Virtual Library
Start Your Search
S. Viteri
Author of
-
+
Poster Display session (Friday) (ID 65)
- Event: ELCC 2018
- Type: Poster Display session
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 4/13/2018, 12:30 - 13:00, Hall 1
-
+
198TiP - Afatinib plus EGF pathway targeting immunization (EGF-PTI) as first line therapy for EGFR mutant NSCLC: The EPICAL study (ID 332)
12:30 - 13:00 | Author(s): S. Viteri
- Abstract
Background:
EGF-PTI elicits an antibody response against EGF and suppresses EGFR signaling. It is a vaccine with autologous humanized recombinant EGF conjugated with recombinant P64K protein of Neisseria meningitides. We previously showed signal transducer and activator of transcription 3 (STAT3) activation as a mechanism of innate resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR mutant (EGFR+) NSCLC1,2. Anti-EGF antibodies block STAT3 activation in EGFR+ cells alone and in combination with EGFR TKIs. They also delay the emergence of resistance to afatinib in vitro3. Sera from patients immunized with EGF-PTI block the EGF-induced EGFR and ERK phosphorylation in serum starved cells. Based on the above data we designed the first phase Ib study to evaluate the safety and efficacy of afatinib plus EGF-PTI as 1st line therapy for metastatic EGFR+ NSCLC patients (NTC….).
Trial design:
This is a multicenter open-label exploratory phase Ib clinical study in Spain and Colombia. Thirty metastatic EGFR+ NSCLC patients will receive treatment with afatinib 40 mg daily plus EGF PTI. EGF PTI will be administered (4 injections, 4.8 mL) on day 1, 14, 28, 43 and 92 (immunization phase) and every 3 months (2 injections, 2.4 mL) (maintenance phase). Treatment will continue until disease progression, intolerable adverse events, consent withdrawal or noncompliance with the study protocol. The primary objective of the study is to evaluate the safety and tolerability of the combination. Secondary objectives include overall response rate, progression free survival, overall survival, time to treatment failure, duration of response and disease control rate. A pre-specified secondary objective of the study is to unravel the molecular mechanisms underlying the potential efficacy of afatinib plus EGF-PTI. To this end, EGFR, ERK, AKT and STAT3 phosphorylation levels will be longitudinally evaluated in EGF-stimulated serum starved cells treated with sera from the patients. Longitudinal blood analyses of EGFR mutations and the expression of a panel of possible predictive biomarkers in the baseline tissue will be also performed.
Clinical trial identification:
EudraCT number: 2017-003237-28
Legal entity responsible for the study:
Pangaea Oncology.
Funding:
Bioven
Disclosure:
All authors have declared no conflicts of interest.
-
+
58P - Co-treatment of trametinib (MEK inhibitor) with TPX-0005 (Src/FAK/JAK2 inhibitor) synergistic in KRAS mutant NSCLC cell lines and CDCP1 acts as a biomarker in KRAS mutant patients (p) (ID 407)
12:30 - 13:00 | Author(s): S. Viteri
- Abstract
Background:
KRAS mutant lung adenocarcinoma has a dismal prognosis. In the current study, we identified combination targets for trametinib, a MEK inhibitor, which acts downstream of KRAS to suppress signaling through MAPK cascade. However, we have previously shown that selumetinib (MEK inhibitor) in KRAS mutant NSCLC cells caused a rebound of ERK, AKT and STAT3, as well as YAP phosphorylation (Y357), NOTCH3 and activation of RTKs, AXL and MET. We hypothesize that, in KRAS mutant NSCLC, suppression of MAPK could lead to activation of Src-YAP1-AXL-MET. Since CUB domain-containing protein 1 (CDCP1) activates Src, we consider that CDCP1 could be a biomarker of Src activation.
Methods:
Cell viability assay, colony formation assay and western blotting were performed to assess the treatment of trametinib plus TPX-0005 in a panel of 8 NSCLC cell lines: A549, Calu6, H23, H460, H2009, H2030, H441, H727. Synergy between trametinib and TPX-0005 was assessed via the Chou-Talalay method to estimate the combination index (CI). CI values <0.7 were considered synergistic, with decreasing CI values indicating greater synergy. We examined tumor samples of 32 KRAS mutant NSCLC p for CDCP1 mRNA levels.
Results:
The combination of trametinib with TPX-0005 was synergistic or additive in all cell lines tested. H23 and Calu6 were the most synergistic, followed by H441 and H2030. In the majority of cell lines examined, the colony formation assay resulted in an almost complete abrogation of tumor cell colonies, particularly in the H23 and A549. Western blotting indicated that the combination of trametinib with TPX-0005 abolished the phosphorylation of STAT3 (Y705), paxillin (Y118), a readout of FAK, and Src (Y416). The median PFS of 32 KRAS mutant NSCLC p was 2.5 months and the overall survival was 13.4 months. According to CDCP1 levels, the median PFS was 3.5 months for those with low CDCP1 and 1.4 months for those with high CDCP1 (P = 0.012). The median survival was 16.3 months for p with low CDCP1, and only 3.2 months for those with high CDCP1 (P = 0.023).
Conclusions:
The combination of trametinib plus TPX-0005 shows significant in-vitro activity in the majority of KRAS mutant NSCLC cell lines and the mRNA levels of CDCP1 could be a biomarker in KRAS mutant NSCLC p, indicating the activation of Src-YAP signaling. Clinical trials with the combination of MEK inhibitors with TPX-0005 are warranted.
Clinical trial identification:
Legal entity responsible for the study:
IGTP, Germans Trias i Pujol Research Institute, Badalona, Barcelona, Spain
Funding:
Fundació Obra Social “La Caixa”
Disclosure:
All authors have declared no conflicts of interest.
