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Min Hee Hong
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FP03 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) (ID 151)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP03.02 - Interim Analysis of Neoadjuvant Chemoradiotherapy and Durvalumab for Potentially Resectable Stage III Non-Small Cell Lung Cancer (NSCLC) (ID 804)
00:00 - 00:00 | Presenting Author(s): Min Hee Hong
- Abstract
- Presentation
Introduction
Although definitive concurrent chemoradiotherapy (CRT) is considered standard of care for most stage III NSCLC patients, neoadjuvant-CRT (N-CRT) followed by surgery is an accepted practice with a potential survival benefit. Regarding synergistic effects of combining PD-1/PD-L1 blockade to CRT, we designed a two-stage phase Ib trial (ACTS-30) which assesses the safety and feasibility of the combination of N-CRT with durvalumab (PD-L1 inhibitor) in potentially resectable stage III NSCLC (ClinicalTrials.gov identifier: NCT03694236).
Methods
Patients with histologically confirmed, potentially resectable stage III NSCLC were eligible. N-CRT comprised intravenous weekly paclitaxel 45 mg/m2 and carboplatin AUC 2 with radiotherapy of 45 Gy in 25 fractions and durvalumab (Day 1 and 29, 1500mg) during 5 weeks and patients who completed N-CRT subsequently underwent surgery. After surgery, one year of adjuvant durvalumab was planned (every 4 weeks, 1500 mg). The primary objective was to determine the safety and tolerability of N-CRT + durvalumab regimen. The trial was composed of two-stages and the first stage included 9 patients and the trial was planned to proceed to the second stage (n = 21) if treatment-related adverse events (TRAEs) grade≥3 occurred in less than 50% of patients. The secondary endpoints are objective response rate (ORR), R0 resection rate, event-free survival (EFS), overall survival (OS), clinical or pathological downstaging rate, pathologic complete response (pCR) rate, and major pathologic response (MPR) rate. The exploratory analyses including immune marker assessment by FACS, whole-exome sequencing, single-cell RNA sequencing, and multispectral immunohistochemical staining using the specimen of pre-treatment, after surgery, and after recurrence will be performed.
Results
At the data cut-off (25th-Feb-2020), a total of 14 patients were enrolled. The median age was 66; 50% were male, and 50% were adenocarcinoma histology including two EGFR mutations. Since there was only one grade 3 TRAE (i.e., neutropenia) during the first stage, the trial entered the second stage. Overall, the grade 3 or more rate of TRAE was 7% (1/14). Currently, 11 patients underwent surgery (R0 resection) while one patient experienced cardiac pacemaker infection grade 3 (not considered as TRAE) and was not able to undergo surgical resection and two others are awaiting surgery. There was no postoperative in-hospital mortality. Among eleven resected patients, the pCR rate and MPR rate were 36.4% (3/11) and 72.7% (8/11), respectively. When excluding two EGFR mutant, the MPR rate was 88.9% (8/9).
Conclusion
These early data suggested that the N-CRT regimen with immunotherapy in stage III NSCLC was safe and feasible and had the potential to provide clinical benefit. The trial is ongoing and the final results and the biomarker analyses will be provided in the future congress and scientific journal.
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FP14 - Targeted Therapy - Clinically Focused (ID 252)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP14.14 - Post Hoc Analyses from an Open Label, Multi-Centre, ASTRIS Trial of Efficacy of Osimertinib for CNS Metastases with T790M-Positive Advanced NSCLC (ID 2279)
00:00 - 00:00 | Author(s): Min Hee Hong
- Abstract
Introduction
Up to 40% of patients with epithelial growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) develop central nervous system(CNS) metastases throughout their disease. CNS metastasis has a negative impact on survival and quality of life including neurological dysfunction and cognitive impairment. However, the first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) have limited efficacy because of their limited blood-brain barrier permeability. Osimertinib, third-generation EGFR-TKI with selective activity for both sensitizing and EGFR T790M mutations, have showed higher CNS penetration ability over first- and second-generation EGFR-TKIs. Herein we conducted post hoc analyses of ASTRIS, a clinical study of osimertinib to demonstrate its potential role of intracranial response in a real-world cohort.
Methods
This was a preplanned, exploratory analysis of CNS activity of osimertinib in Korean subgroup of ASTRIS trial, an open-label, single-arm, real-world treatment study to evaluate the efficacy and safety of osimertinib (80mg orally, once daily) in patients with EGFR T790M mutation-positive NSCLC who progressed upon prior EGFR-TKIs. We classified the patients according to the baseline brain status including leptomeningeal metastases(LM) by blinded independent central review (BICR). A CNS measurable lesion was defined as the lesion which was ≥ 10mm in longest diameter by BICR.We collected the information regarding patients’ baseline characteristics, mutation stutus, intracranial and extracranial responses with duration for ananlysis.
Results
The median age was 60 years and 69.7% of patients were female. Seventy-seven patients (86.5%) were Eastern Cooperative Oncology Group performance status (ECOG) less than 2. All patients had common baseline EGFR mutation (Exon 19deletion or L858R) except one patients with G719X mutation. Sixty-five patient (73.0%) had BM at baseline and 19 patients (23.5%) had additional LM. Among patients with BM, 24 (36.9%) had ≥ 1 measurable lesion and 16 had evaluated for the objective response. For the patient with BM and/or LM at baseline, eventually 28 patient had intracranial progression and for the paitent without BM or LM at baseline two had newly developed lesion during treatment. The Intracranial objective response rate (cORR) and disease control rate(cDCR) was 62.5% (95% confidence interval [CI], 38.3–82.6%) and 93.8% (95% CI, 74.3–99.3%), respectively. The median intracranial progression-free survival (cPFS) which included any cause of death as an event, was 13.0 (95% CI, 7.21–18.8) month including patients with measurable and/or non-measurable BM or LM.
Conclusion
Our cORR, cDCR, and cPFS were comparable to those observed in previous clinical trials. The outcome of this study is expected to be helpful demonstrating the potential role of intracranial efficacies of osimertinib 80 mg administration in T790M-positive advanced NSCLC with/without BM or LM. Further analysis of overall survival, specific response rate of patient with LM and biomarker for intracranial response or progression are ongoing.
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P19 - Locoregional and Oligometastatic Disease - Oligometastatic Disease (ID 129)
- Event: WCLC 2020
- Type: Posters
- Track: Locoregional and Oligometastatic Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P19.03 - Operative Outcomes of Local Consolidation with Cytoreductive Surgery for Oncogenic-Driven Advanced NSCLC (ID 1875)
00:00 - 00:00 | Author(s): Min Hee Hong
- Abstract
Introduction
With the advent of targeted therapy, the survival in oncogenic-driven advanced non-small cell lung cancer (NSCLC) has been improved. Still, all patients who received the targeted therapy finally recur due to resistance to the targeted agent. The local consolidative therapy with targeted therapy has been studied recently, but these studies mainly focused on radiation therapy, and the role of surgery has not been studied yet. This retrospective study was performed to investigate the operative outcomes for oncogenic-driven advanced NSCLC after targeted therapy as a form of local consolidation.
Methods
Between March 2018 and July 2020, 44 patients received the pulmonary resection and mediastinal lymph node dissection for stage IIIB-C or IV NSCLC after targeted therapy. In some patients, the other metastatic lesions were treated with radiation therapy or surgery prior to pulmonary resection. The operative outcomes were analyzed retrospectively.
Results
The median age of patients was 59 years-old (range, 28~75), with 15 (34.1%) male patients. The initial stages were as following; 4 IIIBs, 1 IIIC, and 39 IVs. The initial mutations were 30 EGFRs, 8 ALKs, and 1 ROS1. The initial metastasis sites were as following; 10 brains, 6 bones, 7 lymph nodes, 6 intrathoracic organs, and 17 multiple organs. The median interval from the initiation of targeted therapy to the operation was 10.7 (range, 2.1~46.3) months. The types of operations were as follows; 37 lobectomies, 2 bi-lobectomies, 3 segmentectomies, and 2 wedge resections. The complete resection was achieved in 40 (90.9%) patients. There was no operative mortality. Complications were developed in 15 patients: 5 prolonged air leakages, 3 chyle leakages, 2 vocal cord palsies, 1 broncho-pleural fistula, 1 acute kidney injury, 1 acute lung injury, 1 pneumonia, and 1 pneumothorax. Four patients showed complete remission on the surgical specimen. The median postoperative follow-up periods were 7.8 months (0.4~28.8). During the follow-up periods, 14 patients suffered from the disease progression: 6 lung lesions, 4 brains, 1 bone, 1 pleura, and 2 others. Two patients died during the follow-up periods. Among 32 patients with EGFR mutation, 12 patients showed additional mutations, such as T790M, and targeted agents were changed into another targeted agent in 9 patients after the operation.
Conclusion
The pulmonary resection for advanced NSCLC after targeted therapy was feasible, and the surgical specimen obtained from the operation could be used for further planning of targeted therapy. The long-term benefits of pulmonary resection on survival after targeted therapy have to be studied in further trials.
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.18 - Tissue- and Plasma-Based Landscape of Resistance to Osimertinib (ID 1236)
00:00 - 00:00 | Author(s): Min Hee Hong
- Abstract
Introduction
Osimertinib is a third generation EGFR tyrosine kinase inhibitor (TKI) that is approved for in EGFR-mutant non-small cell lung cancer (NSCLC) patients who failed initial EGFR TKI treatment or in the first-line settings. However, resistance develops invariably within approximately 1 to 2 years. C797S acquired mutation has been reported as the most described resistance mechanism to Osimertinib which is detected in approximately 20% of patients, but the other prevalent resistant mechanisms are still need to be identified. In this study, we investigated the acquired resistance mechanisms to Osimertinib in NSCLC patients using plasma and tumor samples collected at baseline, and at the time of progression.
Methods
Formalin-fixed paraffin-embedded tumor samples and plasma samples from 55 NSCLC patients who were treated with both osimertinb in 2nd line or beyond were prospectively collected at baseline and at progressive disease (PD). Next-generation sequencing was performed in tumor and plasma samples using a 600-gene hybrid capture panel designed by AstraZeneca. Clinicopathological parameters were obtained from chart review and statistical analysis was performed using R -4.0.2. Osimertinib-resistant cell lines and patient-derived xenografts and cells were generated and whole exome sequencing and RNA sequencing were performed. In vitro experiments were performed to functionally study the acquired mutations identified.
Results
A total of 55 patients and a total of 149 samples (57 tumor samples and 92 plasma samples) were analyzed, and among them 33 patients had matched pre- and post-treatment samples. We identified both EGFR-dependent and EGFR-independent mechanisms of resistance to osimertinib. As expected, EGFR C797S (14%) mutation was the most frequent EGFR-dependent mechanism, followed by EGFR G824D (6%), V726M (3%), V843I (3%). Among EGFR-independent mechanisms, alterations in TP53 (58%), NF1 (28%), PIK3CA (14%), APC (11%), ERBB2 (3%), BRAF (3%), NF2 (3%) were for resistance to osimertinib. Matched pre- and post-treatment sample analysis nominated mechanisms of acquired resistance. EGFR C797S was still most frequent (11%), and we noted that EGFR G824D (6%), V726M (3%), V843I (3%) were acquired, all of which the functional effects were unknown. Structure wise, EGFR V726M may produce steric hindrance to Osimertinib binding. Of EGFR-independent mechanisms, PIK3CA ALK, BRAF, EP300, KRAS, RAF1 mutations were notable. MET copy number gain was found to be most frequent (9%) copy number gain, followed by HER2 (6%). Serial plasma sample analysis was performed in six patients who received osimertinib beyond progression. PIK3CA R38H mutation was associated with liver metastasis, whereas EGFR C797S mutation was associated with primary lung cancer progression. Among Osimertinib-resistant cell lines and patient-derived organoids, we noted acquired mutations which were potentially targetable such as NRAS p.Q61K, in which resistance could be overcome with combination of osimertinib and trametinib.
Conclusion
In this study, we explored the genetic profiles of osimertinib resistance NSCLC patient samples using targeted sequencing. Genetic alteration profiles showed that osimertinib resistance was associated with both EGFR dependent and –independent genomic alterations. Further in vitro and in vivo validation studies are ongoing, and are to be presented at the meeting.
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P89 - Targeted Therapy - Clinically Focused - Translational (ID 266)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P89.08 - Real-World Impact of Plasma Cell-Free DNA Next-Generation Sequencing to Detect Actionable Genomic Alterations in Advanced NSCLC (ID 1970)
00:00 - 00:00 | Author(s): Min Hee Hong
- Abstract
Introduction
Next-generation sequencing (NGS) of plasma cell-free circulating tumor DNA (cfDNA) enables noninvasive comprehensive genomic analysis. The ability of cfDNA NGS to detect actionable genomic biomarkers in advanced non-small cell lung cancer (NSCLC) has been reported, but there are limited data on real-world usage. Here we prospectively collected the real-world cfDNA NGS data of treatment naive patients and also patients after progression to chemotherapy and/or immunotherapy and tyrosine kinase inhibitors(TKI) with negative tissue results for conventional tesing which we easily encounter in clinical practice.
Methods
We analyzed data from advanced NSCLC patients who underwent cfDNA NGS (Guardant360; Guardant Health, Inc.) between December 2018 and January 2020 in the clinical practice. Information regarding patient and disease characteristics, treatment decisions, and clinical outcomes were collected. Genomic alterations were considered actionable if they were included in the Onco-KB precision oncology knowledge database and classified in one of four levels of actionability based on the preclinical or clinical evidence.
Results
Among 405 patients, 35.1% were female; 81.2% had adenocarcinoma (LuAd). At the time of plasma collection for NGS, 143 patients (35.3 %) were treatment-naïve, 177 patients (43.7%) had progressed after chemotherapy and/or immunotherapy, and 61 patients (15.1%) had progressed after tyrosine kinase inhibitor (TKI). Tumor DNA was detectable in 356 plasma samples (87.9 %). Regarding LuAd potentially actionable level 1-4 genomic alterations were detected in 177 cases (53.6%), of which 82 patients (24.9%) had level 1-2 alterations. Twelve patients who had started treatment based on tissue data had their treatment changed due to cfDNA NGS results. At the time of data cut-off, one of these patients had a partial response, 6 had stable disease, and 5 were not yet evaluated.
Conclusion
Real-world cfDNA testing identified actionable genomic alterations in NSCLC not only when tissues were unavailable but also when conventional testing failed to detect actionable biomarkers. This study demonstrated that gene profiling of NSCLC using comprehensive cfDNA NGS can be a more efficient and faster strategy for deciding the therapeutic options at initial diagnosis and after progression.
