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Santiago Viteri
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.13-01 - Anti-EGF Antibodies Increase the Effect of ALK and MEK Inhibitors in ALK and KRAS NSCLC and CRC Cell Lines (ID 13160)
16:45 - 18:00 | Author(s): Santiago Viteri
- Abstract
Background
Immunization against Epidermal Growth Factor (EGF) has demonstrated efficacy in a phase III trial including unselected NSCLC patients, and we have recently shown that antibodies generated by vaccination (anti-EGF VacAbs) potentiate the effects of TKIs in EGFR-mut cells growing in vitro. In this study, we aimed to determine if anti-EGF VacAbs show antitumor activity in KRAS-mutant (mut) and Anaplastic Lymphoma Kinase (ALK) translocated non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) cells, alone or in combination.
a9ded1e5ce5d75814730bb4caaf49419 Method
Anti-EGF VacAbs were generated in rabbits. Cell lines were treated with anti-EGF VacAbs alone and in combination with ALK TKIs, trametinib and standard chemotherapeutic agents in ALK translocated (H3122, E13;A20 (v1) and H2228, E6;A20 (v3)) and lung (A549 and H23) and colon (DLD1 and LS174T) KRAS-mut cell lines. Cell viability was analyzed by MTT, changes of total and phosphorylated proteins by Western blot and emergence of resistance by direct microscopic examination in low density cultures.
4c3880bb027f159e801041b1021e88e8 Result
Anti-EGF VacAbs suppressed EGF-induced cell proliferation and inhibited EGFR phosphorylation signaling in all cell lines tested. In combination, the anti-EGF VacAbs significantly enhanced the antitumor activity of alectinib and crizotinib in H2228 cells and trametinib in A549, H23 and DLD1 cells. In these cell lines, the antibodies decreased Erk ½ and Akt phosphorylation. Finally, the addition of the anti-EGF VacAbs to the culture medium significantly delayed the emergence of resistant clones to alectinib and crizotinib in H2228 cells. In previous experiments, H2228 cells had shown a stronger dependency on the EGF/EGFR pathway than H3122. Results for the combination with standard chemotherapy in KRAS-mut cell lines will be presented at the meeting.
8eea62084ca7e541d918e823422bd82e Conclusion
Anti-EGF VacAbs decreased cell proliferation and inhibited EGFR activation in lung and colon ALK translocated and KRAS-mut cell lines. In addition, they potentiated the effects of trametinib in KRAS-mut cells and TKIs in ALK translocated cells (v3), where they also prevented the emergence of resistance to alectinib and crizotinib. Two clinical trials are currently testing anti-EGF vaccination in advanced NSCLC; the Epical Phase I/II trial, in combination with EGFR TKIs in EGFR-mut patients; and the BV-NSCLC-002 Phase III trial, in combination with chemotherapy in EGFR-wt.
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P2.03 - Biology (Not CME Accredited Session) (ID 952)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.03-02 - Cell-Free DNA (cfDNA) Testing in Lung Adenocarcinoma (LUAC) Patients: Spanish Lung Liquid Versus Invasive Biopsy Program (SLLIP) (ID 12561)
16:45 - 18:00 | Author(s): Santiago Viteri
- Abstract
Background
Liquid biopsies are a revolution in cancer diagnostics as a minimally invasive alternative to tissue biopsy. cfDNA is used for the detection of biomarkers in LUAC patients if a tumor tissue sample is not available. We conducted the SLLIP study to prospectively validate Guardant360 for the detection of 7 targetable activating alterations (EGFR, ALK, ROS1, BRAF, MET, RET, and ERBB2) in LUAC.
a9ded1e5ce5d75814730bb4caaf49419 Method
Blood samples from treatment-naïve stage IIIB-IV LUAC patients were analyzed using Guardant360, a next-generation sequencing panel covering 73 genes. The assay includes complete exon sequencing for 19 cancer genes, sequencing of critical exons in 54 genes, and detection of amplifications (18 genes), fusions (6 genes), and indels (23 genes) with high overall clinical sensitivity rates (85%) and ultra-high specificity (>99.9%). Indels and point mutations can be detected at a mutant allele fraction as low as 0.1%. Guardant360 was compared with tissue genotyping performed as standard of care, using a variety of “real life” techniques. The primary objective was to demonstrate the non-inferiority of Guardant360 versus tissue analysis for the detection of the 7 genetic alterations. The study is registered with ClinicalTrials.gov, number NCT03248089.
4c3880bb027f159e801041b1021e88e8 Result
186 LUAC patients were enrolled over a period of 11 months (August 2016-July 2017). Median age 64, 65% male, 72% smoker/ex-smokers, 85% ECOG performance status 0-1. Targetable activating alterations were detected by the Guardant360 assay and by tissue analysis in 25% (n=47) and 26% (n=49) of patients, respectively (non-inferiority P=0.268). Thirty patients (16%) had alterations identified by both modalities. None of the 186 patients was successfully tested in tissue for all 7 alterations. Of the 17 patients who were negative in tissue but for whom Guardant360 identified targetable alterations, 3 had BRAF V600E mutations. For none of these patients was BRAF tested in tissue. Clinical efficacy per biomarker and treatment modality are awaited.
8eea62084ca7e541d918e823422bd82e Conclusion
Guardant360 cfDNA and tissue analysis detect relevant somatic tumor alterations at similar rates in LUAC patients. Under-genotyping in tissue is common but can be mitigated by the use of cfDNA next generation sequencing assays.
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P2.03-15 - Integrin-Linked Kinase (ILK), Protein Tyrosine Phosphatase SHP2 and B lymphoma Mo-MLV Insertion Region 1 Homolog (Bmi-1) in EGFR-Mutant NSCLC (ID 12557)
16:45 - 18:00 | Author(s): Santiago Viteri
- Abstract
Background
The clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is jeopardized by the activation of multiple signaling pathways. ILK regulates the expression of Bmi-1, a well-known epithelial mesenchymal transition-inducing transcription factor. SHP2 function is required for MAPK pathway activation, and also plays a role in receptor tyrosine kinase signaling pathways.
a9ded1e5ce5d75814730bb4caaf49419 Method
Clinical data were assessed in accordance with the protocol approved by the institutional review board and de-identified for patient confidentiality. Pretreatment tumor specimens from advanced EGFR-mutant NSCLC patients (pts) were collected from eight sites in Spain, France, Italy and Colombia. mRNA gene expression analysis was performed by TaqMan (qRT-PCR). We examined the mRNA levels of ILK, SHP2 and Bmi-1.
4c3880bb027f159e801041b1021e88e8 Result
With a median follow-up of 26.7 months, median progression-free survival (PFS) was 9.3 (95% CI, 7.6-14.2) and 15.7 months (95%CI, 12.3-30.1) for pts with high and low ILK mRNA, respectively (P=0.0002), (HR for disease progression, 2.4; 95% CI, 1.3-4.5; P=0.002). Median PFS was 11.4 (95% CI, 8.2-14) and 24.1 months (95% CI, 8.2-30.9) for pts with high and low SHP2 mRNA, respectively (P=0.009), (HR, 2.4; 95% CI, 1.2-4.7; P=0.01). Median PFS was 8.2 (95% CI, 4.8-13.1) and 24.1 months (95% CI, 14.2-36.5) for pts with high and low SHP2 mRNA, respectively (P=0.001), (HR, 2.9; 95% CI, 1.4-5.9; P=0.002). Median overall survival (OS) was 17.9 (95% CI, 13.2-33) and 34.4 months (95% CI, 18.5-44.2) for pts with high and low ILK mRNA, respectively (P=0.200), (HR, 1.5; 95% CI, 0.79-3; P=0.200). Median OS was 18.5 (95% CI, 14-33) and 36.7 months (95% CI, 16.7-47.1) for pts with high and low SHP2 mRNA, respectively (P=0.018), (HR, 2.5; 95% CI, 1.1-5.8; P=0.020). Median OS was 17.6 (95% CI, 8.6-39.1) and 36.7 months (95% CI, 19.1-64.1) for pts with high and low Bmi-1 mRNA, respectively (P=0.004), (HR, 2.2; 95% CI, 1.0-5.1; P=0.040).
8eea62084ca7e541d918e823422bd82e Conclusion
The disturbance of RTKs, including ILK-SHP2-Bmi-1 axis, occurs frequently in EGFR mutant NSCLC patients, significantly limiting the PFS and OS. The levels of ILK, SHP2 and Bmi-1 could be predictive for upfront combinatory therapy of EGFR TKI plus a MAPK pathway inhibitor (SHP2 or MEK inhibitors).
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