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A.T. Le
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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 12.01 - 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.T. Le
- Abstract
- Presentation
Background:
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.
Method:
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).
Result:
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.
Conclusion:
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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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-057 - Comparison of Molecular Testing Modalities for Detection of ROS1 Rearrangements in a Cohort of Positive Patient Samples (ID 10110)
09:30 - 16:00 | Author(s): A.T. Le
- Abstract
Background:
Targeting oncogenic gene fusions with small molecules has proven to be a highly successful treatment strategy in lung cancer. For ALK and ROS1 rearrangement/fusion positive cases, fusion directed therapy is now considered standard of care for advanced disease. Consequently, the accurate clinical detection of rearrangements/fusions is of critical clinical importance. Multiple distinct methodologies are employed in the clinical setting for rearrangement/fusion detection. In this study, we compare the performance of several of these methodologies on a large cohort of ROS1 rearrangement/fusion-positive patient samples.
Method:
Eighteen ROS1 rearrangement/fusion-positive clinical samples were assessed by at least two of the following molecular testing methodologies: break-apart fluorescence in situ hybridization (FISH), DNA-based hybrid capture library preparation followed by next-generation sequencing (NGS), and RNA-based anchored multiplex PCR library preparation followed by NGS.
Result:
None of the testing methodologies demonstrated 100% sensitivity in detection of ROS1 rearrangements/fusions. FISH results were negative in 2/18 tested clinical samples. One of these demonstrated an atypical staining pattern, suggestive of a complex rearrangement. The other occurred in a case of GOPC-ROS1 fusion in which the genes are in close proximity on chromosome 6. The DNA-based NGS assay was negative in 3/11 tested clinical samples. This assay suffered from poor bait coverage in intronic regions containing repetitive sequences, and false negatives were likely due to this deficiency. The RNA-based NGS assay did not identify ROS1 fusions in 3/15 tested clinical samples. However, this assay is highly reliant on RNA quality, and missed calls were associated with metrics derived from the assay suggestive of degraded RNA (and thus the results would have been deemed uninformative). Additionally, we report cases in which the detected fusion at the transcript level (via RNA-based NGS) occurred between exons not predicted by proximal exons bordering the detected genomic breakpoint (via DNA-based NGS), likely due to exon removal via mRNA splicing. For these cases, the detected genomic DNA breakpoint may have resulted in a non-call due to the prediction of an out-of-frame fusion transcript.
Conclusion:
Rearrangement/fusion detection in the clinical setting is complex and all methodologies have inherent limitations that users must be aware of. Consequently, careful scrutiny of negative results must be performed, particularly in cases negative for other known oncogenic drivers (pan-negative cases). Ideally, orthogonal rearrangement/fusion testing methodologies should be employed for such cases.
