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Zofia Piotrowska
Author of
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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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P1.01-89 - A Multicenter Phase 1/2a Trial of CLN-081 in NSCLC with EGFR Exon 20 Insertion Mutations (ID 488)
09:45 - 18:00 | Presenting Author(s): Zofia Piotrowska
- Abstract
Background
First and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are largely ineffective against EGFR exon 20 insertion mutations (ins20) and, while several novel agents targeting EGFR ins20 are in development (poziotinib, TAK-788), preliminary reports suggest that EGFR-related adverse events are common and may limit long-term efficacy (Heymach, WCLC 2018, Neal WCLC 2018). Targeted therapies which are safe and effective in patients with EGFR ins20 are needed. CLN-081 (also known as TAS-6417) is a novel, orally available EGFR TKI that selectively inhibits ins20 mutant EGFRs (Mol Cancer Ther 2018; 17:1648). In a cell-based assay using genetically engineered cell lines, CLN-081 potently inhibited intracellular phosphorylation of a wide spectrum of ins20 mutant EGFRs. The selectivity for mutant over wild type EGFR (WT/mut ratio) ranged from 4 to 134-fold depending on the specific mutation, representing an unprecedented level of mutant specificity.
Method
This is an adaptive phase 1/2a trial evaluating CLN-081 as monotherapy in advanced non-small cell lung cancer (NSCLC) harboring EGFR ins20. Dose escalation will proceed initially according to an accelerated titration (AT) design, converting to a rolling six (R6) design based upon pre-specified safety criteria. Cohort expansion in Phase 1 can occur at one or more doses where responses are observed in R6 cohorts. Transition from Phase 1 into Phase 2a is based upon a Simon-Two Stage design. The starting dose will be 60mg. Once daily and twice daily dosing will be explored. Approximately 90 patients will be enrolled. Eligible patients will have advanced, exon 20 insertion mutation positive NSCLC, and at least one prior platinum containing treatment regimen. EGFR ins20 will be identified based on local testing (tissue or plasma). Patients who have discontinued a previous EGFR TKI due to progressive disease will be allowed in AT dose escalation cohorts but will be excluded from R6, and the Phase 1 and 2a expansion cohorts. The primary objectives in Phase 1 are to demonstrate safety and determine the maximum tolerated dose. Secondary Phase 1 objectives include evaluation of PK and preliminary efficacy. The primary objectives in Phase 2a are to define the recommended phase 2 dose and evaluate the overall response rate. The secondary Phase 2a objectives include additional measures of response and confirmation of CLN-081’s safety profile.
Result
Section not applicable
Conclusion
Section not applicable
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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): Zofia Piotrowska
- 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
Section not applicable
Conclusion
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