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K.R. Coombes



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    MO18 - NSCLC - Targeted Therapies IV (ID 116)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO18.06 - BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 1949)

      16:15 - 17:45  |  Author(s): K.R. Coombes

      • Abstract
      • Presentation
      • Slides

      Background
      Effective therapeutic strategies for mutant KRAS and other biomarkers of resistance in refractory NSCLC remain an unmet medical need, while a personalized medicine approach is increasingly adopted in NSCLC guided by tumor molecular profiling. The BATTLE-2 clinical study is using EGFR, PI3K/AKT and MEK inhibitors and is designed to identify biomarkers for optimal patient selection for these therapies (ClinicalTrials.gov NCT01248247).

      Methods
      This is a four-arm, open-label, multi-center, biopsy-driven, adaptive randomization, phase II clinical trial in NSCLC pts that failed at least 1 prior line of therapy. Patients are adaptively randomized to 4 arms: erlotinib, erlotinib plus the AKT inhibitor MK-2206, MK-2206 plus the MEK inhibitor selumetinib, and sorafenib. The primary objective is 8-week disease control rate (DCR). The trial is conducted in 2 stages. In Stage 1, 200 evaluable pts are adaptively randomized (AR) based on observed 8-week DCR and KRAS mutation status while predictive biomarkers are being developed by means of gene expression profiling, targeted next generation sequencing and protein expression. EGFR sensitizing mutations and EML4/ALK translocation in pts that are erlotinib and crizotinib naïve are exclusion criteria, while erlotinib resistant patients are excluded from erlotinib monotherapy. In Stage 2, the AR model is refined to include the most predictive biomarkers tested in Stage 1, with subsequent Stage 2 AR based on the new algorithm, to a total of 400 evaluable pts. Selection of Stage 2 single and/or composite markers follows a rigorous, internally and externally reviewed statistical analysis that follows a training, testing methodology with validation in stage 2 of the trial. All Stage 1 and 2 randomization biomarker assays are CLIA-certified.

      Results
      286 pts have been enrolled, 236 biopsies performed,172 pts randomized, and 167 pts treated. 144 pts are evaluable for the 8-week DCR endpoint. Within the randomized pts group KRAS mutation rate is 22.8%, and EGFR mutation rate 14.8%, while 36.3% patients have been previously treated with erlotinib. Treatment is well tolerated with no unanticipated toxicity.

      Conclusion
      Accrual updates, demographics, and further details will be presented at the meeting. (Supported by NCI R01CA155196-01A1)

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    MO20 - Preclinical Therapeutic Models II (ID 93)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO20.02 - Proteomic analysis identifies baseline PI3K/Akt pathway activation and treatment-induced supppression of mTOR signaling as determinants of response to MEK inhibition (ID 2845)

      10:30 - 12:00  |  Author(s): K.R. Coombes

      • Abstract
      • Presentation
      • Slides

      Background
      Inhibition of MEK is a promising treatment strategy for non-small cell lung cancer (NSCLC). MEK inhibitors are being investigated for KRAS mutant disease, but KRAS alone is not predictive of efficacy, and other predictors of response and resistance are not known. The downstream effects of MEK inhibition have not been fully described. Here, we report broad proteomic analysis of NSCLC cell lines before and after treatment with MEK inhibitor BAY86-9766.

      Methods
      We treated 109 NSCLC cell lines with BAY86-9766. Drug sensitivity was determined by CellTiter-Glo assay and cell lines were classified as sensitive or resistant based on whether their IC50 values were in the highest or lowest 1/3[rd] of those tested. Proteomic analysis for regular and phospho-proteins was performed by reverse phase protein array. Using paired t-tests, we compared pre- versus post-treatment protein levels in the overall group and between the sensitive vs. resistant cell lines.

      Results
      Increased activation of the PI3 kinase pathway at baseline correlated with resistance to MEK inhibition, with resistant cell lines showing higher baseline levels of pAkt (S437), pAkt (T308), pPDK1, and p4E-BP1 (S65), and lower baseline levels of PTEN (all p<0.05). Cell lines with increased MEK phosphorylation at baseline were more sensitive to MEK inhibition (p=0.048). BAY86-9766 was very effective at reducing pERK (p=1.65x10[-35]) but this modulation was not significantly different between sensitive and resistant cell lines (p=0.64). Increased phosphorylation of MEK was seen with treatment (1.66x10[-16]). mTOR signaling was suppressed by MEK inhibition, with decreased phospho-p70S6K, pS6 (S235/236), and pS6 (S240/S244) and increased eIF4E following treatment (all p<0.02). These effects were significantly more pronounced in sensitive vs resistant cell lines (all p<0.01). Higher levels of LKB1 total protein, pAMPK, and pTSC2 were also seen following treatment (all p<0.02).

      Conclusion
      We have performed broad proteomic analysis of NSCLC cell lines treated with MEK inhibitor BAY86-9766. Baseline activation of the PI3K/Akt pathway predicts for resistance to MEK inhibition. Sensitive cell lines, but not resistant cell lines, show suppression of mTOR activity with treatment with BAY86-9766. The effects of MEK inhibition of mTOR may be modulated by p90RSK through an LKB1 dependent pathway. This suggests a basis for combining targeted agents to overcome resistance, such as combinations of MEK inhibitors with PI3K inhibitors or mTOR inhibitors.

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