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Hye Ryun Kim
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ES28 - Targeting KRAS (ID 245)
- Event: WCLC 2020
- Type: Educational Session
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/31/2021, 15:30 - 16:30, Scientific Program Auditorium
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ES28.02 - Clinical Data for KRAS G12C Inhibitors (ID 4119)
15:30 - 16:30 | Presenting Author(s): Hye Ryun Kim
- Abstract
- Presentation
Abstract
KRAS mutation is historically considered to be undruggable, but the KRAS G12C mutation has druggable since emerged as an actionable alteration in non–small cell lung cancer (NSCLC). KRAS would be the most mutated oncogene in human cancers (~80%), and it has been associated with poor prognoses in patients with lung cancer. To treat patients with KRAS mutation in the past, medical oncologists have used chemotherapy, PD-1 inhibitor, and a combined therapy of both. Since there has been no approved targeted therapy in these patients, we have medical unmet need.
Several early phase clinical trials revealed that targeting KRAS potentially improves treatment outcomes for patients with KRAS-mutant NSCLC. Herein, I would like to talk about the representative KRAS G12C inhibitors including sotorasib and Adagrasib.
Sotorasib (AMG510)
Sotorasib (AMG 510), the first-in-class KRAS G12C inhibitor, showed the promising data in the phase 1/2 CodeBreak 100 trial across tumor types. Topline results revealed a satisfactory objective response rate (ORR) of 32.2% in heavily treated patients with KRAS G12C + NSCLC. This study was included 20 patients with treatment naïve metastatic NSCLC with KRAS G12C without active brain metastases. The total study population were 129 patients with various KRAS G12C locally advanced or metastatic malignancies. The primary end point was safety, and the secondary end points were pharmacokinetics (PK), ORR, duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS).
Dosing of sotorasib was escalated from the 180mg to 360 mg, 720 mg, followed by 960 mg. Three patients in the study received the 180 mg, 16 patients were treated with 360 mg, 6 patients were given 720 mg, and 34 patients received the 960 mg. Patients were followed on sotorasib for a median of 11.7 months (range, 4.8-21.2). At data cut-off, 14 patients were continuing therapy, 35 had disease progression, 5 had died. Any dose-limiting toxicities or treatment-related deaths were not observed in this study. Treatment-related adverse events (TRAEs) were observed in 66.1% of the overall population. TRAEs were grade 3 and 4 in severity in 18.6% an 1.7% of patients, respectively. Tumor burden at data cutoff compared with baseline showed a reduction after sotorasib in 71.2% of patients. The ORR of 32.2% consisted of all partial responses (PRs), and 55.9% of patients had SD. Contrarily, progressive disease was observed in 8.5% of the population. The overall DCR was 88.1%. Of the patients who had a response to sotorasib, the median DOR was 10.9 months (1.1+ to 13.6), and the median duration of SD was 4.0 months (1.4 to 10.9+). The median PFS was 6.3 months (0.0+ to 14.9).
Currently the phase 3 CodeBreak 200 trial of sotorasib in combination with docetaxel is recruiting patients with locally advanced and unresectable or metastatic NSCLC with KRAS G12C who are previously treated with 1 prior therapy. The primary end point of the study is PFS, and the secondary end points include OS, ORR, patient-reported outcomes, quality of life, DOR, time to response, DCR, and safety.
Adagrasib
In a phase 1/2 multi-expansion cohort trial (KRYSTAL-1), adagrasib was evaluated in patients with advanced solid tumors harboring KRAS G12C mutations. From the phase 1 dose-escalation part, it was determined that the maximum tolerated dose (MTD) of adagrasib was 600 mg twice daily. The agent was administered at the 600-mg level as monotherapy in the phase 1b of the study. The agent was also administered in combination with either pembrolizumab, afatinib, or cetuximab in various expansion cohorts. The phase 1 coprimary end points were safety, MTD, PK, and the recommended phase 2 dose.
The phase 2 segment of KRYSTAL-1 looked at adagrasib therapy in 61 patients with NSCLC, who were evaluated for the primary end point of ORR per RECIST 1.1, as well as the secondary end point of safety. Eligibility criteria for this phase 1/2 trial were a solid tumor with a KRAS G12C mutation, unresectable or metastatic disease, treated or stable brain metastases, and patients must have progressed on or after treatment with a PD-1/PD-L1 inhibitor after or in combination with chemotherapy for patients with NSCLC.
Pooled data on responses to adagrasib showed an ORR of 43% in the 14 evaluable patients treated with the single agent in the phase 1/1b, which included PRs in 43% and SD in 57%, for a DCR of 100%. And amongst all patients treated at the recommended phase 2 dose with adagrasib across all segments of the trial, the ORR was 45% with PRs in 45% and SD in 51%, for a DCR of 96%. With a median duration of treatment of 8.2 months (1.4-13.1+). Treatment with adagrasib in KRYTAL-1 led to TRAEs of any grade in 85% of the population, as well as grade 3/4 TRAEs in 30% and grade 5 TRAEs in 2%.
Upcoming trials exploring KRAS inhibition would be phase 1 studies of JNJ-74699157 and GDC-6036 as treatment of patients with KRAS G12C mutations.
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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 | Author(s): Hye Ryun Kim
- 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): Hye Ryun Kim
- 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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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): Hye Ryun Kim
- 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): Hye Ryun Kim
- 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.
