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David R. Gandara
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MA 02 - Emerging Targets (ID 656)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Ravi Salgia, Shun Lu
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 511 + 512
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MA 02.11 - A Phase I Trial of Erlotinib and Onalespib in EGFR-mutant NSCLC: Focus on EGFR Exon 20 Insertions (ID 9046)
12:10 - 12:15 | Author(s): David R. Gandara
- Abstract
- Presentation
Background:
Onalespib (AT13387) is a non-ansamycin small molecule that inhibits heat shock protein-90 (Hsp90). Hsp90 inhibitors (Hsp90i) preferentially degrade overexpressed and mutated oncoproteins including those that mediate resistance to EGFR-TKIs. Previous Hsp90i studies demonstrated activity in EGFR-mutant NSCLC including EGFR Exon 20 insertions (EGFRex20ins) - uncommon EGFR mutations typically refractory to 1[st] and 2[nd] generation EGFR-TKIs. A phase I study of onalespib plus erlotinib was conducted to determine the MTD, DLT, RP2D, pharmacokinetics (PK) and preliminary antitumor activity for a planned phase 2 trial in EGFR-mutant NSCLC including EGFRex20ins.
Method:
Using a 3 + 3, dose escalation design, onalespib was examined at 2 dose levels (DL) from 150 (DL0) to 120 (DL-1) mg/m[2] IV weekly (D1, D8, D15 on a q28 day cycle). Daily erlotinib was given at 150 mg at both DL. Key eligibility: NSCLC with EGFR activating mutation including EGFRex20ins, age ≥ 18, ECOG PS≤2, acceptable organ function, and ≥1 systemic therapy for advanced disease (platinum-based chemotherapy for EGFRex20ins and EGFR-TKI for other EGFR-mutations). Plasma for PK and ctDNA for next-generation sequencing of ~70 cancer related genes was collected at relevant timepoints.
Result:
9 pts have been treated on 2 DL (3 DL0, 6 DL-1). Pt characteristics: median age 65, M/F (2/7), ECOG PS 0-1 (4/5), EGFRex20ins (8), EGFR E19del (1). 7 pts completed ≥1 cycle. Two DLTs (grade (Gr) 3 maculopapular rash and Gr 3 hypophosphatemia) occurred in DL0. Common drug-related adverse events (AE) of any Gr were diarrhea (100%) and rash (44%), fatigue (55%), increased bilirubin (22%), nausea (44%) and vomiting (33%). Drug-related Gr 3 AEs were diarrhea (55%), maculopapular rash (11%) and hypophosphatemia (11%). At the planned 2-month evaluation, 5 pts had SD, 3 PD, and 1 had withdrawn for toxicity. Of the 5 pts continuing, 2 had SD and 1 PD at the 4-month evaluation. Kaplan-Meier estimate on therapy without progression at the second evaluation is 30% (95% CI: 10 to 87%).
Conclusion:
In patients with EGFR-mutant NSCLC, onalespib plus erlotinib is feasible, tolerable and demonstrates disease control in EGFRex20ins, thereby addressing a key unmet need in NSCLC. The RP2D is erlotinib 150 mg PO daily and onalespib 120 mg/m[2] weekly (D1, D8, D15 q28days). Diarrhea was the most common AE, and generally manageable with supportive care and dose reduction to DL-1. Updated results including PK as well as ctDNA for EGFR-mutation and relevant bypass tracts mediating EGFR-TKI resistance will be presented.
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.09 - Pre-Existing Immunity Measured by Teff Gene Expression in Tumor Tissue is Associated with Atezolizumad Efficacy in NSCLC (ID 10759)
16:35 - 16:40 | Author(s): David R. Gandara
- Abstract
- Presentation
Background:
Association between T-effector (Teff) gene expression (GE), a marker of pre-existing immunity, and OS benefit with atezolizumab (anti–PD-L1) was demonstrated in the Phase II study POPLAR of atezolizumab vs docetaxel in 2L+ NSCLC. We analyzed Teff GE association with atezolizumab efficacy in a larger Phase III study, OAK.
Method:
Patients with 2L+ NSCLC were randomized to receive atezolizumab or docetaxel. Teff signature was defined by 3 genes (PD-L1, CXCL9, and IFNγ), and Teff GE was measured by averaging the normalized expression of each gene. Teff GE subgroups were defined by quartiles. PD-L1 expression was assessed using the SP142 IHC assay; the TC1/2/3 or IC1/2/3 subgroup had ≥ 1% PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC).
Result:
753 of 850 patients from the OAK primary analysis constituted the biomarker evaluable population (BEP) for Teff GE. Expression of the Teff signature was associated with PD-L1 expression by IHC (P = 7.3×10[−45]). Although no significant PFS benefit with atezolizumab vs docetaxel was observed in the BEP (HR, 0.94 [95% CI: 0.81, 1.10]) or the TC1/2/3 or IC1/2/3 subgroup (HR, 0.93 [95% CI: 0.76, 1.15]), a gradient of improved PFS benefit with atezolizumab was observed with increasing Teff GE. Significant PFS benefit occurred with ≥ median Teff GE cutoff (HR, 0.73 [95% CI: 0.58, 0.91]; Table). Teff GE also enriched for improved OS; however, a trend toward OS benefit was still observed in patients with low Teff GE (Table).Table. PFS and OS with atezolizumab vs docetaxel by PD-L1 IHC and Teff GE subgroups PFS, HR (95% CI) OS, HR (95% CI) OAK primary population (N = 850)[a] ITT[a] 0.95 (0.82, 1.10) 0.73 (0.62, 0.87) TC1/2/3 or IC1/2/3[a ](n = 463) 0.91 (0.74, 1.12) 0.74 (0.58, 0.93) TC2/3 or IC2/3[a] (n = 265) 0.76 (0.58, 0.99) 0.67 (0.49, 0.90) OAK BEP for Teff GE (N = 753) BEP 0.94 (0.81, 1.10) 0.71 (0.59, 0.85) TC1/2/3 or IC1/2/3 (n = 420) 0.93 (0.76, 1.15) 0.74 (0.58, 0.95) Teff GE subgroups ≥ 25% (n = 570) 0.91 (0.76, 1.09) 0.67 (0.54, 0.83) < 25% (n = 183) 1.11 (0.82, 1.49) 0.87 (0.63, 1.21) ≥ 50% (n = 379) 0.73 (0.58, 0.91) 0.59 (0.46, 0.76) < 50% (n = 374) 1.30 (1.05, 1.61) 0.87 (0.68, 1.11) ≥ 75% (n = 190) 0.66 (0.48, 0.91) 0.60 (0.42, 0.87) < 75% (n = 563) 1.10 (0.92, 1.31) 0.76 (0.62, 0.92) [a]Rittmeyer A. et al. Lancet, 2017;389:255-265. NCT02008227.
Conclusion:
This is the first demonstration of the association between markers of Teff biology and clinical outcomes with cancer immunotherapy in a randomized Phase III trial. Teff GE may reflect pre-existing immunity and be a more sensitive biomarker compared with PD-L1 IHC, identifying more patients (50% prevalence) likely to experience PFS benefit with atezolizumab.
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MA 07 - ALK, ROS and HER2 (ID 673)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Robert C. Doebele, J.C. Ho
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 316
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MA 07.14 - Change in Practice Patterns from an Online NSCLC Treatment Decision Support Tool (ID 11066)
17:10 - 17:15 | Presenting Author(s): David R. Gandara
- Abstract
- Presentation
Abstract not provided
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MA 13 - New Insights of Diagnosis and Update of Treatment (ID 674)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:S. Ishikura, H. Nakayama
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 311 + 312
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MA 13.02 - Comprehensive Genetic Analysis Related to PD-L1 Expression in Early-stage Lung Squamous Cell Carcinoma (ID 9077)
15:50 - 15:55 | Author(s): David R. Gandara
- Abstract
- Presentation
Background:
Recently, anti PD-1/PD-L1 immunotherapies have yielded promising outcomes in advanced squamous NSCLC. Several studies have suggested that tumor PD-L1 protein expression status might correlate with outcome and response to treatment. The aim of this study is to identify mRNA gene signatures and microRNAs associated with tumor PD-L1 expression in early-stage lung squamous cell carcinoma (SCC).
Method:
Early stage (I-II) SCC resected patient tumors were collected from 6 cancer centers as part of the SPECS II program. Gene expression profiling was performed on the specimens. PD-L1 protein expression was evaluated by immunohistochemistry on SCC FFPE tissue using the Dako 22C3 PD-L1 antibody. The tumor proportion score (TPS) for PD-L1 protein expression was compared with comprehensive clinicopathological, mRNA and miRNA data.
Result:
The prevalence of PD-L1 expression in this cohort of 255 Stage I-II SCC patients was 46.7% with a TPS cutoff of ≥ 1%, and 9.8% with a cutoff of ≥ 50%. Among 202 cases with available clinical and expression data, no significant association was observed between PD-L1 expression and clinical outcome. We identified a 12-gene signature from mRNA microarray using the Minimax Concave Penalty (MCP) regression method with an AUC of 0.92 at ≥ 5% TPS cutoff. A subset of 138 miRNAs was shown to be significantly differentially expressed between PD-L1 positive and PD-L1 negative groups at false discovery rate (FDR) of 0.05 with TPS cutoffs of ≥ 1%, ≥ 5% and ≥ 10%. No miRNAs were found to be significantly differentially expressed between the groups using a TPS cutoff of ≥ 50%. Gene Set Enrichment Analysis (GSEA) identified two pathways with gene sets that were significantly enriched (FDR < 0.05) in the PD-L1 negative group. No significant association was found between tumor mutation burden and PD-L1 expression level.
Conclusion:
PD-L1 expression prevalence is lower in early-stage lung SCC than in advanced NSCLC. No significant association was found between PD-L1 expression and prognosis in this cohort. Both mRNA gene signatures and miRNAs were identified to be predictive of PD-L1 expression. Through GSEA, two distinct gene sets were identified with expression correlated to PD-L1, one comprising genes related to ovary and another related to collagens and extracellular matrix (ECM). No significant association was found between tumor mutation burden and PD-L1 expression level. Following validation, these predictive signatures could be used to select patients with positive PD-L1 expression who may benefit from immunotherapy.
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MS 05 - Clinical Issues of Immune Checkpoint Inhibitors (ID 527)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Luis E Raez, Nico Van Zandwijk
- Coordinates: 10/16/2017, 15:45 - 17:30, Main Hall
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MS 05.05 - Continuation of Immunotherapy in Post-Progressive Disease (ID 7661)
16:45 - 17:00 | Presenting Author(s): David R. Gandara
- Abstract
- Presentation
Abstract not provided
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OA 12 - Emerging Genomic Targets (ID 679)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:H. Akita, Maurice Pérol
- Coordinates: 10/18/2017, 11:00 - 12:30, F203 + F204 (Annex Hall)
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OA 12.05 - Spectrum of 1,014 Somatic BRAF Alterations Detected in Cell-Free DNA of Patients with Advanced Non-Small Cell Lung Cancer (ID 9984)
11:40 - 11:50 | Author(s): David R. Gandara
- Abstract
- Presentation
Background:
Somatic BRAF V600E is a National Comprehensive Cancer Network clinical therapeutic target in non-small cell lung cancer (NSCLC), occurring in 6% of tumors from patients with lung adenocarcinoma. However, approximately half of BRAF alterations are non-V600E that do not respond to FDA-approved vemurafenib or dabrafenib. Emerging evidence suggests some non-V600E mutations exhibit clinical response to novel therapeutic agents. We analyzed the landscape of BRAF mutations in a very large cohort of patients with NSCLC who underwent somatic genomic testing utilizing a CLIA-certified/CAP-accredited/NYSDOH-approved 73 gene cell-free circulating tumor DNA (cfDNA) panel which evaluates single nucleotide variants, and selected indels, fusions, and copy number amplifications.
Method:
The Guardant Health laboratory database was queried for cfDNA tests from patients with a diagnosis of NSCLC where a BRAF variant was identified. Literature was queried for a description of the known function of non-V600E BRAF mutations on serine-threonine kinase activity.
Result:
A total of 1,014 BRAF alterations were observed in 914 tests, with 234 unique alterations identified. The majority of variants were observed only once (75.6%; N=177). 43 alterations were synonymous and excluded from analysis. Plasma-detected BRAF amplification was the most common alteration, observed in 484 tests. Of the remaining variants, 33 of 190 had functional consequence reported in the literature (17.4%), 18 with gain of function or predicted gain of function, 13 with loss of function or predicted loss of function and 2 with no effect. BRAF V600E accounted for 51.1% of occurrences of variants with gain of function or predicted gain of function (N=95 occurrences). Recurrent (>10 occurrences) non-V600E gain of function mutations included G469A (13.4%; N=25 occurrences), K601E (8.0%: N = 15 occurrences), and N581S (7.0%; N=13 occurrences). Fourteen additional gain of function variants comprised the remaining 21% of occurrences. Recurrent loss of function BRAF mutations (>10 occurrences) included G466V and D594G.
Conclusion:
This is the largest reported cohort of somatic BRAF alterations in metastatic non-small cell lung cancer. Non-V600E alterations accounted for almost 50% of the gain of function variants. The spectrum of non-V600E alterations was consistent with reports from The Cancer Genome Atlas and prior published results from tissue genomic sequencing. The recurrent non-V600E variants identified in this cohort are emerging therapeutic targets with promising early clinical data. These findings advocate for more comprehensive BRAF genomic profiling and identification of patients eligible for clinical trials targeting these non-V600E classic mutations and demonstrate the ability of plasma-based cfDNA to detect these alterations.
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OA 14 - New Paradigms in Clinical Trials (ID 681)
- Event: WCLC 2017
- Type: Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Alex Adjei, Eun Kyung Cho
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 311 + 312
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OA 14.07 - Progress in Lung Squamous Cell Carcinoma from the Lung-MAP Master Protocol (S1400) Sub-Studies S1400A, S1400B, S1400C and S1400D (ID 9593)
12:05 - 12:15 | Author(s): David R. Gandara
- Abstract
- Presentation
Background:
Lung-MAP (S1400) is a master umbrella protocol designed to establish genomic screening for previously treated squamous cell lung cancer patients (SqCCA), and independently evaluate targeted therapies with matching biomarkers and alternative therapies (designated non-match therapy) in patients without putative markers. The protocol opened June 16, 2014 with four biomarker-driven sub-studies and one non-match sub-study.
Method:
Eligibility stipulated advanced SqCCA, progressing after at least one prior platinum-based chemotherapy, PS 0–2, and EGFR/ALK wild-type. Tumor samples were required and analyzed for gene alterations by FoundationOne NGS assay (Foundation Medicine). The original biomarker and non-match studies were: S1400B evaluating taselisib for PI3K mutations, S1400C evaluating palbociclib for cell cycle gene alterations (CCGA), S1400D evaluating AZD4547 for FGFR mutations, S1400E evaluating rilotumumab and erlotinib for c-MET positive tumors, and S1400A evaluating durvalumab in patients with no matching biomarkers. The original design included randomization to a control arm, but was amended to a single-arm phase 2 design. The primary endpoint for each modified sub-study was response.
Result:
As of June 16, 2017 all original sub-studies have been closed to accrual; 1298 patients registered to the screening component of the trial and 486 patients have registered to a sub-study. Two new sub-studies have been launched and are currently accruing. Details of the completed sub-studies are included in the table.Sub-study Final Accrual Biomarker prevalence/% of sub-study registrations Closure Date Response to investigational therapy N (%) Status S1400A (non-match) Total: 116 Durvalumab: 78 Docetaxel: 38 NA/59% 12/18/15 Docetaxel arm closed: 4/22/15 11 (16%) Administratively closed to enable activation of new non-match study. S1400B PI3K Total: 39 taselisib: 31 Docetaxel: 8 8%/9% 12/12/16 Docetaxel arm closed: 12/18/15 1 (4%) Closed at interim futility analysis. S1400C (CCGA+) Total: 54 Palbociclib: 37 Docetaxel: 17 19%/15% 09/01/16 Docetaxel arm closed: 12/18/15 2 (6%) Closed at interim futility analysis. S1400D (FGFR+) Total: 45 AZD4547: 35 Docetaxel: 10 16%/12% 10/31/16 Docetaxel arm closed: 12/18/15 2 (7%) Closed at interim futility analysis. S1400E (MET+) Total: 9 R+E: 4 E: 5 N/A (closed too early) 11/26/2014 N/A Closed d/t discontinuation of development of rilotumumab
Conclusion:
Lung-MAP as a master genomic screening protocol has demonstrated feasibility with respect to accrual and evaluation of targeted therapies in lower prevalence patient populations. This dynamic, centralized, single-IRB platform is well positioned to efficiently assess multiple novel therapeutics for advanced SqCCA patients.
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OA 17 - Immunotherapy II (ID 683)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yuichiro Ohe, Anne Tsao
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 301 + 302
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OA 17.07 - Long-Term Survival in Atezolizumab-Treated Patients with 2L+ NSCLC from Ph III Randomized OAK Study (ID 8663)
15:35 - 15:45 | Author(s): David R. Gandara
- Abstract
- Presentation
Background:
Atezolizumab (anti–PD-L1) inhibits PD-L1 binding to PD-1 and B7.1, restoring anti-cancer immunity. OAK, a Phase III study of atezolizumab vs docetaxel demonstrated superior OS of atezolizumab. The characteristics of the long-term survivors (LTS) in the OAK primary population (n = 850) are evaluated and describe the largest cohort of cancer immunotherapy-treated NSCLC LTS yet reported.
Method:
Patients received IV q3w atezolizumab (1200 mg) until PD / loss of clinical benefit or docetaxel (75 mg/m[2]) until PD / unacceptable toxicity. No crossover was allowed. LTS were defined as patients with OS ≥ 24 months and non-LTS as those who died within 24 months of randomization. Patients with OS censored prior to 24 months were not included. Data cutoff, January 23, 2017.
Result:
A higher 2-year survival rate was observed for the atezolizumab-arm (31%) vs docetaxel-arm (21%). After a minimum follow-up of 26 months, there were 119 LTS vs 279 non-LTS in the atezolizumab-arm and 77 LTS vs 299 non-LTS in the docetaxel-arm. Characteristics of atezolizumab-arm LTS and non-LTS are shown (Table). Atezolizumab-arm LTS were enriched for non-squamous histology and high PD-L1–expressing tumors, but also included low/no PD-L1–expressing tumors (40.3%). Atezolizumab-arm LTS had higher ORR (39.5%) than non-LTS (5.0%) but included LTS subjects with PD. 52.9% atezolizumab-arm vs 71.4% docetaxel-arm LTS received anti-cancer non-protocol therapy (NPT) after discontinuation of protocol-defined therapy. 51.9% of docetaxel-arm LTS vs 12.7% non-LTS received non-protocol immunotherapy. Median treatment exposure in atezolizumab-arm LTS was 18.0 months. Atezolizumab-arm LTS had a comparable safety profile to all atezolizumab-treated population.
Conclusion:
Atezolizumab provides superior 2-year OS benefit vs docetaxel and is well tolerated. The majority of docetaxel-arm LTS received a checkpoint inhibitor as NPT. Atezolizumab LTS appeared to have favorable prognostic factors, including non-squamous histology, but notably were not limited to patients with RECIST v1.1 response or with PD-L1 expression.Table. Characteristics of Atezolizumab-Arm Long-Term Survivors (LTS) vs Non-Long Term Survivors (Non-LTS) Atezolizumab LTS (n = 119) n (%) Atezolizumab Non-LTS (n = 279) n (%) Sex Male 61 (51.3) 183 (65.6) Female 58 (48.7) 96 (34.4) Tobacco use history Never smoker 29 (24.4) 47 (16.8) Current/previous smoker 90 (75.6) 232 (83.2) Histology Non-squamous 101 (84.9) 195 (69.9) Squamous 18 (15.1) 84 (30.1) No. of prior therapies, 1 89 (74.8) 209 (74.9) ECOG performance status at baseline 0 60 (50.4) 89 (31.9) 1 59 (49.6) 190 (68.1) EGFR mutation status, positive 11 (9.2) 26 (9.3) PD-L1 IHC subgroup TC3 or IC3 28 (23.5) 39 (14.0) TC1/2/3 or IC1/2/3 71 (59.7) 156 (55.9) TC0 and IC0 48 (40.3) 119 (42.7) Best overall response Complete response 5 (4.2) 0 (0) Partial response 42 (35.3) 14 (5.0) Stable disease 47 (39.5) 97 (34.8) Progressive disease 25 (21.0) 142 (50.9) IC, tumor-infiltrating immune cell; TC, tumor cell. TC3 or IC3 = PD-L1 ≥ 50% TC or 10% IC; TC1/2/3 or IC1/2/3 = PD-L1 ≥ 1% on TC or IC; TC0 and IC0 = PD-L1 < 1% on TC and IC. NCT02008227.
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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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P3.01-046 - Longitudinal Analysis of Plasma CtDNA in EGFR-Mutant NSCLC: SWOG S1403 Trial of Afatinib with or Without Cetuximab (ID 9535)
09:30 - 09:30 | Author(s): David R. Gandara
- Abstract
Background:
Detection of actionable mutations using circulating tumor DNA (ctDNA) isolated from patient plasma is now accepted as clinical practice in NSCLC. Nevertheless, the full extent to which longitudinal plasma analysis can be utilized to guide clinical decision-making has yet to be realized. We prospectively incorporated serial next-generation sequencing (NGS) of ctDNA into the ongoing SWOG S1403 clinical trial (NCT02438722) of afatinib+cetuximab vs afatinib in treatment-naïve NSCLC patients with EGFR-mutant tumors.
Method:
Time points for specimen collection were pre-treatment, after two months of therapy on Cycle 3 Day1 (C3D1) and at progression. Objectives were to: 1) determine the prognostic and predictive significance the EGFR mutant allele frequency (MAF) at each time point; 2) correlate changes in MAF over time with regard to patient outcome, and 3) identify putative emergent resistance mechanisms and companion mutations. Specimen analysis was conducted using the Guardant360 73-gene digital NGS panel.
Result:
To date, 53 patients with advanced EGFR-mutant NSCLC have contributed baseline samples. Of these, 46 had ctDNA detectable at baseline (87%). 39 of these 46 (85%) had detectable, tissue-identical EGFR mutations, for an overall EGFR detection rate of 74% (39/53). A positive finding for EGFR amplification (Amp) in plasma correlated with high ctDNA MAF: median for Amp 16.9 vs nonAmp 0.9 (range/n: 11.6-43.7/10 vs 0.11-7.7/17; p<0.0001). Of patients with detectable EGFR mutation at baseline, 27 had analyzable ctDNA collected at C3D1. Of these, 26/27 showed decreasing MAFs on-treatment (mean for baseline: 9.8 vs C3D1: 0.14; p<0.0001), with 20 cases having no detectable EGFR mutation at C3D1 (mean of 7 positives at C3D1: 0.55). At progression, samples were collected from 14 patients and 10 had EGFR mutations detectable, with T790M present in 3. Another patient had an FGFR3 fusion at PD, but no previous draws were available to determine if it was emergent.
Conclusion:
Longitudinal analysis of plasma ctDNA in S1403 patients demonstrated significant treatment-induced changes in mutation burden and identified resistance mechanisms at progression. EGFR gene amplification, as assessed in plasma, was significantly associated with increased ctDNA MAFs. Patients showed a significant, one-to-two orders of magnitude decline in EGFR MAF after two months of therapy, with 74% dropping below detectable levels. At progression, EGFR mutation detection rates increased, often concomitantly with a putative emergent resistance factor. Accrual to S1403 is ongoing and patient treatment and outcomes remain blinded. The prognostic and predictive utility of baseline and therapy-induced changes in ctDNA MAF kinetics will be determined at study unblinding.
