalmologic examination. In total, 1145 patients had disease-related or unrelated ocular complications. Among 16 patients with treatment-related ocular complications, three patients had treatment-related radiation retinopathy and one patient showed treatment-related corneal ulcer. Finally the authors identified that, in 12 patients, three EGFR inhibitors and two FGFR inhibitors caused corneal epithelial lesions. Vandetanib, Osimertinib, and ABT-414 caused vortex keratopathy in nine patients, while ASP-5878 and FPA-144 caused epithelial changes resembling corneal dysmaturation in three patients. The mean interval until symptoms appeared was 246 days with vandetanib, 196 days with osimertinib, 30 days with ABT-414, 55 days with ASP-5878, and 70 days with FPA-144. The mean of the lowest logarithm of minimal angle of resolution visual acuity results of the right and left eyes after chemotherapy were 0.338 and 0.413. The incidence rates of epithelial changes were 15.79% with vandetanib, 0.5% with osimertinib, 100% with ABT-414, 50.0% with ASP-5878, and 18.2% with FPA-144. After excluding deceased patients and those who were lost to follow-up or still undergoing treatment, we confirmed the reversibility of corneal lesions after the discontinuation of each agent. Seven patients showed full recovery of their vision and corneal epithelium, while three achieved a partial level of recovery. Although patients diagnosed with glioblastoma used prophylactic topical steroids before and during ABT-414 therapy, all developed vortex keratopathy.

Conclusions: EGFR and FGFR inhibitors are chemotherapy agents that could make corneal epithelial changes. Contrary to the low probability of ocular complication with old EGFR drugs, recently introduced EGFR and FGFR agents showed a high incidence of ocular complication with severe vision distortion. Doctors should forewarn patients planning chemotherapy with these agents that decreased visual acuity could develop due to corneal epithelial changes and also reassure them that the condition could be improved after the end of treatment without the use of steroid eye drops.

Trial Registration: This study was approved by the institutional review board (IRB) of Samsung Medical Center (IRB no. 2019-04-027) and was conducted according to the principles expressed in the Declaration of Helsinki.
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http://dx.doi.org/10.1186/s12886-019-1285-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953164PMC
January 2020

Benefit of Targeted DNA Sequencing in Advanced Non-Small-Cell Lung Cancer Patients Without EGFR and ALK Alterations on Conventional Tests.

Clin Lung Cancer 2020 05 21;21(3):e182-e190. Epub 2019 Nov 21.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea. Electronic address:

Background: Genetic sequencing testing has become widely used to inform treatment decisions for advanced non-small-cell lung cancer (NSCLC) patients. We analyzed benefits of genetic sequencing testing in real practice.

Patients And Methods: We retrospectively reviewed 209 NSCLC patients who had no EGFR and ALK alterations on routine molecular tests and underwent next-generation targeted DNA sequencing of 380 cancer-related genes between November 2013 and October 2016. Median patient age was 59 years. A total of 96 patients (46%) were never smokers, and 195 patients (93%) had adenocarcinoma.

Results: Among 209 total patients, 64 (31%) demonstrated actionable genetic alterations; 20 had EGFR mutations (6 L858R, 8 exon 19 deletions, 1 L861Q, 1 G719S, 4 exon 20 duplications), 4 ALK fusions, 9 ROS1 fusions, 6 BRAF V600E mutations, 15 RET fusions, 1 MET high-level amplification, 6 MET exon 14 skipping mutations, and 3 ERBB2 exon 20 insertion mutations. Of the 64 patients harboring actionable alterations, 28 patients received therapy targeted to their own actionable alterations (15 EGFR, 3 ALK, 1 ROS1, 8 RET, 1 BRAF). There were significant differences in overall survival between individuals with no actionable alterations, those with actionable alterations but no targeted therapy, and those with actionable alterations and targeted therapy (20.1 vs. 17.1 vs. 66.2 months, P < .001).

Conclusion: The results of targeted DNA sequencing testing could provide improved treatment options for some NSCLC patients and result in a survival benefit to NSCLC patients with no EGFR and ALK alterations on routine tests who are treated with targeted therapy.
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http://dx.doi.org/10.1016/j.cllc.2019.11.006DOI Listing
May 2020

Comparative effectiveness of palliative chemotherapy versus neoadjuvant chemotherapy followed by radical cystectomy versus cystectomy followed by adjuvant chemotherapy versus cystectomy for regional node-positive bladder cancer: A retrospective analysis: KCSG GU 17-03.

Cancer Med 2019 Sep 29;8(12):5431-5437. Epub 2019 Jul 29.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

The regional lymph node-positive bladder cancer was classified as stage IV in the AJCC 7th edition but was changed to stage IIIB in the 8th edition, revised in 2018. Among the various studies involving immune checkpoint inhibitors, groups that had only lymph node metastasis showed better outcomes than those with distant metastasis. Therefore, it is necessary to rethink the treatment strategy for lymph node-positive bladder cancer. The aim of this study was to compare the treatment outcomes of chemotherapy, surgery, and combination therapy in patients with lymph node-positive bladder cancer. From 1 January 2010 to 31 December 2015, patients with bladder cancer presenting local lymph node metastasis at the time of diagnosis were treated with a single treatment strategy, with either radical cystectomy or chemotherapy or with a combined strategy using both. Treatment outcomes were retrospectively analyzed on the basis of clinical indices and survival time. Out of 230 patients with bladder cancer, 44 (19.1%) were treated with palliative chemotherapy, 30 (13.0%) with neoadjuvant chemotherapy followed by cystectomy, 129 (56.1%) with cystectomy followed by adjuvant chemotherapy, and 27 (11.7%) with cystectomy alone. Median survival among all groups was 30.4 months. For each group, median overall survival was 19.3, 49.1, 42.6, and 11.2 months, respectively. This study represents an advancement in understanding the impact of clinical treatment patterns of lymph node-positive bladder cancer through comparison of survival data of patients treated with different therapeutic strategies. Combined treatment resulted in better outcomes than did single treatments.
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http://dx.doi.org/10.1002/cam4.2446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745843PMC
September 2019

Clinical Characteristics and Outcomes of Non-small Cell Lung Cancer Patients with HER2 Alterations in Korea.

Cancer Res Treat 2020 Jan 26;52(1):292-300. Epub 2019 Jul 26.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Purpose: Human epidermal growth factor receptor 2 (HER2) alterations are found in approximately 1%-3% of non-small cell lung cancers (NSCLCs). We evaluated the clinical features and outcomes of NSCLC harboring HER2 alteration detected by next-generation sequencing (NGS) in Korea.

Materials And Methods: A total of 1,108 patients who were diagnosed with NSCLC between December 2015 and December 2017 were screened and analyzed by NGS. Medical records were reviewed retrospectively to analyze the clinical characteristics and outcomes from various treatments.

Results: HER2 alterations were identified in 36 NSCLC patients. Of the patients, 22 (61.1%) had an exon 20 in-frame insertion mutation, 15 (41.7%) had HER2 amplification, and one had both. The median patient age was 58 years, 55.6% were male, and 50.0% were never-smokers. Adenocarcinoma was predominant (88.9%). The most common metastatic site was bone (58.3%), and 66.7% of patients were stage IV at initial diagnosis. Six patients (16.7%) had a coexistent sensitizing epidermal growth factor receptor (EGFR) mutation, and two patients (5.6%) had anaplastic lymphoma kinase (ALK) rearrangement. With a median 14 months of follow-up, the median progression-free survival of first-line treatment was 6 months (95% confidence interval, 4.172 to 7.828), and median overall survival was not reached. The proportions of adenocarcinoma, never-smokers, and metastasis to the liver were higher in the exon 20 in-frame insertion mutation group, whereas coexistence of EGFR mutation was more frequently found in the HER2 amplification group.

Conclusion: HER2-altered NSCLC showed distinct clinical features. Moreover, different characteristics were identified between the HER2 in-frame insertion mutation group and the HER2 amplification group.
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http://dx.doi.org/10.4143/crt.2019.186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962476PMC
January 2020
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