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Maria E Arcila
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MA16 - Novel Mechanisms for Molecular Profiling (ID 917)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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MA16.04 - Clinical and Molecular Characteristics of EGFR Mutant Lung Cancers with Concurrent TP53 and RB1 Mutations. (ID 12513)
13:55 - 14:00 | Author(s): Maria E Arcila
- Abstract
- Presentation
Background
20% of patients with metastatic lung adenocarcinoma have activating EGFR-mutations. EGFR-mutant lung cancers can undergo histologic transformation to small cell lung cancer (SCLC) as a response to the selective pressure of EGFR-TKIs in <5% of patients after earlier-generation EGFR-TKIs and have been reported after osimertinib. SCLC nearly universally harbor TP53/RB1-alterations which are rarely seen in EGFR-mutant lung adenocarcinomas. We sought to identify this subset of patients, describe their clinical course and likelihood of SCLC transformation.
a9ded1e5ce5d75814730bb4caaf49419 Method
Retrospective review of targeted next generation sequencing (NGS, MSK-IMACT) at Memorial Sloan Kettering (MSK) was performed to identify patients with concurrent EGFR-activating mutations and TP53/RB1-mutations within the same tumor sample from NGS between April 2014 to February 2018 with a data cutoff of March 2018. For comparison, consecutive patients with lung cancers harboring EGFR-mutations who were EGFR-TKI naïve and TP53/RB1-wildtype were also collected during that time-period.
4c3880bb027f159e801041b1021e88e8 Result
Of the 21% of lung cancer patients with activating EGFR-mutations (759/3662), 5% (40/759) had concurrent TP53/RB1-mutations. 43% (17/40) were female, 58% former-smokers (23/40, median pack-years: 8), and median age of 68 (range 25-86 years). 88% (35/40) were adenocarcinoma at diagnosis, of which 11% (4/35) transformed to SCLC during treatment; 10% (4/40) were de-novo SCLC at diagnosis, and 1 was large cell neuroendocrine. The transformation rate was significantly higher compared to previous work from MSK evaluating EGFR-mutant patients showing 4% (4/155) transformation (p=0.04). Concurrent PIK3CA mutations were more frequently seen in the EGFR/TP53/RB1 mutant group compared to the TP53/RB1-wildtype group (17% (n=6/35) vs 7% (n=4/60), p=0.11). 20 patients were EGFR TKI-naïve at the time of NGS; the median time on EGFR-TKI (ToT) was 7.6 months versus 14.2 months in the TP53/RB1-wildtype group (HR 4.48, p=0.0003). The overall survival (OS) of this cohort versus TP53/RB1-wildtype was not different (4.3 vs 4.1 years, HR 1.35, p=0.51). In the 4 patients with SCLC transformation, the median time to transformation was 2.4 years after a median of 1.5 EGFR-TKI therapies (range 1-5 lines). Median OS from time of transformation was 7 months. 63% (25/40) of the EGFR/TP53/RB1-mutant cohort had brain metastases during their disease course as compared to 50% (n=30) in the TP53/RB1-wildtype group (p=0.30).
8eea62084ca7e541d918e823422bd82e Conclusion
SCLC transformation is enriched in EGFR/TP53/RB1-mutant lung cancers, occurring in 11% of patients. Once SCLC transformation occurs, overall survival is short. Patients with EGFR/TP53/RB1 have a shorter time on EGFR-TKI. Further investigation into optimal treatment for this subset of EGFR/TP53/RB1 mutant lung cancers is critical.
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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 3
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-74 - MET Exon 14-Altered Lung Cancers: Central Nervous System (CNS) Metastases and Patterns of CNS Progression on MET Inhibition. (ID 14263)
16:45 - 18:00 | Author(s): Maria E Arcila
- Abstract
Background
MET exon 14 (METex14) alterations are targetable drivers found in 3-4% of lung cancers. The frequency of intracranial disease and patterns of central nervous system (CNS) progression on MET tyrosine kinase inhibitors (TKI) are not well characterized.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with advanced METex14-altered lung cancers identified by next-generation sequencing (MSK-IMPACT) between January 2014 and March 2018 were eligible for analysis. A retrospective review of clinical features, patterns of metastases, and CNS progression on MET-TKI was performed. The frequency of intracranial disease was compared to cohorts single-center of EGFR-mutant (n=200), ERBB2-mutant (n=98) and KRAS-mutant (n=200) lung cancers.
4c3880bb027f159e801041b1021e88e8 Result
82 patients with metastatic METex14-altered lung cancers were identified. The median age was 73; 56% (n=46) were female and 54% (n=44) were former smokers. The frequency of brain metastases at baseline was 11% (n=9/82). The lifetime frequency of intracranial metastases from diagnosis of metastatic disease was 34% (n=28/82). By comparison, the frequency of brain metastases was 47% (94/200, p=0.05) with EGFR-, 47% (46/98), p=0.09) with ERBB2-, and 32% (64/200, p=0.78) with KRAS-driven tumors. 6% (n=5/82) of patients developed leptomeningeal disease. The overall survival (OS) of patients who developed intracranial disease on therapy compared to those who did not develop intracranial disease was not significantly different (HR 0.66, 95% CI 0.30-1.43, p=0.29). 51 patients received crizotinib, 26 of whom developed progressive disease. The frequency of intracranial (alone), intracranial and extracranial, and extracranial (alone) progression was 8% (2/26), 19% (5/26), and 73% (19/26), respectively.
8eea62084ca7e541d918e823422bd82e Conclusion
A third of patients with METex14-altered lung cancers develop intracranial disease. This proportion is lower than that seen in EGFR- and ERBB2-mutant lung cancers and comparable to KRAS-mutant lung cancers. The frequency of CNS failure on crizotinib was lower than expected compared to historical rates in ALK-rearranged lung cancers.
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P1.01-75 - Utility of cfDNA Testing for Acquired Resistance: The Memorial Sloan Kettering Experience with Plasma EGFR T790M Clinical Testing. (ID 12514)
16:45 - 18:00 | Author(s): Maria E Arcila
- Abstract
Background
Liquid biopsy for circulating tumor DNA (ctDNA) has been increasingly adopted for the detection of oncogenic drivers and drug resistance mechanisms. Practice guidelines for liquid biopsy are lacking and biologic factors influencing ctDNA detection and shedding are poorly understood. We evaluated factors influencing ctDNA detection, using EGFR-T790M as a case-study, in patients with acquired resistance to first/second-generation EGFR tyrosine kinase inhibitors (EGFR-TKI).
a9ded1e5ce5d75814730bb4caaf49419 Method
This single-center study included metastatic sensitizing EGFR-mutant lung cancer patients (exon 19 deletions, L858R, G719) who underwent plasma EGFR-T790M testing after acquired resistance to erlotinib, gefitinib, or afatinib between January 2016 and August 2017. Plasma T790M was performed by digital PCR. Variant allele fraction (VAF) was calculated as mutant/(wildtype+mutant) allele. Concordance between plasma and tissue testing was examined if tissue analysis (MSK-IMPACT and/or targeted PCR) occurred within 90 days of blood draw. Turnaround time (TAT) was measured from date of blood draw and/or biopsy to result. ctDNA results were correlated with metastatic site and the number of organs involved.
4c3880bb027f159e801041b1021e88e8 Result
177 patients underwent plasma T790M testing; 65% female, 47% current/former smokers. Plasma T790M was positive in 32% (56/177) of patients, tissue testing was T790M-positive in 46% (45/97), and overall T790M-positivity by either platform was 49% (86/177). The median TAT was shorter for plasma T790M compared to tissue PCR (9 vs 15 days, p<0.0001), and led to osimertinib use in 84% (47/56) of positive patients. Concordance between plasma and tissue T790M was 80% (32/40). 15 patients with positive plasma had matched tissue, 87% (13/15) were concordant on tissue. 76% (19/25) of the patients that were T790M-negative on plasma also tested negative on tissue. Median plasma T790M-VAF was 0.98% (range 0.1–49.5%), lower than tissue T790M-VAF (12.8%, range 2.58–27.8, p<0.0001). Plasma T790M-VAF did not correlate with time on osimertinib (p=0.72). Plasma T790M status correlated with a higher number of metastatic sites (4 vs 3, p<0.0001). Plasma T790M detection by organ sites were: pleura (58% with metastases vs 34% without metastases, p=0.14), bone (80% vs 21%, p=0.0002), hepatic (61% vs 41%, p=0.28), nodal (61% vs 33%, p=0.07), adrenal (64% vs 44%, p=0.60), brain (71% vs 38%, p=0.08), and bone/hepatic concurrently (94% vs 98%, p=0.04).
8eea62084ca7e541d918e823422bd82e Conclusion
Using plasma T790M as an archetypal example, cfDNA testing showed concordance and a shorter turnaround compared to tissue testing. cfDNA was more likely to result positive in patients with more metastatic sites, or osseous and hepatic metastases possibly driven by increased ctDNA shedding.
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P1.01-99 - Detecting HER2 Alterations by Next Generation Sequencing (NGS) in Patients with Advanced NSCLC from the United States and China (ID 11285)
16:45 - 18:00 | Author(s): Maria E Arcila
- Abstract
Background
Advances in NGS have led to an increase in identifying specific actionable gene alterations across tumor types. We collected data on HER2 gene alterations detected by NGS from patients with advanced NSCLC and analyzed clinical characteristics and HER2 targeted treatments.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients diagnosed with advanced NSCLC and underwent NGS testing from Jun 2014 to Dec 2017 at Memorial Sloan-Kettering Cancer Center (MSK) and Guangdong General Hospital (GGH) were included. NGS platforms were MSK-IMPACTTM in MSK and GeneSeek or BurnStone in GGH. Descriptive statistics are used in data analysis.
4c3880bb027f159e801041b1021e88e8 Result
2200 patients from MSK and 490 patients from GGH underwent NGS testing. HER2 mutation and/or amplification were detected in 91/2200(4.1%) patients and 28/490(5.7%) patients from MSK and GGH respectively. Clinical characteristics were listed in Table1. 37.4%(34/91) and 21.4%(6/28) patients from MSK and GGH received HER2 targeted therapies. More patients were enrolled to HER2 inhibitors clinical trials in MSK(24.2%) than GGH(7.1%). The characteristics of HER2 alterations are summarized in Table2.
Table 1. Comparison of HER2 alterations in advanced NSCLC patients from U.S. and China
MSK
N (%)
GGH
N (%)
Total Patients
91
28
Age at Diagnosis (years)
<=60
34 (37.4%)
13 (46.4%)
>60
57 (62.6%)
15 (53.6%)
Sex
Male
37 (40.7%)
14 (50%)
Female
54 (59.3%)
14 (50%)
Smoking History
Former/Current Smoker
53 (58.2%)
7 (25%)
Non-Smoker
38 (41.8%)
21 (75%)
Histology
Adenocarcinoma
84 (92.3%)
25 (89.3%)
Squamous Cell Carcinoma
5 (5.5%)
0
Misc
2 (2.2%)
3 (10.7%)
HER2 status
Mutation
48 (52.7%)
16 (57.1%)
Amplification
32 (35.2%)
11 (39.3%)
Mutation + Amplification
11 (12.1%)
1 (3.6%)
HER2 targeted treatment
34 (37.4%)
6 (21.4%)
Enrolled to HER2 inhibitors clinical trials
22 (24.2%)
2 (7.1%)
8eea62084ca7e541d918e823422bd82e ConclusionTable 2. HER2 alteration in advanced NSCLC patients from U.S. and China combined
NGS Result
Mutation Only
N (%)
Amplification Only
N (%)
Mutation + Amplification
N (%)
Total Patients 64 43 12 Age at Diagnosis (years)
<=60
31 (48.4%)
20 (46.5%)
8 (66.7%)
>60
33 (51.6%)
23 (35.9%)
4 (33.3%)
Sex
Male
39 (60.9%)
19 (44.2%)
7 (58.3%)
Female
25 (39.1%)
24 (55.8%)
5 (41.7%)
Smoking History
Former/Current Smoker
31 (48.4%)
24 (55.8%)
5 (41.7%)
Non-Smoker
33 (51.6%)
19 (44.2%)
7 (58.3%)
Histology
Adenocarcinoma
58 (90.6%)
39 (90.7%)
12 (100%)
Squamous Cell Carcinoma
1 (1.6%)
4 (9.3%)
0
Misc
5 (7.5%)
0
0
HER2 targeted treatment
Yes
19 (29.7%)
14 (32.6%)
7 (58.3%)
No
45 (70.3%)
29 (67.4%)
5 (41.7%)
The incidence and clinical characteristics of HER2 alterations in advanced NSCLC were similar between two large cancer centers in the U.S. and China. These data support U.S.-China collaboration in clinical trials for patients with rare molecular subsets of NSCLC to accelerate new cancer drug development.
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.13-43 - Molecular and Imaging Predictors of Response to Ado-Trastuzumab Emtansine in Patients with HER2 Mutant Lung Cancers: An Exploratory Phase 2 Trial (ID 14068)
16:45 - 18:00 | Author(s): Maria E Arcila
- Abstract
Background
Ado-trastuzumab emtansine is a HER2 targeted antibody drug conjugate (ADC) that has demonstrated clinical activity in patients with HER2 mutant lung cancers, independent of HER2 protein expression. We hypothesize that the degree of HER2 homo- and/or heterodimerization may lead to preferential trastuzumab binding and internalization, and may serve as a predictor of response to HER2 ADC.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with metastatic HER2 mutant lung cancers were enrolled in a phase 2 trial of ado-trastuzumab emtansine, treated at 3.6mg/kg IV every 3 weeks. The primary endpoint was overall response rate (ORR) using RECIST v1.1. An expansion cohort included patients assessed using PERCIST, with pre-treatment 89Zr-trastuzumab PET/CT as correlative HER2-targeted imaging. HER2 mutation was identified by next generation sequencing (NGS), and tumors with adequate tissue were subsequently tested by fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), quantitative protein mass spectrometry, as well as quantitative HER2-HER3 heterodimerization by fluorescence lifetime imaging microscopy - Förster resonance energy transfer (FLIM-FRET).
4c3880bb027f159e801041b1021e88e8 Result
A total of 35 patients with HER2 mutant lung cancers were treated across 2 cohorts. ORR was 44% (8/18, 95% CI 22-69%) for RECIST cohort, and 46% (6/13, 95% CI 19-75%) for PERCIST cohort with 4 patients awaiting response assessment. Responders were seen across mutation subtypes (A775_G776insYVMA, G776delinsVC, V659E, S310F, L755P). Concurrent HER2 amplification was observed in 6 of 35 (17%) patients by either NGS or FISH. IHC ranged from 0 to 3+ and did not predict response. HER2 protein expression was low or absent in 15/18 cases tested by mass spectrometry. HER3 overexpression was seen in 7/18 cases tested and among them 5/6 evaluable patients had a partial response. FLIM-FRET efficiency was tested positive for HER2-HER3 heterodimer, which has been shown to be affected by the symmetrical heterodimer interface mutations (Claus et al, 2018), in 3 patients thus far and 1 of them had a partial response. Pre-treatment 89Zr-trastuzumab PET/CT showed increased uptake in 3/8 patients tested to date, and all 3 patients subsequently had partial metabolic response.
8eea62084ca7e541d918e823422bd82e Conclusion
This study confirmed the efficacy of ado-trastuzumab emtansine in patients with HER2 mutant lung cancers. HER2-containing dimers as indicated by HER3 overexpression or FLIM-FRET efficiency, and HER2-targeted imaging with 89Zr-trastuzumab PET/CT, may predict response to HER2 ADCs.
6f8b794f3246b0c1e1780bb4d4d5dc53
