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Chul Kim



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    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA09.01 - A Phase I/II Trial of Dasatinib and Osimertinib in TKI Naïve Patients with Advanced EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 2710)

      15:15 - 16:45  |  Presenting Author(s): Chul Kim

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy is the standard of care in patients with EGFR-mutant NSCLC. However, a fraction of patients do not respond to EGFR-TKI therapy or have short duration of response. In addition, virtually all patients develop resistance. In a preclinical study, we have shown that overexpression of Cripto-1, a member of the EGF–CFC family, contributes to the development of resistance to EGFR-TKI therapy through the Src pathway and that the combination of EGFR-TKI therapy and Src inhibition works synergistically.

      Method

      This is an open-label, single-arm phase I/II trial of osimertinib and dasatinib, a Src inhibitor, in treatment-naïve patients with advanced EGFR-mutant NSCLC (NCT02954523). Patients with pleural or pericardial effusions were excluded. The primary endpoint of the phase I portion was to establish a safe and tolerable phase II dose of osimertinib and dasatinib. Dose escalation includes 2 dose levels (DLs) (DL1: osimertinib 80 mg QD, dasatinib 50 mg BID, DL2: osimertinib 80 mg QD, dasatinib 70 mg BID). 2 DLs below the starting dose level (DL-1: osimertinib 80 mg QD, dasatinib 70 mg QD; DL-2: osimertinib 80 mg QD, dasatinib 50 mg QD) could be explored if necessary. Adverse events (AEs) were assessed per CTCAE 4.03.

      Result

      10 patients (DL2: 3, DL1: 6, DL -1: 1) were enrolled. None of the patients enrolled at DL2 had dose limiting toxicities (DLTs) but given the frequent dose reductions required and toxicities beyond the DLT period, DL1 was further assessed. 3 (50%) of 6 patients at DL1 experienced a DLT (grade 3 headaches and body pain, grade 3 neutropenia, grade 3 rash, one each). One patient was enrolled at DL -1 and did not have a DLT. The most common treatment-related adverse events (TRAEs) included pleural effusion (n=9), diarrhea (n=8), rash (n=7), AST elevation (n=6), ALT elevation (n=6), most of which were grade 1 or 2. 4/4/1 patients had grade 1/2/3 pleural effusion, respectively. 7 (70%) patients had grade 3 TRAEs. No grade 4 or 5 toxicities were observed. Eight (80%) patients had a partial response (including 1 unconfirmed partial response) and 2 had stable disease. Median PFS was 27.2 months; median OS was not reached. The recommended phase II dose was determined as osimertinib 80 mg QD and dasatinib 70 mg QD. Pharmacokinetics (PK) analysis is being performed and will be presented. Due to slow accrual after approval of osimertinib in first-line, the trial was closed to enrollment.

      Conclusion

      The combination of dasatinib and osimertinib demonstrated encouraging anticancer activity. Median PFS is longer than what is historically reported with osimertinib alone in first-line setting, although definitive conclusions cannot be drawn given the small sample size. The tolerability of the combination was limited by TRAEs, but they were generally manageable with dasatinib dose reductions and supportive measures.

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    MA20 - Thymic Tumors: From Molecular to Clinical Results and New Challenges in Other Rare Thoracic Tumors (ID 149)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 1
    • Now Available
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      MA20.05 - Follow-Up Update of 2 Phase II Studies of Pembrolizumab in Thymic Carcinoma (Now Available) (ID 1120)

      11:30 - 13:00  |  Author(s): Chul Kim

      • Abstract
      • Presentation
      • Slides

      Background

      Two phase II studies of pembrolizumab 200 mg every 3 weeks in advanced thymic carcinoma have recently been published (Giaccone et al. Lancet Oncol. 2018, study #1; Cho et al. JCO 2018, study #2). Both studies reported a response rate in about 20% of patients and a rate of autoimmune disorders that is higher than in other tumor types.

      Method

      This report provides a follow-up update of these 2 studies, with particular emphasis on duration of response, and occurrence of autoimmune disorders. Both studies included patients with thymic carcinoma who had progressed after at least one line of chemotherapy.

      Result

      In study #1 a total of 40 patients with advanced thymic carcinoma were treated, with a median follow up of 40.6 months. The response rate did not change (22.5%) compared to the original publication, however one patient who had developed myositis, myocarditis and myasthenia gravis (MG), continues to be in nearly complete response after only two cycles of pembrolizumab, 36 months from initiation of treatment. One patient who had developed myositis and hepatitis with unclear signs of MG developed overt MG symptoms several months after the interruption of therapy. No other new autoimmune disorders were observed (6/40 = 15%). Five patients completed 2 years of treatment according to protocol and 4 of them elected to continue treatment. Three patients who had been off therapy were rechallenged with pembrolizumab upon progression (one responded). Median duration of response was 38 months (from 22.4 in initial report), median PFS was 4.2 months (identical) and median survival was 25.8 months (24.9 in the initial report).

      At completion of this study, an amendment was introduced to add epacadostat 10 mg BID to pembrolizumab in the same patient population. Four patients were treated before the study was closed after the results of a randomized trial of the combination in melanoma failed to meet its primary endpoint. No patient responded (2 stable and 2 progressions). One patient developed grade 2 myocarditis.

      In study #2 a total of 26 patients with advanced thymic carcinoma were included, with a median follow up of 33.4 months. The response rate (19.2%) did not change, and no other autoimmune disorder appeared since the initial publication (5/26 = 19%). Median duration of response (9.7 months), median PFS (6.1 months) and median survival (14.5 months) did not change compared to the initial publication. No additional autoimmune disorders were documented compared to the original publication. A total of 5 patients received 2 years of pembrolizumab according to protocol; no patient continued beyond 2 years or was retreated upon progression with pembrolizumab.

      Conclusion

      These two studies confirm definite activity of pembrolizumab in advanced thymic carcinoma. Recently pembrolizumab was included in the NCCN guidelines for thymic carcinoma. No additional autoimmune disorders were noted after discontinuation of pembrolizumab. There are significant differences in duration of response and overall survival in the 2 studies and potential factors are being investigated. In study #1 pembrolizumab was continued beyond 2 years in several patients and rechallenge was an available option.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-27 - Serial Circulating Tumor DNA (ctDNA) Analysis of Blood and Saliva Predicts Osimertinib Response and Resistance in EGFR-Mutant NSCLC (ID 2909)

      09:45 - 18:00  |  Presenting Author(s): Chul Kim

      • Abstract

      Background

      ctDNA has emerged as a promising non-invasive tool to detect lung cancer associated genomic alterations. We assessed whether serial ctDNA monitoring of plasma and saliva correlates with tumor burden and predicts response, resistance, and progression free survival to osimertinib, the 3rd generation EGFR TKI during treatment of EGFR mutated NSCLC.

      Method

      Plasma and saliva samples were collected at every clinic visit from patients with metastatic EGFR mutant NSCLC enrolled in a clinical trial of local ablative therapy (LAT) upon oligoprogression (5 or less sites of progression) on osimertinib (NCT02759835). Plasma ctDNA was analyzed by droplet-digital PCR (ddPCR) EGFR mutation detection and InVisionSeq Tagged-Amplicon next-generation sequencing. Saliva ctDNA was analyzed by Electric Field-Induced Release and Measurement (EFIRM) liquid biopsy (eLB) assay. Tumor burden was assessed by volumetric CT scoring of all target lesions and other soft tissue lesions ≥10 mm. ctDNA-level changes were correlated with clinical response.

      Result

      We analyzed 389 plasma samples from 20 patients by ddPCR, 126 plasma samples from 16 patients by NGS and 298 saliva samples from 18 patients by eLB. A high correlation between ddPCR and NGS allele frequencies (AFs) was found (Spearman g=0.96; p<0.001). Plasma ddPCR and NGS also correlated with saliva eLB assay for mutant EGFR detection (Spearman g=0.42 and 0.45, respectively; p<0.001 for both). Among 14 patients who progressed, ctDNA progression (AFs increased two consecutive times by ddPCR) predated RECIST progression by a median of 87 days (range: 28-216 days) in 8 patients. Of 6 patients without ctDNA progression, 2 patients had increase in EGFR mutation-level by eLB and 1 patient by NGS. ctDNA clearance on day 42 or 56 (2 cycles of osimertinib treatment) predicted PFS (HR=0.22, 95% CI=0.06-0.79, p=0.02; figure 1). Both baseline sensitizing EGFR mutation AF and copy number, but not baseline tumor volume, were significantly associated with PFS. Acquisition of MET, EGFR, and ERBB2 amplifications and the EGFR C797S mutation were identified as key resistance mechanisms by NGS in this cohort of patients.

      pfs by ctdna clearance.jpg

      Conclusion

      Serial assessment of plasma and saliva ctDNA is clinically useful for monitoring the therapeutic response to osimertinib and for early detection of resistance mechanisms for clinical decision making. Three assays used in this study, the ddPCR and NGS for plasma ctDNA detection, and eLB for saliva ctDNA detection are complementary with each having unique advantages.

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    P1.12 - Small Cell Lung Cancer/NET (ID 179)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.12-04 - A Phase I Study of the <sup>177</sup>Lu-DOTA<sup>0</sup>-Tyr<sup>3</sup>-Octreotate in Combination with Nivolumab in Patients with Extensive-Stage Small Cell Lung Cancer (ID 2887)

      09:45 - 18:00  |  Presenting Author(s): Chul Kim

      • Abstract

      Background

      Despite initial sensitivity to systemic treatment, most patients with extensive-stage small cell lung cancer (ES-SCLC) relapse. It has been shown that somatostatin receptors are expressed in SCLC. Lutathera is a 177Lutetium-labeled somatostatin analog approved for treatment of gastroenteropancreatic neuroendocrine tumors (NETs). Nivolumab, an anti-PD-1 antibody, in combination with lutathera may act synergistically to generate anti-tumor immunity. Here we report the final results of the phase I study of this combination in patients with ES-SCLC.

      Method

      This is a phase I/II trial of lutathera and nivolumab in patients with ES-SCLC (NCT03325816). For phase I, patients with either relapsed/refractory ES-SCLC or non-progressing ES-SCLC after first-line platinum-based chemotherapy, or advanced grade I-II pulmonary NETs were eligible. The primary objective was to determine the recommended phase 2 dose (RP2D). The phase I portion followed the standard 3+3 design, assessing two dose levels (dose level 1: Lutathera 3.7 GBq Q8W for 4 doses with nivolumab 240 mg Q2W; dose level 2: Lutathera 7.4 GBq Q8W for 4 doses with nivolumab 240 mg Q2W). The DLT period was defined as first 8 weeks after treatment initiation. Adverse events (AEs) were assessed per CTCAE 4.03.

      Result

      A total of 9 patients were enrolled. Three patients with ES-SCLC (2 relapsed ES-SCLC, 1 non-progressing ES-SCLC after first-line chemotherapy) were enrolled at dose level 1 and no DLTs were observed. At dose level 2, six patients (3 relapsed/refractory ES-SCLC, 2 metastatic atypical carcinoid, and 1 high-grade NET) were enrolled. One patient with refractory ES-SCLC developed a DLT (grade 3 rash). The most common treatment-related AEs (trAEs) were lymphopenia (n=7), thrombocytopenia (n=4), anemia (n=3), and nausea (n=3). 5 (55.5%) of 9 patients had grade 3 trAEs, but the most common grade 3 trAE was lymphopenia (n=4). Grade 3 anemia, thrombocytopenia, pneumonitis, and rash occurred in one patient each. No grade 4/5 trAEs were reported. Among 7 patients with measurable disease, 1 patient with non-progressing ES-SCLC had a confirmed partial response and 2 patients with metastatic atypical carcinoid had stable disease lasting 6 months. The RP2D was lutathera 7.4 GBq Q8W for 4 doses with nivolumab 240 mg Q2W.

      Conclusion

      Evidence from this phase I study of lutathera and nivolumab suggests that the combination has a manageable safety profile and showed initial signs of antitumor activity. The safety and efficacy of the combination may be further explored in phase II as maintenance therapy in patients with ES-SCLC.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-52 - Clinical Response to Osimertinib in a Patient with Metastatic NSCLC Harboring EGFR A763_Y764insFQEA Exon 20 Insertion Mutation: A Case Report (Now Available) (ID 1268)

      09:45 - 18:00  |  Author(s): Chul Kim

      • Abstract
      • Slides

      Background

      Epidermal growth factor receptor (EGFR) exon 20 insertion mutations represent approximately 4-10% of EGFR-mutant non-small-cell lung cancer (NSCLC). The majority of EGFR exon 20 insertion mutations do not respond to approved EGFR tyrosine kinase inhibitors (EGFR-TKIs). Preclinical data suggest that EGFR A763_Y764insFQEA mutation is associated with sensitivity to EGFR-TKI therapy.

      A few case reports have shown that patients with this rare variant of EGFR exon 20 insertion mutation may respond to first- and second-generation EGFR-TKIs. However, efficacy of the third-generation EGFR-TKI osimertinib against the EGFR A763_Y764insFQEA mutation has not been described. Here, we present a patient with metastatic NSCLC harboring EGFR A763_Y764insFQEA alteration treated with osimertinib.

      Method

      A 56-year-old never-smoker Asian female presented with complete atelectasis of the left upper lobe, a left circumferential pleural effusion, and diffuse osseous sclerotic lesions. Pathology confirmed the diagnosis of metastatic lung adenocarcinoma. Circulating tumor DNA (ctDNA) assay utilizing InVisionSeqTM Tagged-Amplicon next-generation sequencing (NGS) identified EGFR A763_Y764insFQEA, MET amplification, and TP53 G266*. The patient was started on osimertinib 80 mg once a day. Later, tumor NGS came back positive for EGFR A763_Y764insFQEA, TP53 G266*, and BRCA-2 A2351G.

      Result

      The patient’s symptoms of cough and shortness of breath started to improve shortly after initiation of osimertinib. A CT scan of the thorax and abdomen obtained 5 weeks after starting osimertinib showed improvement in aeration of the previously collapsed left upper lobe, visualization of a 1.9 x 1.4 cm spiculated left upper lobe lung mass, improved infiltrative soft-tissue in the left hilum, and improved partially loculated left pleural effusion, suggesting response to osimertinib.

      Conclusion

      In this patient with the EGFR A763_Y764insFQEA mutation, osimertinib has shown effectiveness as monotherapy, suggesting it could serve a viable therapeutic treatment option in NSCLC with this rare variant of exon 20 insertion mutations. Future studies should validate this finding.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-100 - Spectrum of EGFR Exon 20 Insertion Mutations and Co-Occurring Genetic Alterations in Patients with Non-Small-Cell Lung Cancer (ID 2538)

      10:15 - 18:15  |  Author(s): Chul Kim

      • Abstract

      Background

      Epidermal growth factor receptor (EGFR) exon 20 insertion mutations are associated with a low response rate to approved EGFR tyrosine kinase inhibitors (EGFR-TKIs) and short progression-free survival. Pre-clinical studies have shown differences in the affinity of EGFR exon 20 insertion mutations for EGFR-TKIs, suggesting that the location of the insertion within the C-helix may play an important role in determining EGFR-TKI sensitivity. Several EGFR-TKIs designed to target EGFR exon 20 insertion mutations are in clinical development. Comprehensive genomic profiling has allowed for identification of co-occurring genomic alterations, which may help us identify additional pathways that may drive disease progression and drug resistance.

      Method

      Formalin-fixed paraffin-embedded (FFPE) samples from patients with non-small cell lung cancer (NSCLC) were profiled by targeted next-generation sequencing (NGS) using Caris Molecular Intelligence (Caris Life Sciences, Phoenix, AZ). Mutations and copy number variations (CNV) were assessed for each gene included in the NGS panel. Gene amplification (including low amplifications) was defined as gene copy number ≥ 4 and copy number loss as gene copy number < -1.4.

      Result

      Among the 1,556 patients with EGFR mutations, 104 (6.7%) patients were found to harbor an EGFR exon 20 insertion mutation. There were 70 (67.3%) females and 34 (32.7%) males with a mean age 62 (± 11.5 years). 61 (58.7%) samples came from primary lung sites and 43 samples (41.3%) came from metastatic sites. The main histological types were: adenocarcinoma 89 (85.5%), acinar adenocarcinoma 6 (5.7%), papillary adenocarcinoma 5 (4.8%), adenocarcinoma with bronchoalveolar features 1 (1%), squamous cell carcinoma 1 (1%) and carcinoma not otherwise specified 2 (2%). The most common exon 20 insertion mutation was A767_V769dup (25%), followed by S768_D770dup (13%), H773_V774insAH (5%) and H773dup (5%). The most common pathogenic mutations (including presumed pathogenic) included TP53 (51%), followed by CTNNB1 (6%), PIK3CA (4%), PTEN (3%), SMAD4 (3%), and CHEK2 (2%). Of the 104 cases, CNVs were available from 54 patients. Among these patients, commonly amplified genes included CDK4 (11%), EGFR (9%), MDM2 (9%), FOXA1 (7%), and HMGA2 (6%). Copy number loss was observed with CDKN2A (7%), CTNNB1 (2%), ATR (2%), BRCA2 (2%), and FANCL (2%).

      Conclusion

      The diverse spectrum of EGFR exon 20 insertion mutations shows molecular heterogeneity of this rare type of EGFR mutations. The presence of co-occurring genomic alterations that may promote tumor progression and drug resistance suggests that combination approaches may be necessary to overcome resistance to EGFR-TKI therapy in some patients with an EGFR exon 20 insertion mutation.