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Natasha Leighl
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ES22 - Quality of Life (ID 173)
- Event: WCLC 2020
- Type: Educational Session
- Track: Palliative and Supportive Care
- Presentations: 2
- Moderators:
- Coordinates: 1/31/2021, 10:30 - 11:30, Scientific Program Auditorium
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ES22.02 - Chair (ID 3994)
10:30 - 11:30 | Presenting Author(s): Natasha Leighl
- Abstract
Abstract not provided
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ES22.03 - Quality of Life - Does It Really Matter (ID 4281)
10:30 - 11:30 | Presenting Author(s): Natasha Leighl
- Abstract
Abstract not provided
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FP14 - Targeted Therapy - Clinically Focused (ID 252)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP14.06 - Multicenter Analysis of Mechanisms of Resistance to Osimertinib (O) in EGFR Mutated NSCLC: An ATOMIC Registry Study (ID 1287)
00:00 - 00:00 | Author(s): Natasha Leighl
- Abstract
- Presentation
Introduction
O is highly active in EGFR mutated NSCLC, but resistance is nearly inevitable. Oncologists can now perform serial blood or tumor molecular testing on such patients. A few single center series have documented a heterogeneous list of mechanisms of resistance to O in the 1st or later lines of therapy, but these have been limited by sample size. A consortium of cancer centers, such as The Academic Thoracic Oncology Medical Investigator’s Consortium (ATOMIC), is uniquely poised to combine patient populations and describe baseline and on treatment molecular features associated with benefit or resistance.
Methods
We created a database and secure web portal whereby investigators at sites throughout ATOMIC could enter comprehensive deidentified clinical, molecular, treatment and radiographic information on patients with metastatic EGFR mutated NSCLC, under IRB approval. All patients were eligible for inclusion, regardless of diagnosis date. Patients who received first line O (1L) and later line O (2+L) were included. For the purposes of this analysis, we evaluated all tissue and plasma samples obtained from the time of O was initiated until 45 days after stopping O. To evaluate for loss of alterations such as T790, we also assessed samples obtained prior to O treatment.
Results
We identified 799 patients across 12 sites in the United States and Canada who had been treated with O. In our cohort, median age at diagnosis was 63 (range 30-95), 541 (67.7%) were female, 429 (53%) were Caucasian, 753 (94.2%) presented with adenocarcinoma, and 314 (39.3%) received 1L O. Out of the 799 patients, 337 tissue samples and 176 plasma/urine samples were obtained after starting O, from which we have detailed molecular data on 161 and 170 samples, respectively from 162 patients. The columns in the table describe the patients for whom we have detailed molecular data, identify the proportion of these alterations only seen after O, the alterations identified in tissue/plasma, and the alterations seen with 1L/2+L O.
ConclusionMolecular Alteration
Overall,
n=162
Seen only
after
OIn Tissue,
n=94
In Plasma/ Urine,
n=87
1L O,
n=35
2+L O, n=126
#
%
#
#
%
#
%
#
%
#
%
T790 Loss
64
39.5
64
34
36.2
32
36.8
2
5.7
62
49.2
EGFR Amplification
29
17.9
8
12
12.8
21
24.1
6
17.1
22
17.5
CDKN2A/B Mutation/Loss
29
17.9
10
10
10.6
10
11.5
9
25.7
19
15.1
PIK3CA Mutation
27
16.7
15
15
15.9
15
17.2
6
17.1
21
16.7
MET Amplification
24
14.8
18
16
17
9
10.3
5
14.3
17
13.5
EGFR C797 S
18
11.1
18
11
11.7
11
12.6
2
5.7
16
12.7
KRAS Mutation
17
10.5
12
6
6.4
11
12.6
6
17.1
5
4
BRAF Mutation/ Amplification
13
8
5
7
7.4
8
9.2
2
5.7
11
8.7
PIK3CA Amplification
7
4.3
0
1
1.1
6
6.9
2
5.7
5
4
MET Mutation
7
4.3
3
2
2.1
7
8
1
2.9
6
4.8
KRAS Amplification
7
4.3
4
3
3.2
4
4.6
2
5.7
5
4
FGFR2 Mutation
6
3.7
0
2
2.1
4
4.6
1
2.9
5
4
Rearrangements/ Fusions (in ALK, BRAF, FGFR3, NTRK1, and RET)
5
3.1
5
4
4.3
2
2.3
0
0
5
4
FGFR1 Mutation
5
3.1
3
3
3.2
2
2.3
1
2.9
4
3.2
FGFR3 Mutation
4
2.5
2
4
4.3
1
1.1
0
0
4
3.2
FGFR4 Mutation
3
1.9
1
3
3.2
0
0
0
0
2
1.6
EGFR G724S
3
1.9
3
2
2.1
1
1.1
0
0
3
2.4
EGFR L718Q/V
2
1.2
2
0
0
2
2.3
1
2.9
1
0.8
In the largest analysis of mechanisms of resistance to O performed to date, we found that potential mediators of resistance were heterogeneous, including PIK3CA, MET, BRAF, CDKN2A/B and FGFR1-4, in addition to alterations within EGFR itself. Abstraction was completed in mid-August (final total 1186 EGFR mutated patients), so we expect numbers to increase in our final analysis. At the time of presentation, we will share information on histologic transformations, specific alterations seen, co-mutation status and survival as a function of mechanisms of resistance and line of therapy.
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OA04 - New Data from Rare EGFR Alterations (ID 223)
- Event: WCLC 2020
- Type: Oral
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 11:45 - 12:45, Scientific Program Auditorium
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OA04.04 - Amivantamab in Post-platinum EGFR Exon 20 Insertion Mutant Non-small Cell Lung Cancer (ID 3031)
11:45 - 12:45 | Author(s): Natasha Leighl
- Abstract
- Presentation
Introduction
Despite sharing similar tumor biology to other epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) tumors, no targeted therapies have been approved for NSCLC harboring EGFR Exon 20 insertion mutations (Exon20ins). The standard of care remains platinum-based chemotherapy for the front-line, with no clear subsequent options available. Amivantamab (JNJ-61186372) is a novel, fully human EGFR-MET bispecific antibody with immune cell-directing activity that targets activating and resistance EGFR mutations, as well as MET mutations and amplifications, and has received FDA Breakthrough Therapy Designation for the treatment of patients with EGFR Exon20ins NSCLC after platinum-based chemotherapy. Here we present updated results on the Exon20ins cohort from the CHRYSALIS study (NCT02609776).
Methods
The dose escalation phase enrolled patients with advanced NSCLC to determine the recommended phase 2 dose (RP2D) of 1050 mg (1400 mg for ≥80 kg) amivantamab. The dose expansion phase assessed the safety and efficacy of amivantamab in patients with EGFR- and MET-mutant NSCLC treated at the RP2D. Disease response was assessed by the investigator per RECIST v1.1 and is presented for those patients with Exon20ins NSCLC who had progressed on prior platinum-based chemotherapy, were treated at the RP2D, and had at least 3 post-baseline disease assessments (18 weeks) or discontinued, progressed, or died prior to the 3rd assessment (the Post-Platinum Cohort). The data cutoff date was 8 Jun 2020.
Results
In the Post-Platinum Cohort (n=81), median age was 62 (42 – 84), 59% were women, 49% were Asian, median prior lines of therapy was 2 (1 – 7), and 53% were never-smokers. At a median follow-up of 6.5 months (1.1 – 29.3), investigator-assessed overall response rate (ORR) was 36% (29/81; 95% CI, 25 – 47), with all responders achieving partial response (PR). The clinical benefit rate (≥PR or stable disease ≥11 weeks) was 73% (59/81; 95% CI, 62 – 82). Responses were durable at a median of 6.8 months (95% CI, 5.0 – not reached) with ongoing responses in 18/29 (longest at 16+ months). Median progression-free survival was 8.3 months (95% CI, 5.5 – 12.7) and median overall survival was 22.8 months (95% CI, 14.0 – not reached).
Among all phase 1 patients, across a variety of EGFR genomic alterations and lines of therapy, treated with amivantamab monotherapy at the RP2D (n=258), the most common adverse events (AEs) were rash (78%), infusion related reaction (IRR; 65%), and paronychia (40%). Additional EGFR-related AEs were stomatitis (19%), pruritus (19%), and diarrhea (11%). Grade ≥3 AEs were reported in 39% of patients; 14% were considered treatment-related, with rash (3%) and IRR (2%) being most frequent. No treatment-related deaths were reported. The incidence of treatment-related AEs leading to dose reduction and discontinuation was 10% and 3%, respectively.
Conclusion
Amivantamab treatment led to promising efficacy with durable responses in patients with EGFR Exon20ins NSCLC post-platinum doublet and continues to demonstrate a manageable safety profile in over 250 patients treated at the RP2D. A phase 3 study, PAPILLON, evaluating amivantamab in combination with chemotherapy in the front-line setting is in planning stages.
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P14 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Immuno-Biology (ID 153)
- Event: WCLC 2020
- Type: Posters
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P14.24 - Evolution of TCR Clonality during Chemoradiation and Durvalumab as Predictors of Survival in Stage 3 NSCLC (ID 1955)
00:00 - 00:00 | Author(s): Natasha Leighl
- Abstract
Introduction
Novel blood-based biomarkers evaluating T-cell receptor (TCR) clonality and the frequency/activation of immune populations hold significant potential for predicting the immune response in stage 3 NSCLC treated with durvalumab. TCR repertoire analysis includes characterization using diversity indices and quantification of individual clones. We hypothesized that low TCR clonality on treatment signals the lack of expansion of functional tumor-specific clones and predicts for worse outcomes. In this study, we characterized the evolution of TCR clonality on CRT and durvalumab and its correlation with response and survival.
Methods
Stage 3 NSCLC patients undergoing chemoradiation (CRT) and maintenance durvalumab were recruited prospectively to undergo serial blood collections at baseline and pre- and post- durvalumab. TCR repertoire analysis (capTCRseq) was performed on cfDNA using hybrid-capture TCR sequencing and TCR diversity/clonality was estimated using the Shannon’s and Simpson’s entropy index. Correlations between TCR clonality, response and PFS were examined using logistic and cox regressions.
Results
Among 73 stage 3 NSCLC patients prospectively recruited to study, a pilot group of 22 patients who had completed induction CRT was analyzed for clonal TCR changes on treatment. In total, 17 received consolidation durvalumab, with best response of CR/PR in 7(41%) SD in 8(47%) and PD in 2 (12%). The median PFS from the start of durvalumab is 12.0 months (3.3-NR) and 53% of patients had progressed at the time of analysis. Baseline TCR clonality was not associated with response to CRT or durvalumab. However, lower TCR clonality measured pre-durvalumab trended with lower response (OR 0.82, p=0.09). Lower TCR clonality pre-durvalumab also trended with worse PFS (HR 1.16 P=0.10). Importantly, a decrease in TCR clonality compared to baseline, signaling the lack of clonal expansion on treatment, is significantly associated with a worse PFS (p=0.05). In patients whose TCR clonality decreased by 50% after CRT, the median PFS was 1.7 vs 12.0 months (HR 3.5, p=0.14) (Figure A). Clonal tracking, flow cytometry and measurement of minimal residual disease (CAPPseq) is in progress.
Conclusion
A decrease in TCR clonality on CRT is associated with poor PFS on consolidation durvalumab. TCR clonality may be a potential biomarker that can select for patients likely to benefit from durvalumab. Further characterization of TCR clonality, clonal tracking with treatment, percentage of shared tumor TCR clones is ongoing in the larger cohort.
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P35 - Pathology - Genomics (ID 105)
- Event: WCLC 2020
- Type: Posters
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P35.03 - Methylation Signatures Associated with T790M Status in Progressive NSCLC (ID 2337)
00:00 - 00:00 | Author(s): Natasha Leighl
- Abstract
Introduction
Emergence of the EGFR T790M mutation accounts for acquired first generation EGFR tyrosine kinase inhibitor (TKI) resistance in over half of patients with EGFR mutant NSCLC. In patients without emergent T790M, resistance mechanisms are less well understood. We explored the impact of DNA methylation status and TKI treatment failure in these patients.
Methods
Using a prospective cohort of patients with acquired TKI resistance, tumour tissue samples pre/post TKI exposure were identified. DNA was extracted from FFPE tissue using the Qiagen AllPrep DNA/RNA FFPE Extraction Protocol, and subsequently analyzed using the Illumina Infinium EPIC array. Raw microarray data files were processed using the software package minfi for data normalization (Illumina method) and extraction of methylation levels (M-values). Samples were split into two groups according to the T790M status of each sample (T790M + or T790M-). The set of most informative probes, those whose M-value profiles align most closely with the T790M status of the study samples, was generated by selecting the 1,000 probes with lowest ANOVA’s p-value. The stability of the resulting sample clustering was assessed by hierarchical clustering (Euclidean distance), classification with internal cross-validation (SVM leave-one-out), and non-parametric dimensional reduction (t-SNE).
Results
40 samples from 36 EGFR mutant NSCLC patients were successfully profiled. Pre TKI samples were available in 10 patients with an EGFR mutation of which 4 had matched post TKI tissue (3 T790M+, 1 T790M-). The remaining 26 samples in post TKI patients included 17 T790M + and 9 T790M- cases. A DNA methylation-based signature was developed by selecting the array probes that best discriminated T790M+ from T790M- cases. Group membership was stable, as shown by cross-validation by three different methods (hierarchical clustering, SVM leave-one-out and t-SNE). The 1,000 probe cut-off was arbitrarily selected; however, identical sample clusters were obtained using 500 or 2,000 methylation array probes. When analyzing the genomic location of the set of probes that form the signature, we found broad distribution across all chromosomes, thus, ruling out the possibility of selection bias due to focal or chromosome-level aberrations. Several genes contained a higher number of the selected probes, including EGFR, whose expression levels are known to be regulated at the methylation level in certain cancer types. Cluster analysis using the 1,000-probe signature revealed a high degree of concordance between EGFR T790M and DNA methylation status. All post-TKI (n=20) T790M+ samples concentrated within epi-group 2, whereas 8/10 T790M- samples were found within epi-group 1. Of the 4 patients with matched samples, 2 had baseline samples within epi-group 2 and went on to develop EGFR T790M post TKI. Of the 2 with baseline samples within epi-group 1, one went on to develop T790M (post-TKI epigroup 2) and one did not (post-TKI epigroup 1).
Conclusion
We observed a concordance between T790M status and epi-group suggesting that the development of resistance to EGFR-TKIs may be associated with distinct DNA methylation signatures. This signature may be present at baseline and predict for subsequent emergence of T790M.
