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OA 12 - Emerging Genomic Targets (ID 679)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
OA 12.01 - The Preclinical and Clinical Activity of Poziotinib, a Potent, Selective Inhibitor of EGFR Exon 20 Mutant NSCLC (ID 10369)
11:00 - 12:30 | Author(s): A. Truini
Approximately 10% of EGFR mutant NSCLCs have an insertion/mutation in exon 20 of EGFR resulting in primary resistance to currently available tyrosine kinase inhibitors (TKIs). We previously reported that the structural features of poziotinib could potentially enable it to circumvent the steric hindrance induced by exon 20 mutations. Here we further characterize the preclinical activity of poziotinib and report on initial clinical activity of poziotinib in patients with EGFR exon 20 mutations from an ongoing phase II study.
We evaluated poziotinib activity in vitro using human NSCLC cell lines and the BAF3 model as well as several patient-derived xenograft (PDX) models and genetically engineered mouse models (GEMMs) of exon 20 insertion. We launched a phase 2 investigator-initiated trial of poziotinib in patients with metastatic NSCLC with EGFR exon 20 insertions (NCT03066206).
In vitro poziotinib was approximately 100x more potent than osimertinib and 40x more potent than afatinib against a common panel of EGFR exon 20 insertions. Furthermore, it had ~65-fold greater potency against common exon 20 insertions compared with EGFR T790M mutations; 3[rd] generation inhibitors osimertinib, EGF816, and rociletinib were all significantly less potent for exon 20 mutations/insertions compared with T790M. in vivo poziotinib led to >85% reduction in tumor burden in GEM models of EGFR exon 20 insertion (D770insNPG) NSCLC and the PDX model LU0387 (H773insNPH). To date, 8 platinum-refractory patients with EGFR exon 20 insertion mutation metastatic NSCLC have been enrolled in the clinical trial and treated with poziotinib at a dose of 16 mg PO daily. Two patients have reached the first interval-imaging time point (at 8 weeks of therapy per protocol). Both patients exhibited dramatic partial response, with one patient reporting improvement in dyspnea and cough at one week of therapy. In this early stage of the study, one case of grade 3 paronchycia was observed. One additional platinum- and erlotinib-refractory patient with EGFR exon 20 insertion was treated with poziotinib on compassionate basis. The patient achieved partial response after three weeks of treatment.
Poziotinib has selective activity against EGFR exon 20 mutations and potent activity in cell lines, PDX, and GEM models. Three platinum-refractory patients with EGFR exon 20 mutations have been treated thus far and are evaluable for response; all three had partial responses at the time of the initial scan. Updated data from the ongoing phase 2 clinical trial of poziotinib will be presented at the meeting.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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 - 16:00 | Author(s): A. Truini
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.
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.
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.
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.