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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): M. Nilsson
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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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
P3.03-027 - LKB1 Loss Is Associated with Resistance to Anti-Angiogenic Therapy in Non-Small Cell Lung Cancer Mouse Models (ID 10259)
09:30 - 16:00 | Author(s): M. Nilsson
LKB1 is a protein kinase that is mutated and down-regulated in 20-30% of non-small cell lung cancer (NSCLC). LKB1 mutations co-occur with KRAS alterations in 7%-10% of NSCLC, resulting in an aggressive phenotype with short survival. Because LKB1 activates AMPK, the master sensor of cellular energy, many of the best known functions of LKB1 are attributed to its ability to control metabolic alterations in the cells. However LKB1 also plays an important role in regulating angiogenesis, likely as a strategy to overcome energetic depletion of tumor microenvironment. Bevacizumab, the human anti-VEGF antibody, improves the PFS and OS of NSCLC patients combined with chemotherapy, but often the benefit is transient and therapeutic resistance occurs. Our laboratory has previously identified alterations in cell metabolism and in vasculature of LKB1-deficient tumors when compared to LKB1 wild type in NSCLC.
LKB1 KO murine NSCLC cell lines were generated using CRISPR/Cas9 system in a KRAS[G12D] mutant background (LKR10 & LKR13). Syngeneic NSCLC models were established via s.c. injection of LKB1 intact and KO murine cells in immunocompetent mice. After tumors reached 150 mm mice were randomly assigned to treatment groups consisting of vehicle, mouse anti-VEGF and nintedanib. Tumor volumes were measured and compared using student’s t test and samples were collected for vasculature analysis. Survival curves will be calculated using log rank test. Hypoxia experiments were preformed and apoptosis was measured using annexin V and 7ADD staining.
Treatment with anti-VEGF or nintedanib significantly inhibited tumor progression in LKB1 wt KRAS[G12D] mutant mouse model (p<0.001) but did not show any therapeutic effect in the LKB1 KO KRAS[G12D] group. Furthermore in the LKB1 wt group, the median survival of anti-VEGF and nintedanib treated mice was 111 days and 84 days respectively and 37 days in the vehicle group. No improvement in survival was detected in the LKB1 KO group after treatment with anti-VEGF. In vitro studies showed that LKB1 loss is associated with a decrease in oxygen consumption and enhanced glycolysis. Furthermore LKB1 KO NSCLC cells showed a decrease in apoptosis under hypoxic and low nutrient conditions compared to LKR13 LKB1 wt cells.
NSCLC LKB1-deficient tumors showed resistance to anti-angiogenic therapy and this effect is driven by the regulation of metabolic adaptations that allow cells to survive under hypoxic and low nutrient conditions.