Virtual Library
Start Your Search
E.H. Tan
Author of
-
+
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
-
+
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): E.H. 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.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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)
-
+
P3.01-017 - Clinical Outcomes of Patients with EGFR T790M + NSCLC on Osimertinib (ID 8802)
09:30 - 09:30 | Author(s): E.H. 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.
