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Jonathan W. Riess
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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
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-46 - Response Assessment Using Plasma Cell-Free DNA (cfDNA) – When Is the Optimal Time to Assess Response? (ID 958)
09:45 - 18:00 | Author(s): Jonathan W. Riess
- Abstract
Background
Plasma cfDNA analysis is routine for non-invasive genotyping of advanced NSCLC, however response assessment using plasma cfDNA is not well characterized. We hypothesized that response in cfDNA would be an early process occurring well before routine imaging timepoints.
Method
We retrospectively analyzed a total of 48 baseline and serial on-treatment plasma samples collected from 16 patients enrolled across three Experimental Therapeutics Clinical Trials Network (ETCTN) phase I trials of osimertinib combinations in advanced EGFR-mutant NSCLC. For validation, we also retrospectively analyzed a total of 201 baseline and serial on-treatment samples from an institutional cohort of 67 advanced NSCLC patients receiving systemic treatment. Using droplet digital PCR (ddPCR) of key EGFR or KRAS driver mutations, plasma response was defined as any decrease in mutation concentration to below baseline levels. We compared the magnitude of initial (baseline to day 11-30) and subsequent (day 11-30 to day 36-84) plasma response. Finally, we prospectively assessed response using serial amplicon-based plasma next-generation sequencing (NGS) in a pilot cohort of 8 NSCLC patients starting systemic therapy.
Result
Of 15 ETCTN patients with any plasma response, best plasma response was seen at the initial response timepoint in 12 patients (80.0%) and ≥90% of the total plasma response was seen at the initial response timepoint in 14 patients (93.3%). In the validation cohort of 61 patients with any plasma response (Figure), best plasma response was seen at the initial response timepoint in 39 patients (63.9%) and ≥90% of the total plasma response was seen at the initial response timepoint in 52 patients (85.2%). Complete plasma responses (-100%) were seen as early as 11 days after initiating therapy. In the prospective clinical cohort, plasma NGS detected genomic alterations and enabled monitoring of changes in mutant allele fraction in all 8 patients. The median turnaround time of the assay was 8 days.
Conclusion
Plasma response is an early phenomenon, with the vast majority of plasma response seen within 30 days, and as early as 11 days. These findings suggest that early plasma cfDNA analysis may permit response assessment well before standard imaging timepoints, with potential as an early marker of drug effect. Additional investigation to understand the relationship between early plasma response, radiographic response, and durability of treatment effect is still needed.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-22 - ORCHARD: A Phase II Platform Study in Patients with Advanced NSCLC Who Have Progressed on First-Line Osimertinib Therapy (ID 1303)
10:15 - 18:15 | Author(s): Jonathan W. Riess
- Abstract
Background
Osimertinib is a third-generation, central nervous system (CNS)-active, irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitising mutations (EGFRm) and EGFR T790M. First-line osimertinib has demonstrated superiority in progression-free survival (PFS) compared with first-generation EGFR-TKIs in patients with EGFRm advanced NSCLC (Soria et al, NEJM 2018). The most common resistance mechanisms to first-line osimertinib identified from plasma samples are MET amplification (15%) and EGFR C797S (7%) (Ramalingam et al, Ann Oncol 2018). Further clinical studies are needed to better understand resistance mechanisms and evaluate post-progression targeted treatment options.
Method
ORCHARD is an open-label, multicentre, biomarker-directed, Phase II platform study evaluating the optimal treatment for individual patients with EGFRm NSCLC depending on their underlying resistance mechanism to first-line osimertinib.
Adult patients with EGFRm locally advanced/metastatic NSCLC and radiological progression on first-line osimertinib monotherapy will be eligible.
Treatment assignment will be based on molecular characterisation of the tumour at progression from a mandatory tissue biopsy.
ORCHARD will comprise of three groups assigned by tumour molecular profile (Figure). An adaptive design allows addition of new treatments based on emerging findings. Tumour assessments (RECIST 1.1) will be performed every 6 weeks for the first 24 weeks and every 9 weeks thereafter until progression. An interim analysis of each cohort will be performed when ≈16 patients have reached the second on-treatment RECIST assessment. Based on preliminary signals, the cohort may be stopped or expanded to 30–40 patients for further evaluation.
The primary outcome is investigator-assessed objective response rate; secondary outcomes include PFS, duration of response, overall survival, and pharmacokinetics of each treatment module, evaluated independently. Exploratory outcomes include tumour and plasma biomarker and resistance analyses, and correlation between biomarker profiles and treatment effect. Safety data will also be reported.
Result
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Conclusion
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