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O08 - Preclinical Therapeutic Models I (ID 92)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Biology
- Presentations: 1
- Moderators:C. Mascaux, R. Natale
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside Auditorium A, Level 1
O08.07 - Patient-derived primary non-small cell lung carcinoma (NSCLC) xenograft models for mechanistic studies of resistance to EGFR tyrosine kinase inhibitor therapy (ID 2380)
16:15 - 17:45 | Author(s): L. Kim
Non-small cell lung cancer (NSCLC) patients with tumors bearing “driver” mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain have very high response rates to small molecule EGFR TK inhibitors (TKIs). However, all patients eventually develop resistance to the TKIs, and more recent reports have shown that patients who have stopped TKI therapy may be sensitive again upon re-treatment. While several genetic mechanisms of resistance have been documented, including the gate keeper T790M mutation and Met amplification, cell line studies in vitro have also implicated alternate epigenetic mechanisms that may explain the clinical progression observed in patients with EGFR mutations treated by TKIs. Studies in vivo using patient-derived primary lung tumor xenograft models have not been reported.
Patient-derived primary tumor xenografts were established from surgically resected early stage NSCLC implanted subcutaneously in non-obese diabetic severe combined immune deficient (NOD-SCID) mice. Tumors were passaged after reaching the humane endpoint 1.5 cm maximum diameter. EGFR TKI therapy was initiated when tumors reached ~6 mm diameter. Treatment included daily oral gavage for erlotinib (50 mg/Kg) and dacomitinib (3 mg/Kg). Cetuximab was administered weekly intraperitoneally (50 mg/Kg).
Among 33 tumors with EGFR mutations engrafted into the mice, only 6 (18.2 %) formed tumors that could be propagated beyond first passage. Three models have been studied for their responses to EGFR TKIs. Model 148 with L858R mutation showed intrinsic pan-resistance to erlotinib and dacomitinib, as well as to cetuximab. This model was derived from a patient who received pre-operative erlotinib in a window of opportunity trial and did not respond. The patient relapsed after surgery and did not receive additional TKI therapy. Model 137 with exon19 E746-A750 deletion mutation demonstrated complete response to both erlotinib and dacomitinib. However, microscopic examination of tissue from the implantation site revealed viable tumor cells, consistent with the inability of TKI to completely eradicate tumor cells even when complete response is observed clinically. The patient subsequently developed disease recurrence and responded to third line gefitinib treatment. Model 164 has double exon19 L747-T751 deletion/T790M mutations. As anticipated, the xenograft failed to respond to erlotinib but responded dramatically to cetuximab alone. Importantly, model 164 xenograft showed transient stabilization of the tumor growth when treated by dacomitinib, but eventually developed progressive growth after 2 weeks of treatment. Resistance was reversible each time the dacomitinib-resistant tumor was propagated, without drug in new mice. The reversibility of resistance observed upon re-initiation of dacomitinib treatment suggests an epigenetic mechanism for TKI resistance. This patient developed recurrence after surgery and failed to respond to second line erlotinib treatment.
Patient-derived primary lung cancer xenografts may provide important patient-like models to study mechanisms of resistance to targeted therapies, and to test novel treatment strategies that may improve further treatment efficacy.
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P3.12 - Poster Session 3 - NSCLC Early Stage (ID 206)
- Event: WCLC 2013
- Type: Poster Session
- Track: Medical Oncology
- Presentations: 1
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
P3.12-015 - Surgery for Early Non-Small Cell Lung Cancer with Preoperative Erlotinib (SELECT): A Correlative Biomarker Study (ID 2529)
09:30 - 16:30 | Author(s): L. Kim
Erlotinib has demonstrated major activity in EGFR mutation positive NSCLC, but may also benefit those with wild type tumours. We conducted a single-arm trial of pre-operative erlotinib in early stage NSCLC to assess radiologic and functional response as well as correlation with known and investigational biomarkers.
Patients with clinical stage IA-IIB NSCLC received erlotinib 150 mg daily for 4 weeks followed by surgical resection. Tumor response was assessed using pre- and post-treatment CT and PET imaging. Tumor genotype was established using Sequenom MassARRAY analysis. EGFR, PTEN, cMET and AXL expression levels were determined by immunohistochemistry. Pre- and post-treatment circulating markers/ligands for EGFR activation (TGF-α, amphiregulin, epiregulin, EGFR ECD) were measured by ELISA. Tumor MET copy number by FISH and VeriStrat® analysis of pre-treatment serum samples is ongoing. Secondary endpoints included pathological response, toxicity and progression-free survival.
Twenty-five patients were enrolled; 22 received erlotinib treatment with a median follow up of 4.4 years (range 2.2 to 6.4 years). Histology was predominantly adenocarcinoma (15) with smaller numbers of squamous cell carcinoma (7). PET response (25% SUV reduction) was observed in 2 patients (9%), both with confirmed squamous carcinoma histology. All patients met criteria for stable disease by RECIST and several experienced minor radiographic regression with histologic findings of fibrosis/necrosis, including 2 with squamous histology. The presence of an EGFR activating mutation was detected in two adenocarcinoma cases; one patient experienced minor radiographic response to treatment (exon 19 deletion) and the other stable disease (L858R). High pre-treatment serum levels of TGF- α correlated with tumor growth or primary resistance to erlotinib therapy (p=0.04), whereas high post-treatment soluble EGFR levels correlated with tumor response (p=0.02). Expression of EGFR, PTEN, cMET and AXL did not correlate significantly with tumor response.
Erlotinib appears to demonstrate some activity in EGFR wild-type tumors including those with squamous histology. These findings support that certain EGFR wild-type patients may respond to EGFR TKIs. Further research is needed to characterize these patients and elucidate the predictive ability of potential biomarkers such as TGF- α, EGFR copy number and others.