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H.R. Kim
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MINI 09 - Drug Resistance (ID 107)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:L. Villaruz, J. Minna
- Coordinates: 9/07/2015, 16:45 - 18:15, 205+207
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MINI09.07 - Activation of the MET Kinase Confers Acquired Resistance to FGFR-Targeted Therapy in FGFR-Dependent Squamous Cell Carcinoma of the Lung (ID 1212)
16:45 - 18:15 | Author(s): H.R. Kim
- Abstract
- Presentation
Background:
Fibroblast growth factor receptor (FGFR) tyrosine kinase plays a crucial role in cancer cell growth, survival, and resistance to chemotherapy. FGFR1 amplification occurs at a frequency of 10-20% and is a novel druggable target in squamous cell carcinoma of the lung (SCCL). A number of FGFR-targeted agents are currently being developed in SCCL harboring FGFR alterations. The aim of the study is to evaluate the activity of selective FGFR inhibitors (AZD4547, BAY116387) and the mechanisms of intrinsic and acquired resistance to these agents in SCCL.
Methods:
The antitumor activity of AZD4547 and BAY116387 was screened in a panel of 12 SCCL cell lines, among which 4 cell lines harbored FGFR1 amplification. To investigate mechanisms of acquired resistance, FGFR1-amplified H1581 cells which were exquisitely sensitive to FGFR inhibitors, were exposed to AZD4547 or BAY116387 to generate polyclonal resistant clones (H1581-AR, H1581-BR). Characterization of these resistant clones was performed using receptor tyrosine kinase (RTK) array, immunoblotting and microarray. Migration and invasion assays were also performed.
Results:
Among 12 SCCL cell lines, two FGFR1-amplified cells, H1581 and DMS114, were sensitive to FGFR inhibitors (IC~50~<250 nmol/L). Compared with resistant cells, sensitive cells showed increased phosphorylation of FRS2 and PLC-γ, but decreased phosphorylation of STAT3. There was no noticeable difference in FGFR1-3 protein expression level between sensitive and resistant cells. Importantly, phosphorylation of ERK1/2 was significantly suppressed upon treatment of FGFR inhibitors only in sensitive cells, suggesting phospho-ERK1/2 as a pharmacodynamic marker of downstream FGFR signaling. RTK array and immunoblots demonstrated strong overexpression and activation of MET in H1581-AR and H1581-BR, in comparison to almost nil expression in parental cells. Four different SCCL cells with intrinsic resistance to FGFR inhibitors also showed intermediate to high MET expression, suggesting that MET may be involved in both intrinsic and acquired resistance to FGFR inhibitors. Gene-set enrichment analysis against KEGG database showed that cytokine-cytokine receptor interaction pathway was significantly enriched, with MET contributing significantly to the core enrichment, in H1581-AR and H1581-BR, as compared with parental cells. Stimulation with HGF strongly activated downstream FGFR signaling or enhanced cell survival in the presence of FGFR inhibitors in both acquired and intrinsic resistant cells. Quantitative PCR on genomic DNA and fluorescent in situ hybridization revealed MET amplification in H1581-AR, but not in H1581-BR. MET amplification led to acquired resistance to AZD4547 in H1581-AR by activating ERBB3. The combination of FGFR inhibitors with ALK/MET inhibitor, crizotinib, or small interfering RNA targeting MET synergistically inhibited cell proliferation in both H1581-AR and H1581-BR, whereas it resulted in additive effects in SCCL cells with intrinsic resistance to FGFR inhibitors. Acquisition of resistance to FGFR inhibitors not only led to a morphologic change, but also promoted migration and invasion of resistant clones via inducing epithelial to mesenchymal transition phenotype, as documented by a decrease in E-cadherin and an increase in N-cadherin and vimentin.
Conclusion:
MET activation is sufficient to bypass dependency on FGFR signaling and concurrent inhibition of these two pathways may be desirable when targeting FGFR-dependent SCCL.
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MINI 26 - Circulating Tumor Markers (ID 148)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:M. Macmanus, C. Aggarwal
- Coordinates: 9/09/2015, 16:45 - 18:15, 205+207
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MINI26.11 - Longitudinal Monitoring of EGFR Mutations in Plasma of EGFR Mutant NSCLC Patients Treated with EGFR TKIs: Korean Lung Cancer Consortium (ID 1130)
16:45 - 18:15 | Author(s): H.R. Kim
- Abstract
- Presentation
Background:
Detection of epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC) patients is mainly based on tissue biopsy, which is invasive and time consuming. Furthermore, there is still a need for serial monitoring of EGFR mutations and detection of EGFR tyrosine kinase inhibitors (TKIs) resistance. We hypothesized that plasma-based EGFR mutation analysis may be feasible for monitoring response to EGFR TKIs and could be used to predict the resistance.
Methods:
From January 2012 to October 2014, 200 EGFR mutant NSCLC patients were enrolled and treated with EGFR TKIs (141 patients for gefitinib, 46 patients for erlotinib, and 13 patients for afatinib). Plasma samples were prospectively obtained every 2 months from baseline until disease progression. The longitudinally collected plasma samples (n = 368) from 81 patients who progressed were analyzed using droplet digital PCR (ddPCR). We identified an association between serial EGFR mutant titers in plasma cell-free DNA (cfDNA) samples and the patient’s clinical response to EGFR TKIs.
Results:
Of a total 58 baseline cfDNA samples available for ddPCR, 43 (74%) samples demonstrated same mutation in the matched tumors (i.e. sensitivity: 70.8% (17/24) for L858R vs 76.5% (26/34) for exon 19 deletions). The concordance rate of plasma with tissue results of EGFR mutation was 88% for L858R and 86% for exon 19 deletion, respectively. Of the 54 patients with both before and after treatment plasma samples, 40 patients showed a dramatic decrease of mutant copies (greater than 50%) in blood in the first 2 months after treatment. We also found the secondary mutation (T790M) emerged in 28 patients around 3~13 months after treatment and in 4 patients before the treatment. Elevated circulating mutations (L858R/ex19/T790M) can be detected in 5 patients before disease progression as determined by CT scan.
Conclusion:
These results suggest that ddPCR is an appropriate method for determining plasma-based EGFR mutation status and may aid in monitoring response to EGFR TKIs and early detection of EGFR TKIs resistance.
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ORAL 06 - Next Generation Sequencing and Testing Implications (ID 90)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:G. De Lima Lopes, V. Miller
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 1a-1f
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ORAL06.02 - Targeted Deep Sequencing of EGFR/KRAS/ALK-Negative Lung Adenocarcinoma Reveals Potential Therapeutic Targets (ID 622)
10:45 - 12:15 | Author(s): H.R. Kim
- Abstract
- Presentation
Background:
Identification of clinically relevant molecular drivers in patient tumors is essential in selecting appropriate targeted therapy. Using next-generation sequencing (NGS) -based clinical cancer gene test, we performed genomic profiling of lung adenocarcinoma tumors.
Methods:
We collected formalin-fixed paraffin-embedded tumors from 41 lung adenocarcinoma patients whose tumors previously tested negative for EGFR/KRAS/ALK by conventional methods in an ongoing trial (NCT01964157). We performed hybridization capture of 4,557 exons from 287 cancer-related genes and 47 introns from 19 genes frequently rearranged in cancer (FoundationOne). Illumina HiSeq2000 platform was used to sequence to high uniform depth.
Results:
Figure 1Tumors were sequenced to a median coverage of 529x. Overall, we identified a total of 170 known and 492 unknown individual genomic alterations. The number of known alterations per sample was average of 3.8 alterations (range 0-10). Cancer genomes are characterized by 45% (77/170) non-synonymous base substitutions, 17% (29/170) insertions or deletions, 2% (4/170) splice site mutations, 20% (34/170) gene amplifications, 5% (8/170) homozygous loss and 5% (8/170) gene fusions. TP53 was the most commonly mutated gene (13%, n=10/77) among non-synonymous base substitutions, followed by KRAS (10%, n=8/77) and PIK3CA (8%, 6/77). Insertions or deletions commonly occurred TP53 (17%, 5/29) and ERBB2 (14%, 4/29), and splice site mutations occurred in TP53, INPP4B, ATR, and MAP2K4 (n=1 each). Among gene amplification, MDM2 amplification was the most frequent (12%, 4/34), followed by ERBB2 (8%, 3/34) and CDK4 (8%, 3/34) amplification. All 8 cases of homozygous loss were observed with CDKN2A and CDKN2B. Fusion genes were most commonly observed with RET (50%, n=4/8). Based on NCCN guidelines, actionable genomic alterations with a targeted agent were identified in 16 patients (39%) (BRAF mutation [n=1], EGFR mutation [n=7], ERBB2 mutation [n=4], MET amplification [n=1], KIF5B-RET rearrangement [n=2], CCDC6-RET rearrangement [n=1], and CD74-ROS1 rearrangement [n=1]). Nine out of all patients (22%) showed discordance in targetable alterations when compared between NGS and conventional non-NGS methods.
Conclusion:
Thirty-nine percent of lung adenocarcinoma wild type for EGFR/KRAS/ALK may harbor a genomic alteration revealed by NGS approach. These results highlight the importance of profiling lung adenocarcinomas using NGS in the clinic.
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-003 - Co-Expression of Programmed Death Ligand-1 (PD-L1) and CD3 in Patients with EGFR Mutant NSCLC Treated with EGFR Tyrosine Kinase Inhibitors (TKI) (ID 1163)
09:30 - 17:00 | Author(s): H.R. Kim
- Abstract
Background:
Recent reports have suggested an association between non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) gene mutations. Other studies have indicated that EGFR signaling can activate PD-L1 expression and immune escape in mutant EGFR driven NSCLC. Furthermore PD-L1 expression is down-regulated by EGFR TKI. In this study, we aim to determine the association between tumoral and immune cell PDL1 expression and clinical characteristics and outcome in EGFR mutant NSCLC patients treated with first line EGFR TKI.
Methods:
Tumors from 90 patients with advanced stage NSCLC with EGFR mutations and treated with first line EGFR TKI were analyzed. Double staining for CD3 and PDL1 was performed by immunohistochemistry. PDL1 expression in tumour membrane, and PDL1 and CD3 expression in tumor and stromal immune cells were segmented and quantified using the Vectra slide imaging system (Perkin Elmer, Waltham, MA).
Results:
The median age of patients was 62 (range 34-88) years, 64 (71%) were female, 69 (77%) were never smokers, and 43 (48%) harbored EGFR exon 19 deletion. Most immune cells were CD3-ve and PDL1-ve in the tumor (median 99%) and stroma (median 86%). PDL1 tumor membrane expression was associated with PDL1 expression in CD3+ve immune in the tumor and stroma. There was no association between PDL1 or CD3 expression with response rate or time to progression.
Conclusion:
This is the first study to characterize PDL1 expression in immune cells in advanced stage NSCLC harboring EGFR mutations. PDL1+ve immune cells are rare in this patient population. PDL1 expression in tumor membrane and immune cells may not be associated with outcome in NSCLC patients harboring EGFR mutations and treated with EGFR TKIs.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-077 - A Randomized, Phase II Study of Nimotuzumab Plus Gefitinib vs Gefitinib in Advanced Non-Small Cell Lung Cancer After Platinum- Based Chemotherapy (ID 1176)
09:30 - 17:00 | Author(s): H.R. Kim
- Abstract
Background:
Nimotuzumab is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody. We aim to evaluate the efficacy of dual inhibition of EGFR with nimotuzumab plus gefitinib in advanced non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.
Methods:
An open label, randomized, phase II trial was conducted in 6 centers; 160 patients were randomized (1:1) to either nimotuzumab (200mg, IV weekly) plus gefitinib (250mg p.o. daily) or gefitinib alone until disease progression or intolerable toxicities. The primary endpoint was progression free survival (PFS) rate at 3 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR) and safety.
Results:
A total of 155 patients (78 in nimotuzumab plus gefitinib, 77 in gefitinib) were evaluable for efficacy and toxicity. Patient characteristics were well balanced in both groups. Majority of patients had adenocarcinoma histology (65.2%) and ECOG performance status 0 to 1 (83.5%). Among 102 patients with EGFR mutation results available, activating EGFR mutation was documented in 27 patients (12/50 in nimotuzumab plus gefitinib, 15/52 in gefitinib). With a median follow-up of 12.1 months, PFS rate at 3 months was 37.2% in nimotuzumab plus gefitinib and 48.1% in gefitinib [HR 1.03; 95% CI, 0.71–1.40; P=0.98]. Median PFS and OS were 2.0 months and 14.0 months in nimotuzumab plus gefitinib and 2.8 months and 13.2 months in gefitinib [HR 1.03, 95% CI 0.71-1.41, P=0.98 for PFS; HR 0.86, 95% CI 0.57–1.30, P=0.47 for OS]. The ORRs were 14.1% in nimotuzumab plus gefitinib and 22.1% in gefitinib, which was not statistically significant (P=0.76). As expected, patients with EGFR mutation showed significantly longer survival than those with wild-type EGFR or unknown EGFR mutation status (10.3 vs. 1.2 vs. 2.7 months, P < 0.001 for PFS; 23.5 vs. 13.5 vs. 10.5 months, P= 0.001 for OS). Combined treatment of nimotuzumab plus gefitinib did not show superior PFS compared to gefitinib alone in patients with EGFR mutation (13.5 vs. 10.2 months in gefitinib alone, P=0.30) and patients with wild-type EGFR (0.9 vs. 2.0 months in gefitinib alone, P=0.90). The median PFS was not significantly different between two treatment arms according to histology (2.8 vs. 2.9 months in gefitinib alone for adenocarcinoma, P=0.64; 1.2 vs. 2.8 months in gefitinib alone for non-adenocarcinoma, P=0.35). Adverse events (AEs) in both treatment arms were mostly grade 1 to 2 and easily manageable. Importantly, combined EGFR inhibition with nimotuzumab and gefitinib did not increase EGFR inhibition-related AEs, such as acneiform rash (32.4 vs. 30.3% in gefitinib alone, P=0.38), diarrhea (30.7 vs. 35.7% in gefitinib alone, P=0.32), and stomatitis (11.5 vs. 13.4% in gefitinib alone, P=0.19). There was no treatment-related death.
Conclusion:
The dual inhibition of EGFR with nimotuzumab plus gefitinib did not show superiority over gefitinib alone for second-line treatment of advanced NSCLC (NCT01498562).
