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Wan Ling Tan
Moderator of
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MA 12 - Circumventing EGFR Resistance (ID 665)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 12
- Moderators:Wan Ling Tan, Nobuyuki Yamamoto
- Coordinates: 10/17/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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MA 12.01 - A Phase Ib Study of the Combination of Afatinib and Ruxolitinib in EGFR Mutant NSCLC Progressed on EGFR-TKI: An Updated Analysis (ID 9021)
11:00 - 11:05 | Presenting Author(s): Ji Soo Park | Author(s): M.H. Hong, Byoung Chul Cho, Hye Ryun Kim
- Abstract
- Presentation
Background:
T790M mutation of EGFR exon 20 is observed in approximately 50% of the non-small cell lung cancer (NSCLC) patients progressed on EGFR tyrosine kinase inhibitors (TKIs). Based on a preclinical study demonstrating that pharmacologic JAK1 inhibition increased the anti-tumor activity of afatinib in T790M-positive NSCLC cell lines, we conducted a phase Ib study to evaluate the safety and efficacy of the combination of afatinib and ruxolitinib, a selective JAK inhibitor, in NSCLC patients who had progressed on EGFR-TKIs.
Method:
We used the classical 3+3 design for dose-escalation cohort (DAC). Patients with histologically diagnosed, EGFR mutant stage IV NSCLC and documented disease progression on EGFR-TKIs were considered eligible. Afatinib was administered alone once daily from day 1 through day 8 (run-in period), then ruxolitinib was orally administered twice daily concomitantly with afatinib until progression. The primary endpoint was to determine RP2D and DLT. If DLT was not observed in 9 patients at the cohort of the highest level, we planned to decide RP2D and enroll 6 additional patients in the dose-expansion cohort (DEC).
Result:
As of June 14, 2017, 21 patients (12 with exon19 deletion, 9 with exon21 L858R) were enrolled in DAC, 8 of which had T790M mutations. All patients were previously treated with erlotinib (n=6) or gefitinib (n=15), and previously received a median of 2 (range, 1-4) lines of chemotherapy. Because no DLT was observed in the 9 patients at the highest dose level (afatinib 50 mg once daily plus ruxolitinib 25 mg twice daily), 6 patients with T790M mutation were enrolled in the DEC. Frequent AEs included paronychia (G1 in 11 cases, G2 in 2 cases), diarrhea (G1 in 14 cases, G2 in 2 cases, and G3 in 2 cases), acneiform rash (G1 in 13 cases), and oral mucositis (G1 in 7 cases, G2 in 3 cases). SAEs were reported in 6 patients, which were not related to the investigational products. Partial responses were observed in 7 patients (25.9%) with disease control rate (CR+PR+SD) of 96.3%. Median PFS was 5.7 months (95% CI, 4.2-7.2) and 3 patients remain on study.
Conclusion:
The combination of afatinib with ruxolitinib was well tolerated with clinical benefit of disease control in NSCLC with acquired resistance to EGFR-TKIs (NCT02145637).
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MA 12.02 - Phase I/II Study of S49076, a MET/AXL/FGFR Inhibitor, Combined with Gefitinib in NSCLC Patients Progressing on EGFR TKI (ID 7974)
11:05 - 11:10 | Presenting Author(s): Gee-Chen Chang | Author(s): G. Curigliano, Wan-Teck Lim, S. Viteri, F. Ciardiello, T. Hida, Chia-Chi Lin, H. Murakami, Makoto Nishio, Luis Paz-Ares, F. Cantero, C. Gabarroca, E. Gandossi, N. Kamsu-Kom, S. Pennaforte, M.-. Secouard-Faure, Keunchil Park
- Abstract
- Presentation
Background:
S49076 is a potent ATP-competitive TKI that targets MET, AXL and FGFR1/2/3 at clinically relevant doses. Preclinical data showed that combination of S49076 with 1[st] generation EGFR-TKI can overcome acquired resistance to EGFR inhibition in a NSCLC EGFR-mutated MET-amplified cell model. Here we report interim phase I data from NSCLC patients treated with S49076 in combination with gefitinib to overcome acquired non-EGFR-T790M-mediated resistance to EGFR TKI (1[st]/2[nd] generation).
Method:
This is a phase I dose-finding study of S49076 combination with a standard dose of gefitinib using a modified Bayesian Continual Reassessment Method with S49076 doses of 500 and 600mg. Both agents are administered orally once daily. The primary objective is to determine the safety profile of the combination and the recommended phase 2 dose (RP2D) based on safety assessments. Patients are selected according to tumor status; they carried an activating-EGFR mutation without secondary T790M mutation and with at least one of the following dysregulations: MET IHC3+, MET FISH 2+/3+, or AXL IHC 2+/3+.
Result:
In June 2017, molecular screening was performed in 48 EGFR/T790M-negative tumor samples to assess MET and AXL dysregulation. 17/48 met the molecular eligibility criteria: 12/17 with MET overexpression/amplification; 4/17 with both MET overexpression/amplification and AXL overexpression; and 1/17 with AXL overexpression. As regards S49076 dose levels, 4 patients were included at 500 mg and 4 at 600 mg. Five patients discontinued treatment: 4 disease progression and 1 consent withdrawal. The most frequent related AEs (≥2 patients) were asthenia (n=5), diarrhea, nausea and paronychia (n=4 each), ASAT/ALAT increase, anemia, and yellow skin (n=3 each), peripheral edema, stomatitis, blood creatinine increase, vomiting, hypoalbuminemia, and decreased appetite (n=2 each); most were grade 1-2. A DLT occurred in 1 patient at 600mg (grade 3 stomatitis). The other severe related AEs included grade 3 ALAT increase, asthenia, and neutrophil count decrease. Concomitant intake of gefitinib did not appear to modify the S49076 PK profile as compared to previous data. The best overall response rate were partial response (PR, 1/8), stable disease (SD, 6/8), and progressive disease (1/8), including 3 patients with PR/SD ≥6 months.
Conclusion:
According to preliminary data, the frequency of MET and AXL dysregulations is consistent with the literature. Combination of S49076 and gefitinib is well tolerated and safety data are consistent with the overall safety profile of each drug. The phase II part of this study will start once the RP2D is defined to evaluate the anti-tumour activity of the combination.
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MA 12.03 - Kinase Fusions as Recurrent Mechanisms of Acquired Resistance in EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC) (ID 10309)
11:10 - 11:15 | Presenting Author(s): Sai-Hong Ignatius Ou | Author(s): S.J. Klempner, B. Creelan, W.S. Hsieh, D. Costin, P.J. Stephens, Jeffrey S. Ross, V.A. Miller, Siraj M Ali, A.B. Schrock
- Abstract
- Presentation
Background:
Resistance invariably develops in EGFR-mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKI). In approximately 50% of cases, resistance is mediated by the EGFR T790M mutation; however, multiple other mechanisms of resistance have also been described, including case reports of acquired kinase fusions (PMIDs: 26187428, 28089157).
Method:
Hybrid-capture based genomic profiling (FoundationOne® or FoundationACT™) was performed prospectively on DNA isolated from tissue-based FFPE samples or blood-based circulating tumor (ctDNA) samples from NSCLC patients.
Result:
From a dataset of 3,014 unique EGFR-mutated (exon 19 deletion, L858R, G719X, L861Q, or S768I) TKI naïve or relapsed NSCLCs we identified 28 (0.9%) cases with co-occurring likely activating kinase rearrangements (BRAF [12], FGFR3 [5], RET [5], ALK [4], NTRK1 [1], EGFR [1]), including 24 confirmed fusions. Treatment histories were available for 21/28 cases, and prior evidence of EGFR mutation and treatment with an EGFR TKI was evident in 21/21 (100%) cases. In 25/28 cases no other known mechanisms of acquired resistance co-occurred with the primary EGFR mutation and the kinase fusion. The 3 cases with co-occurring known resistance mechanisms (T790M or MET amplification) were those with BRAF rearrangements for which no fusion partner was identified. Additionally, our dataset included 10 paired pre- and post-EGFR TKI treatment samples where the latter sample showed an acquired kinase fusion (4 FGFR3-TACC3, 2 EML4-ALK, 2 CCDC6-RET, 1 AGK-BRAF, 1 TPM3-NTRK1) in addition to the primary EGFR alteration. Notably, in 3/10 paired cases (2 FGFR3 and 1 BRAF) the fusion was acquired in the setting of dropout of an existing T790M mutation.
Conclusion:
Acquired kinase fusions are rare yet recurrent mechanisms of acquired resistance in EGFR-driven NSCLCs, and may be enriched in the setting of resistance to T790M-specific inhibitors. Genomic profiling capable of detecting all classes of genomic alterations, including base substitutions, indels, copy number alterations, and fusions, is warranted at the time of progression on EGFR TKIs, and often provides rationale for treatment in such cases.
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MA 12.04 - Discussant - MA 12.01, MA 12.02, MA 12.03 (ID 10814)
11:15 - 11:30 | Presenting Author(s): Miguel-Angel Molina-Vila
- Abstract
- Presentation
Abstract not provided
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MA 12.05 - Genomic Profiling of EGFR T790M Mutated Non-Small Cell Lung Cancer to Evaluate the Mechanisms of Resistance to Osimertinib (ID 9555)
11:30 - 11:35 | Presenting Author(s): Sonam Puri | Author(s): J.K. Hicks, T.C. Knepper, M. Smith, T.A. Boyle, Jhanelle Elaine Gray
- Abstract
- Presentation
Background:
The T790M mutation in the epidermal growth factor receptor (EGFR) gene altering the kinase domain is the most common mechanism of resistance to first or second-generation EGFR tyrosine kinase inhibitors (TKIs). Osimertinib is currently approved for treatment of metastatic EGFR T790M mutation positive non-small cell lung cancer (NSCLC). However, resistance to osimertinib is an emerging issue. Evaluation of the genomic profiles of patients with EGFR T790M mutated NSCLC treated with osimertinib is necessary to gain an understanding of the potential resistance mechanisms.
Method:
Between January 2014 and June 2017, we retrospectively reviewed DNA profiling data from blood and/or tissue (FoundationONE/ACT, Guardant 360, TruSight panel and/or Pyrosequencing) from patients with advanced NSCLC to identify those with an EGFR T790M mutation. For patients harboring the EGFR T790M mutation, electronic health records were reviewed to identify the clinical variables , outcomes and genotyping at the time of progression on osimertinib. Survival analysis was done using the Kaplan-Meier method (SPSS version 23).
Result:
We identified a total of 433 NSCLC patients who underwent genotypic profiling; EGFR T790M mutation was present in 29 (6.7%) patients. All patients received EGFR-TKIs prior to testing. Patient demographics included: Caucasian (76%), female (76%), adenocarcinoma (100%), never-smokers (52%) with a median age of 65 years and 3 median prior lines of treatment. At the time of identification of the T790M mutations, 27 (93%) patients retained their EGFR exon 19 deletion or exon 21 mutations and 24 (82%) patients received osimertinib. The median overall survival was 4.9 ± 3 months in patients not on osimertinib, and was not reachable in patients on osimertinib in the current follow up period. 7 of the 24 patients had repeat genotyping at the time of progression on osimertinib which revealed presence of acquired secondary mutations including EGFR C797S (43%, N=3), EGFR C797G (14%, N=1), amplifications in EGFR (43%, N=3), ERBB2 (HER2, 28%, N=2) and cell cycle genes (CD-K4, CCND1, CCND2, 28%, N=2), MAPK/ERK pathway alteration (KRAS amplification and Q61R mutation, 28%, N=2), PI3K/AKT/mTOR pathway alteration (ATK3 and PIK3C2B amplification, 14%, N=1) and RET fusion (NCOA4-RET, 14%, N=1).
Conclusion:
There is limited data regarding the mechanisms of resistance to osimertinib. In addition to the acquired mutations in C797S, our study identified several potential pathways for developing resistance to osimertinib including emergence of acquired amplification in EGFR and ERBB2, as well as MAP Kinase and PI3K/AKT pathway aberrations. Updated data will be presented at the meeting.
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MA 12.06 - Using Population Dynamics Mathematical Modeling to Optimize an Intermittent Dosing Regimen for Osimertinib in EGFR-Mutant NSCLC (ID 9110)
11:35 - 11:40 | Presenting Author(s): Xiuning Le | Author(s): S. Chakrabarti, F. Michor, D.B. Costa, Matthew Meyerson
- Abstract
- Presentation
Background:
Acquired resistance to therapy occurs with both first- and newer-generation epidermal growth factor receptor (EGFR) inhibitors. One strategy to delay the emergence of resistance is to use the most active/least toxic inhibitor and replace the traditional daily dosing with a biologically-rational dosing approach. Osimertinib is a covalent mutation-specific EGFR tyrosine kinase inhibitor (TKI) with activity against common EGFR plus EGFR-T790M mutations and less activity against the wild-type receptor. This drug is poised to become a 1[st] line EGFR TKI for treatment-naïve EGFR mutated lung adenocarcinomas. Therefore, it is an ideal candidate to devise rationale dosing schemes to maximize its efficacy and minimize tumor adaptation.
Method:
We explored pulse dosing of osimertinib, to delay the emergence of acquired resistance. We applied population dynamics mathematical modeling to this question, using key parameters (“birth rate” and “death rate”), established through cellular assays. These parameters are presumed to be dose-dependent. First, we experimentally determined the “birth-rates” of PC9 lung cancer cells, PC9 cells bearing the T790M resistance mutation, and PC9 cells that were resistant to osimertinib, with increasing concentrations of osimertinib (0 - 10μM, total of eight doses at half log intervals) using cell viability assays (MTS assay). Next, we determined cellular “death-rates” using annexin V/propidium iodide (PI) fluorescence-activated cell sorting (FACS). We then applied those parameters to our population dynamics model and simulated various treatment conditions with different dosing strategies, to identify the most effective regimens at delaying or preventing the emergence of resistance to osimertinib.
Result:
Using our mathematical model, we predicted that high-dose weekly treatment of osimertinib with a low maintenance dose led to minimal cell proliferation in comparison to daily dosing. Following this in silico prediction of the superiority of pulse dose treatment, we experimentally compared the frequency of emergence of resistance with different treatment dosing regimens, using a long-term cell culture system. Indeed, weekly administration of 5uM osimertinib to PC9 cells, followed by a maintenance dose of 0.25uM, suppressed the emergence of resistance for up to 5-7 weeks in culture.
Conclusion:
We have established a population dynamics mathematical model to predict optimal dosing regimens for osimertinib in treatment-naïve EGFR mutated lung cancers. The model was experimentally validated using a long-term culture system. Future validation in additional preclinical models (cell lines, xenografts and genetically engineered mice) can lead to rationale development of pulse-maintenance clinical trials of osimertinib and eventually establish a novel paradigm for clinical use of EGFR TKIs.
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MA 12.07 - Adjusted Indirect Comparison of Osimertinib to Chemotherapy in NSCLC Patients with EGFRm T790M Who Progressed after EGFR-TKI (ID 8558)
11:40 - 11:45 | Presenting Author(s): Christopher Hoyle | Author(s): F. Andersohn, Tetsuya Mitsudomi, Tony SK Mok, James Chih-Hsin Yang, M. Green, H. Mann
- Abstract
- Presentation
Background:
Osimertinib was granted conditional marketing authorization from the EMA and accelerated approval by the FDA based on single-arm trial (SAT) data. Subsequent full FDA approval was supported by the RCT AURA3 (NCT02151981) and based on superior progression-free survival (PFS) of osimertinib versus platinum-based doublet chemotherapy (PDC) for patients with epidermal growth factor receptor (EGFRm) T790M-positive non-small-cell lung cancer (NSCLC). Accelerated and conditional approval coupled with a large treatment effect led to increased treatment switching post-progression from the control arm to the intervention arm in the RCT as clinicians and patients demanded the new treatment. This will confound analysis of overall survival (OS) benefit in the RCT. Adjusted indirect comparison from other sources can offer a robust analysis of OS without confounding owing to treatment switching and difference in subsequent therapies post-progression.
Method:
Recent SAT data (data cut-off, 1 November 2016) for osimertinib were provided by the AURA (NCT01802632) and AURA2 (NCT02094261) studies (N=405). Data for PDC were provided for a subgroup of the control arm of an RCT, IMPRESS (NCT01544179), which comprised patients with centrally confirmed EGFRm T790M-positive NSCLC whose prior treatment with an EGFRm TKI had failed and were subsequently treated with PDC (N=61). A propensity score (PS) approach was used to adjust for differences in baseline demographics and disease characteristics. Baseline characteristics of both groups were compared using statistical tests.
Result:
Following estimation of PS for each patient and adjustment for heterogeneity across the groups by matching, 288 patients from the osimertinib group and 53 patients from the PDC group were retained for analysis. Osimertinib demonstrated a statistically significant improvement in median PFS of 10.9 months versus 5.3 months for PDC (HR 0.28, 95% CI 0.19 to 0.41, P<0.0001), which was consistent with the gain in PFS from the RCT AURA3 (10.1 months versus 4.4 months; HR 0.30, 95% CI 0.23 to 0.41, P<0.001), and a statistically significant improvement in OS (HR 0.41, 95% CI 0.27 to 0.62, P<0.0001). Median OS for osimertinib was not reached and was 14.1 months for PDC.
Conclusion:
The indirect comparison estimated a statistically significant improvement in PFS and OS with osimertinib compared with PDC. The PFS benefit was consistent with that of the confirmatory RCT. The combined evidence from RCT data and indirect comparisons described may bridge the potential gap and confounding in evidence for OS produced by subsequent treatments after first progression in the RCT.
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MA 12.08 - Discussant - MA 12.05, MA 12.06, MA 12.07 (ID 10815)
11:45 - 12:00 | Presenting Author(s): Dae Ho Lee
- Abstract
- Presentation
Abstract not provided
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- Abstract
- Presentation
Background:
EGFR TKI therapy has improved lung adenocarcinoma patients’ prognosis tremendously, but almost all of the patients inevitably develop acquired resistance, and EGFR T790M mutation is the major contributors. T790M restores the EGFR tyrosine kinase domain affinity to ATP, and therefore gefitinib is displaced from the binding pocket, and the ‘driving’ signal for proliferation is switched on again. Previous work has shown that after TKI therapy, lung adenocarcinoma patients kept the sensitive mutation and acquired resistance mutation simultaneously by sequencing methods or in vitro cell line experiments. Whether the two different type mutations are in the same cell group or in two different cell groups is unknown. None of them has observed what was happening in the tumor cells after TKI therapy.
Method:
RNA in situ hybridization methods was employed to examined EGFR T790M and L858R mutation in lung adenocarcinoma cancer tissues which was obtained before and after TKI therapy. EGFR expression was examined by immunohistochemistry. EGFR mutation were detected by ARMS PCR methods.
Result:
Twenty five patients were enrolled in this study which were divided into 3 groups. Group 1: 5 patients who had concurrent primary T790M and sensitive EGFR mutation. Group 2: 14 patients who acquired T790M mutation after receiving TKI therapy. Among them, 6 patients had biopsy tissues before and after TKI therapy. 8 patients only own tissues after TKI therapy. Group 3: 6 patients who had sensitive EGFR mutation and received TKI therapy, but re-biopsy tissues didn’t had EGFR T790M. We found that the results of RNA ISH and ARMS PCR methods was identical in the majority of the examined tissues. Only one repeated biopsy tissue didn’t identify EGFR T790M after TKI therapy by PCR in group 3, while the RNA ISH method detected T790M in this tissue which contain only 150 tumor cells. In the serial cut slides, we observed that T790M and L858R mutations were in the same cell group, not only in the primary resistance cases, but also in the acquired resistance cases. For the two cases which had tissues available after receiving third generation TKI therapy, we observed that T790M disappeared in the repeated biopsy specimen, leaving the sensitive mutation which existed from the beginning.
Conclusion:
In the primary and acquired resistance tissues, EGFR sensitive mutation and T790M co-exist in the same cell groups. EGFR sensitive mutation is a trunk and drive mutation, while T790M is a passenger mutation during the treatment process by TKI therapy.
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MA 12.10 - Clinical Utility of Plasma EGFR T790M Mutation Detection in Advanced Non-Small Cell Lung Cancer Patients According to RECIST Criteria (ID 9620)
12:05 - 12:10 | Presenting Author(s): Lourdes Barrera | Author(s): J.R. Borbolla-Escoboza, E. Montes-Servin, E.O. Macedo-Perez, Feliciano Barron, C. Molina Romero, J.M. Hernandez Martinez, Oscar Arrieta
- Abstract
- Presentation
Background:
Circulating tumor DNA (ctDNA) has emerged as a specific and sensitive blood based biomarker for detection of several mutations in non–small cell lung cancer (NSCLC). Other clinical applications for ctDNA include molecular assessment of patients at diagnosis and serial (real-time) monitoring of biomarker status or the development of resistance mutations.
Method:
Eighty patients with advanced NSCLC who either (Group 1) had a new diagnosis or (Group 2) had developed acquired resistance to an EGFR kinase inhibitor were analyzed with highly sensitive Biocept, Inc. TargetSelector[TM] Real Time PCR based plasma assays genotyping for the detection of EGFR mutations L858R, Del19 and T790M. In addition, group 1 was analyzed for KRAS, BRAF, ROS1 and ALK and circulating tumor cells (CTCs) before and after TKI treatment.
Result:
Our results showed concordance rates of EGFR, KRAS and ALK mutations for up to 90% between the tissue and blood samples in newly diagnosed patients (Group 1). Paired analysis of mutations status monitoring in this group (P= 0.016) showed that the pattern of mutant ctDNA and CTCs changed in response to systemic therapy in 83% of the cases (Partial response or disease progression; R2=0.808). Plasma ctDNA analysis of multiple mutations showed that 40% of patients had at least one more mutation besides the one detected in tissue biopsy; 28% of EGFR tissue positive patients also had a KRAS mutation. In addition, 75% of KRAS positive patients had a BRAF mutation. These results demonstrate that plasma ctDNA analysis may even detect mutations missed by standard tissue genotyping due to tissue heterogeneity. Plasma EGFR T790M mutation was analyzed in patients with clinical progression to TKI inhibitors. Considering the RECIST criteria, 58% of progressive disease, 10% of stable disease and 16% of partial response patients were positive for T790M. According to metastatic disease type (locoregional, oligometastatic, polimetastatic), the T790M mutation was found on 64.3% of polimetastatic patients, 30.8% of oligometastatic patients and 17.6% of loco-regional patients.
Conclusion:
TargetSelector[TM] ctDNA assay is capable of rapidly detecting EGFR, KRAS and ALK mutations and is highly concordant with mutations present in tumor tissue with the robustness needed for real world testing to identify patients who progress on first line TKI therapy as well as for real-time monitoring of patients’ clinical status. Our findings highlight the importance of the RECIST criteria to define the progressive disease and determine the right moment to test for T790M mutation regardless the metastatic disease type.
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MA 12.11 - The Alteration of T790M Prevalence Between 19 Deletions and L858R in NSCLC After EGFR-TKIs Therapy, a Meta-Analysis (ID 10077)
12:10 - 12:15 | Presenting Author(s): Hengrui Liang | Author(s): D. Chen, J. He, W. Liang
- Abstract
- Presentation
Background:
Pre-treatment EGFR T790M mutation is more likely to coexist with L858R mutation than with exon 19 deletions (19del) in NSCLC. However, EGFR-TKIs might alter this status. We sought to compare the prevalence of T790M upon acquired resistance to EGFR-TKIs between 19del and L858R by assembling all existed data.
Method:
Electronic databases were comprehensively searched for eligible studies. The primary endpoint was the odds ratio (OR) of T790M mutation in NSCLC co-existing with L858R mutation and 19del upon resistance to first-generation EGFR-TKIs. A random effects model was used. Stratified analysis was performed based on study type (retrospective and prospective), race (Asians and Caucasians) and sample type (tissue and plasma).
Result:
A total of 25 studies involving 1,770 patients were included. The overall T790M existent rate was 45.25%. Post-resistance T790M was more frequent in 19del than in L858R mutated patients (53% vs. 36%; OR 1.87; p=0.00). All outcomes of subgroup and overall analyses were similar. In contrast, we re-analyzed the previous meta-analysis, finding that the pooled rate of pretreatment T790M was 14% and 22% in 19del and L858R respectively (OR 0.59; p<0.01). The increase of T790M rate was 2.79-fold in 19del and only 0.63-fold in L858R in the course of EGFR-TKIs therapy.
Conclusion:
Opposite to the situation of de novo T790M, it was observed that T790M was more frequent in exon 19del than in L858R among EGFR-TKI resistant acquired patients. The difference in T790M alteration between 19del and L858R encourages development of specific resistance mechanism detection or treatment strategies.
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MA 12.12 - Discussant - MA 12.09, MA 12.10, MA 12.11 (ID 10816)
12:15 - 12:30 | Presenting Author(s): Kenneth Obyrne
- Abstract
- Presentation
Abstract not provided
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Author of
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OA 09 - EGFR TKI Resistance (ID 663)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Thanyanan Reungwetwattana, Lecia V Sequist
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 301 + 302
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OA 09.07 - Clonality of c-MET Copy Number Gain as a Determinant of Primary TKI Resistance in EGFR-Mutant NSCLC (ID 8887)
12:05 - 12:15 | Author(s): Wan Ling Tan
- Abstract
- Presentation
Background:
cMET activation is a valid mechanism of secondary TKI resistance in EGFR mutation-positive (EGFR-M+) NSCLC. However, its role in the treatment-naïve setting remains unclear. We sought to ascertain the prevalence and clinical impact of co-existing cMET copy number gain(CNG) in TKI-naïve early-stage and metastatic EGFR-M+ NSCLC.
Method:
Multi-region SNP array analysis (n=59 sectors) was performed on 13 early-stage resected EGFR-M+ NSCLC. cMET FISH was performed in a separate cohort of 206 metastatic treatment-naïve EGFR-M+ patients, all of whom were treated with first-line EGFR TKIs. We defined cMET-high as CNG≥5 copies, with an additional criteria of MET:CEP7 ratio >2.0 for amplification. Time-to-treatment failure(TTF) in patients cMET-high/low was estimated by Kaplan-Meier method and compared using log-rank test. A cell line from a cMET-high patient exhibiting primary TKI resistance was established.
Result:
Relative to median ploidy across sectors, 7/13(53.8%) early-stage EGFR-M+ tumors showed cMET CNG in at least one sector, with majority displaying(n=6/7) copy number intra-tumor heterogeneity. In the metastatic cohort, 55/206 patients (26.7%) were found to be cMET-high at diagnosis: 6(10.9%) had MET amplification, 49(89.1%) MET polysomy, with the following distribution: 5-6 copies(n=11), 6-8 copies(n=32), and >8 copies(n=12). We next evaluated clinical outcomes stratified by MET-high v low: median TTF was 14.7m(12.2–NE) vs 14.6m(12.7–16.5), p=0.985 respectively, with no significant difference in response rates(RR) to EGFR TKI (66.7%v73.7%; p=0.940). Further stratification by level of CNG did not reveal any differences in RR (5-6 copies:75.0%, 6-8 copies:63.0%, >8 copies:71.4%; p=0.868). In MET-high amplified group, only 2/6 (33.3%) had a partial response to EGFR TKI. In the cohort with suboptimal TKI response (PFS<6m, n=22), we did not observe significant enrichment for MET-high, relative to rest of the cohort (36.4%v25.5%, p=0.278). Finally, in 6 patients with progressive disease within 4 weeks of initiating EGFR TKI, 2/6(33.3%) were MET-high. In a cell line model derived from a MET-high patient (L858R, cMET:7.3 copies) genomic profiling of cell colonies revealed clonal cMET CNG and subclonal EGFR, with the patient demonstrating clinical response to crizotinib.
Conclusion:
Although up to 26% of TKI-naïve EGFR-M+ NSCLC harbor high cMET CNG by FISH, this occurs on the background of a highly variegated copy number landscape. cMET CNG alone does not significantly impact clinical outcomes to EGFR TKI, with the exception of one patient with a clonal cMET-driven tumor. Our data challenges the utility of arbitrary copy number thresholds to define clinically relevant MET pathway dysregulation and underscores the importance of targeting dominant truncal drivers.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-017 - Clinical Outcomes of Patients with EGFR T790M + NSCLC on Osimertinib (ID 8802)
09:30 - 09:30 | Presenting Author(s): Wan Ling Tan
- Abstract
Background:
Osimertinib (AZD9291) is a third-generation EGFR TKI specific against T790M resistance mutations in patients with metastatic EGFR-mutant (EGFRm+) NSCLC after prior first-line TKI therapy. We aimed to evaluate the clinical efficacy of osimertinib in patients treated under the AZD9291 Early Access Program (EAP) at our local institution.
Method:
This retrospective study included 57 patients who were enrolled on the AZD9291 EAP between Jul 2015 and Nov 2016 after being tested T790M+ on tumor (by direct Sanger sequencing or Roche COBAS EGFR mutation test v2) and/or plasma (cfDNA) specimens (by Lung Colon Panel v2 or ARMS PCR). Of these patients, 52 were treated with osimertinib. Tumor responses were independently assessed by radiologists using RECIST 1.1 criteria. DOR, PFS and OS were estimated by Kaplan-Meier method.
Result:
The median age at diagnosis was 58 years (range: 35-76), 80.7% patients were non-smokers, 89.5% had ECOG 0-2, 96.5% had adenocarcinoma subtype and 87.8% had either EGFR exon 19/ exon 21 mutations. Median line of therapy when osimertinib was administered was third-line (range 2nd – 9th), and 30 (53%) had brain metastasis at osimertinib initiation. RR by RECIST 1.1 was 46% (95% CI 32.2 – 60.5%) (4 CR + 20 PR) with median DOR of 8.7 months. With median follow-up of 6.2 months from osimertinib initiation, median PFS was 10.3 months (95% CI 7.52 to 15.87 months). For the 52 patients treated with osimertinib, EGFR T790M mutation was tested on the following specimens: tumor-only (n=43), plasma-only (n=25), and both (n=17). In patients with paired tumor/plasma T790M testing, 4/17 had concordant results (RR 75%), while 13 patients with discordant results [T790M+ in 8 tumor-only: RR 25% (95% CI 3.2% - 65.1%) or in 5 plasma-only: RR 40% (95% CI 5.3% - 85.3%)] had overall RR 31% (95% CI 9.1% – 61.4%). ECOG status was associated with PFS by univariable analysis, with higher ECOG 2-4 associated with shorter PFS (HR=6.54, 95% CI: 2.48 to 17.26; p<0.001) than ECOG 0-1. Line of osimertinib treatment and presence of brain metastases at osimertinib initiation were not associated with clinical outcome.
Conclusion:
Osimertinib is effective in patients with advanced EGFR T790M+ NSCLC after progression on prior EGFR TKI, regardless of presence/ absence of CNS metastasis or line of therapy. Notwithstanding ongoing optimization of plasma-based assays, T790M tumor-plasma discordance in our patient cohort is likely a reflection of overall burden of T790M subclones, and may represent a potential negative predictive biomarker of response to osimertinib.
