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V.G.R. Peddareddigari



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    MO18 - NSCLC - Targeted Therapies IV (ID 116)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 2
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      MO18.10 - Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with pemetrexed in a phase 1/1B trial involving <em>KRAS</em>-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): efficacy and biomarker results (ID 2922)

      17:10 - 17:15  |  Author(s): V.G.R. Peddareddigari

      • Abstract
      • Presentation
      • Slides

      Background
      KRAS is the most frequently mutated oncogene in NSCLC and represents an unmet need for targeted therapy. Trametinib plus pemetrexed enhances growth inhibition and apoptosis of NSCLC cell lines with and without RAS/RAF mutations in vitro when compared with either agent alone.

      Methods
      This 2-part, multi-arm, open-label phase 1/1B study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase 2 dose (RP2D) for trametinib (1.5 mg daily) and pemetrexed (500 mg/m[2] every 3 weeks) in patients with advanced solid tumors. In part 2, patients with NSCLC were stratified as KRAS WT or KRAS-mutant and treated at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Next-generation sequencing was used to perform exploratory mutational profiling on available archival tissue from 21 patients (50%). Plasma from 38 patients (90%) was analyzed both for tumor-derived mutations in cell-free DNA (eg, KRAS, EGFR) using BEAMing technology as well as cytokine and angiogenic factors using a Searchlight multiplex assay.

      Results
      A total of 42 patients with NSCLC (19 KRAS WT [79% ≥ 2 prior therapies; 74% prior pemetrexed; 16% squamous] and 23 KRAS-mutant [57% ≥ 2 prior therapies; 43% prior pemetrexed; 4% squamous]) were enrolled and treated at the RP2D until disease progression or unacceptable toxicity. Safety and PK data were previously reported (ASCO 2013). Response rate was 17% and disease control rate was 69% for the whole population of NSCLC. Of note, we observed disease control in 75% of patients previously treated with pemetrexed (including 4 partial responses [PRs]) and in 2 patients out of 4 with squamous histology (including one PR). Progression-free survival (PFS) was 5.1 months for all patients with NSCLC. Detailed efficacy results according to mutation status are shown in Table 1. Among KRAS WT, activity was seen in cancers with EGFR mutations or ALK rearrangement. Final biomarker analyses, including assessment of their potential correlation with therapeutic response or resistance, are ongoing and will be reported upon completion. Figure 1

      Conclusion
      MEK inhibition with trametinib + pemetrexed demonstrated activity in both KRAS-mutant and WT NSCLC; efficacy data are encouraging and warrant further study. There was no significant difference in activity or efficacy across KRAS mutation subtypes. Interestingly, activity with this combination was broad and was seen in patients with squamous histology, patients with prior pemetrexed treatment, and those with EGFR mutation or ALK translocation.

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      MO18.11 - Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with docetaxel in a phase 1/1B trial involving <em>KRAS</em>-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): efficacy and biomarker results (ID 2411)

      17:15 - 17:20  |  Author(s): V.G.R. Peddareddigari

      • Abstract
      • Presentation
      • Slides

      Background
      KRAS is the most frequently mutated oncogene in NSCLC and represents an unmet need for targeted therapy. Trametinib enhances docetaxel-induced growth inhibition and apoptosis of NSCLC cell lines. Cell lines with the KRAS G12C point mutation, the most common KRAS mutation subtype (≈50% of KRAS-mutant NSCLC or ≈10% of all NSCLC), are more responsive to apoptosis induced by this combination.

      Methods
      This 2-part, multi-arm, open-label phase 1/1B study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase 2 dose (RP2D) for trametinib (2.0 mg daily) and docetaxel (75 mg/m[2] every 3 weeks) in the presence of growth factors in patients with advanced solid tumors. In part 2, patients with NSCLC were stratified as KRAS WT or KRAS-mutant and treated at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Next-generation sequencing was used to perform exploratory mutational profiling on available archival tissue from 17 patients (36%). Plasma from 42 patients (89%) was analyzed both for tumor-derived mutations in cell-free DNA (eg, KRAS, EGFR) using BEAMing technology as well as cytokine and angiogenic factors using a Searchlight multiplex assay.

      Results
      A total of 47 patients with NSCLC (22 KRAS WT [64% ≥2 prior therapies; 27% squamous] and 25 KRAS-mutant [40% ≥2 prior therapies; 0% squamous]) were enrolled and treated at the RP2D until disease progression or unacceptable toxicity. Safety and PK data were previously reported (ASCO 2013). Progression-free survival (PFS) was 4.2 months for all patients; efficacy results according to mutation status are shown in Table 1. Among KRAS-mutant patients, activity and efficacy were better in G12C compared with non-G12C subtypes. Among KRAS WT, activity was seen in cancers with EGFR mutations; clinical benefit was noted in 2 patients with ALK translocation (disease control 25 weeks and 60+ weeks). Final biomarker analyses, including assessment of their potential correlation with therapeutic response or resistance, are ongoing and will be reported upon completion. Figure 1

      Conclusion
      MEK inhibition with trametinib + docetaxel (+ growth factors) demonstrated activity in both KRAS-mutant and WT NSCLC; efficacy data are encouraging and warrant further study. Cancers carrying the KRAS G12C point mutation may have improved activity and efficacy compared with non-G12C subtypes, consistent with preclinical observations. Additionally, clinical benefit with this combination was broad and was seen in patients with squamous histology and those with EGFR mutation or ALK translocation.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-040 - Circulating cytokines and angiogenic factors (CAFs) as markers of clinical response in a randomized phase II study of trametinib vs docetaxel for patients with KRAS-mutant non-small cell lung cancer (NSCLC) (MEK114653, NCT01362296) (ID 2880)

      09:30 - 09:30  |  Author(s): V.G.R. Peddareddigari

      • Abstract

      Background
      Trametinib is a reversible and highly selective allosteric inhibitor of MEK1/MEK2. In a 2:1 randomized, open-label phase 2 study, trametinib showed an overall response rate of 12% but did not show improvement in progression-free survival (PFS) over docetaxel as second-line treatment in patients with KRAS-mutant NSCLC. Median overall survival (OS) was 8 months in the trametinib arm and has not been reached in the docetaxel arm (ASCO 2013 abstract #8029). Several CAF markers were identified as prognostic and predictive of clinical benefit in patients with renal cell carcinoma (Tran, Lancet 2012), and of tumor shrinkage in patients with NSCLC (Nikolinakos, Cancer Research 2010), after receiving targeted therapy.

      Methods
      Of 134 patients randomized, plasma samples (n = 116 baseline [113 KRAS-mutant], n = 89 day 22) from patients who consented for this optional study were analyzed for 38 CAFs using SearchLight multiplex assays in a CLIA-certified laboratory. Baseline CAF levels were tested for association with PFS using proportional hazards regression within and between arms. Correlation between baseline CAFs and baseline tumor burden was assessed using the Spearman rank correlation test. Change from baseline was assessed using Wilcoxon signed rank tests. P < .01 was considered significant; for treatment arm by CAF-level interaction, P < 0.05 was considered significant.

      Results
      Lower baseline levels of IL-6 and OPN and higher baseline levels of TRAIL were associated with longer PFS in patients treated with trametinib but not those treated with docetaxel. Interaction between CAFs and trametinib or docetaxel treatment was significant for IGFBP-1, MMP-9, E-selectin, and VEGF. There was a positive correlation between IL-6 levels and baseline tumor burden. At day 22, decreases (trametinib: ANG-2, IGF-1, IGFBP-3, IL-10, IL-2R, TIMP-1; docetaxel: IL-6, MIP-1A, MIP-1B, SDF-1) and increases (trametinib: IGFBP-1, IL-6, MMP-2, PIGF, VEGF) in CAF levels were observed. Additional results (pairwise correlation, CAF levels and OS, change from baseline CAF levels and PFS and OS) will be reported.

      Conclusion
      Circulating baseline CAF levels may be predictive of PFS for patients treated with trametinib or docetaxel. CAF levels are modulated by each treatment. The impact of circulating baseline CAFs on PFS warrants additional investigation in well-designed clinical trials. Plasma CAF profiling may aid in the prognostic evaluation of patients and determine potential therapeutic response to trametinib treatment in patients with NSCLC.