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Tejas Patil
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-87 - Acquired Resistance Mechanisms and Clinical Outcomes for Patients with Epidermal Growth Factor Receptor (EGFR) Positive Non-Small Cell Lung Cancer (NSCLC) Treated with Osimertinib (Now Available) (ID 2960)
09:45 - 18:00 | Presenting Author(s): Tejas Patil
- Abstract
Background
Osimertinib is a 3rd generation TKI approved for stage IV EGFR+ NSCLC in the first line or post-progression with T790M. The spectrum of osimertinib resistance mutations and clinical outcomes post-osimertinib progression are not well described.
Method
Single-center retrospective review of patients with stage IV EGFR+ NSCLC treated with osimertinib was conducted. Resistance mutations were determined via tissue biopsy or circulating tumor DNA (Guardant) prior to and at time of progression on osimertinib. PFS was calculated using Kaplan-Meier method. PFS1 is start of osimertinib to radiographic progression. PFS2 is start of next therapy after osimertinib to next radiographic progression.
Result
We identified 95 patients with stage IV EGFR+ lung adenocarcinoma treated with osimertinib detected via NGS (56/95), real-time PCR (29/95), Sanger sequencing (8/95), and other techniques (2/95). Most patients were female (63/95) and never smokers (72/95). Osimertinib resistance and post-progression patterns are shown in Table 1. Potentially targetable mutations were found in 55% (26/47) samples and 14% (6/47) samples had oncogenes targetable with available TKIs. TP53 mutations prior to osimertinib did not significantly influence PFS (36 weeks vs 39 weeks; p = 0.13). MET amplification was only seen in the setting of undetectable T790M or in patients who received first line osimertinib. Median PFS1 for 1st line EGFR TKI (n=17), 2nd line EGFR TKI (n=41), 3rd or greater line EGFR TKI (n=29) was 36, 45 and 39 weeks respectively (p=0.268) with median follow up of 59, 81, and 64 weeks. 10 patients received locally ablative radiotherapy for oligoprogressive disease (defined as ≤ 3 progressive sites) and continued osimertinib post-progression with median PFS2 of 49 weeks.
Conclusion
There is utility to repeat biopsy after progression on osimertinib as targetable oncogenes can be found. Presence of TP53 prior to starting osimertinib did not influence PFS1. Continuing osimertinib and adding radiotherapy for oligoprogressive disease does increase post-progression PFS.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-27 - Duration of Targeted Therapy in Advanced NSCLC (aNSCLC) with Drivers Identified by Circulating Tumor DNA (ctDNA) Analysis (ID 953)
09:45 - 18:00 | Author(s): Tejas Patil
- Abstract
Background
Identifying targetable genomic drivers is critical for optimal first-line treatment planning in aNSCLC. ctDNA testing can aid treatment selection when tissue specimens are inadequate for complete genotyping or when a rapid turnaround time is advantageous. Targeted therapy (TT) outcomes for ctDNA-detected drivers have not been widely reported in the first-line setting given the relatively recent adoption of this technology into clinical practice.
Method
We conducted a multicenter retrospective review of patients with aNSCLC who received matched TT following identification of a driver on a validated commercial ctDNA assay (Guardant360). Eligible patients were tested per regular clinical care between March 2014-October 2018 and must not have received a TT prior to ctDNA testing (prior chemotherapy or immunotherapy was permitted). Kaplan-Meier analysis was used to estimate median duration of TT (DTT) for both the first and all subsequent sequential targeted therapies where applicable (e.g. osimertinib following erlotinib). Patients still on TT were censored at last follow-up.
Result
76 patients met inclusion criteria. Median age of diagnosis of aNSCLC was 64.5 years (range 31-87y), 67% were female, 74% were never smokers, and 97% had adenocarcinoma histology. 21/76 (28%) patients received chemotherapy (n=17), immunotherapy (5), and/or a biologic (4) prior to receiving TT. 41/76 (54%) patients remain on TT at the time of data analysis, 32 of whom are still on their first TT. 38/41 patients still on TT have at least 6 months follow-up. Treatment outcomes are summarized in Table 1.
Table 1. Duration of Targeted Therapy
Driver
Therapy
n, total patients/discontinued therapy
Median (95% CI) DTT in weeks1
EGFR
Erlotinib
Osimertinib
Afatinib
Gefitinib
Any EGFR TKI2
21 / 19
23 / 6
3 / 2
1 / 1
48 / 20
33 (23-54)
NR
3, 13, 93*
63
86 (48-197)
ALK fusion
Alectinib
Crizotinib
Any ALK TKI3
7 / 2
2 / 2
9 / 2
NR
20, 44
NR
BRAF V600E
Dabrafenib + Trametinib
10 / 7
51 (13-88)
MET exon 14 skipping
Crizotinib
Investigational
3 / 2
1 / 1
4, 77, 63*
14
ROS1 fusion
Investigational
2 / 1
50, 79*
ERBB2 exon 20 insertion
Ado-trastuzumab emtansine
2 / 1
46, 14*
RET fusion
Investigational
1 / 1
47
1 – individual data rather than median provided for counts <5
2 – includes 15 patients receiving sequential EGFR TKIs
3 – includes 3 patients receiving sequential ALK TKIs
* indicates therapy is ongoing for individual data points
Abbreviations: NR – not reached; TKI – tyrosine kinase inhibitor
Conclusion
This study provides interim data on targeted therapy outcomes for aNSCLC patients with Guardant360-detected drivers treated in everyday clinical practice. Outcomes are in line with what is expected for tissue-detected drivers in the TT naïve setting and this cohort will continue to be followed. Identification of NSCLC driver mutation using well-validated ctDNA assays can be used for clinical decision-making.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-06 - Detection of ctDNA and Correlation with Tumor Mutation Testing in Early Stage NSCLC (ID 2950)
10:15 - 18:15 | Author(s): Tejas Patil
- Abstract
Background
In advanced disease, circulating tumor (ctDNA) has proven a viable alternative to tissue based molecular testing to identify patients with lung adenocarcinoma (LUAD) eligible for targeted therapies. ctDNA is under investigation for utility in early cancer detection and non-invasive companion diagnostics to allow for identification of targetable biomarkers in patients who may benefit from neoadjuvant targeted therapy. However, in the early stage cancer setting, ctDNA has been limited by reliance on interrogation of genomic alterations alone resulting in low detection rates (13% stage I, 22% stage II, 40% stage III, Abbosh et al, Nature 2017). Herein, we test the ability of the novel ctDNA-based assay to detect ctDNA in patients with early stage LUAD, and secondarily, to identify targetable oncogenes in these patients.
Method
Eligible patients had stage IA-IIIA LUAD deemed surgically resectable. Following consent, plasma samples were collected prior to surgery or neoadjuvant therapy. Circulating free DNA (cfDNA) was analyzed for ctDNA with the LUNAR assay (Guardant Health), which utilizes an integrated genomic and epigenomic ctDNA assessment at a tumor allelic fraction down to 0.01% to report “ctDNA detected” or “ctDNA not detected”. This single blood sample cfDNA assay utilizes a variant filter to distinguish tumor from non-tumor derived cfDNA alterations in the absence of other genomic DNA (e.g. tissue sequencing or peripheral blood mononuclear cells). Molecular analysis of paired FFPE primary tumor specimens was performed using the Illumina TruSight Tumor 26 or ArcherDx VariantPlex Solid Tumor library preparation kits followed by next-generation sequencing (NGS) on the Illumina platform in a CLIA-certified laboratory. Sensitivity for tumor driver mutation detection is evaluated by comparing tumor drivers identified in ctDNA with those identified in corresponding paired primary tumor specimens.
Result
We enrolled 31 patients with early stage LUAD who ultimately underwent surgical resection, 29 of whom completed LUNAR testing (19 with stage I, 4 with stage II and 6 with stage IIIA). Analysis of tumor tissue identified a driver mutation in 83% (24/29) of cases (KRAS=11, EGFR=10, MET=3, ALK=1). A genomic cancer-associated mutation was identified in 16%, 25% and 67% in stage I, II, and III, respectively. The LUNAR assay demonstrated 100% specificity for EGFR and KRAS mutations. The incorporation of the epigenomic classifier enhanced pre-operative ctDNA detection to 26% of Stage I, 50% of stage II, and 67% of stage III patients.
Conclusion
The majority of patients with early stage LUAD had an identifiable oncogene alteration, consistent with data from advanced disease. Utilizing a plasma only, integrated genomic and epigenomic ctDNA assay demonstrated improved performance over tumor informed approaches. The ctDNA detection rate increased with disease stage, consistent with increased tumor burden. With 100% tissue concordance of EGFR and KRAS alterations identified in ctDNA, ctDNA may prove an option for not only identification of early stage LUAD, but also identifying biomarker positive LUAD eligible for clinical trials utilizing targeted therapy in the neoadjuvant setting.
