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K. Kelly



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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): K. Kelly

      • 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): K. Kelly

      • 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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    MO20 - Preclinical Therapeutic Models II (ID 93)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO20.04 - Divergent activity of afatinib (AFAT) and cetuximab (CET) in patient-derived xenograft (PDX) models of acquired erlotinib resistance. (ID 1458)

      10:45 - 10:50  |  Author(s): K. Kelly

      • Abstract
      • Presentation
      • Slides

      Background
      The combination of AFAT and CET has demonstrated remarkable clinical activity in patients with acquired resistance to erlotinib. Preclinical modeling in genetically engineered mice and cell lines predicted activity in cases where erlotinib resistance was mediated by the EGFR T790M gatekeeper mutation. However, in the clinic, patients lacking T790M-positive tumors showed equivalent benefit from this combination, suggesting alternative mechanisms of synergy. We explored the individual and combined molecular and growth inhibitory activity of these agents in PDX models derived from NSCLC patient tumors with distinct mechanisms of acquired resistance to erlotinib. These models were developed by the UC Davis - Jackson Laboratories Consortium, which has xenotransplanted over 170 NSCLC models using the nod/scid/IL2Rgamma chain-null (NSG) mouse.

      Methods
      EGFR-mutant PDX models LG0703 (T790M-negative) and LG1049 (T790M-positive) were established from tumor biopsies from patients who progressed following durable responses to erlotinib. Both patients were subsequently treated with AFAT+CET, with the LG0703 donor patient exhibiting a prolonged response and the LG1049 donor patient exhibiting a transient response followed by rapid progression. Excised tumors from passage 1 PDXs were fragmented and implanted into treatment cohorts. When tumors reached 300mm[3], mice were randomized to erlotinib (50 mg/kg qd po), AFAT (20 mg/kg qd po), CET (10 mg/kg twice weekly iv), AFAT-CET, or vehicle control (n per arm = 12) for 3 weeks followed by a 75-day monitoring period. In a parallel cohort, tumor pharmacodynamic changes in signal transduction mediators and RTKs were assessed after 6 and 24h treatment exposures using kinase arrays (R&D systems) and immunoblotting.

      Results
      In LG0703, AFAT, CET and AFAT-CET resulted in complete tumor response (CR) during the 21-day treatment period. After cessation of treatment, mice treated with CET or AFAT-CET remained in complete remission; whereas AFAT-treated mice progressed within 2 weeks. Clinical activity in this model was associated with complete blockade of EGFR and Her2 phosphorylation. Substantial down-regulation of AKT1, AKT2, ERK1, p38a, RSK1 and p70S6K phosphorylation was evident within 6h of treatment. In contrast, the T790M-postive LG1049 model demonstrated only modest clinical benefit from AFAT, with no single-agent CET activity, and no CET-mediated synergy with AFAT. No treatments were able to ablate EGFR phosphorylation or downstream signal transduction, and compensatory induction of EGFR, HER2, ERK1 and p38 were noted after 24h of drug exposure.

      Conclusion
      In these PDX models derived from patients with EGFR-activating mutant cancer with acquired resistance to erlotinib, treatment with AFAT+CET recapitulated the clinical experience of the donor patients receiving this combination. In the LG0703 model, both the AFAT-CET combination as well as single-agent CET resulted in complete tumor regression associated with total ablation of EGFR phosphorylation and subsequent blockade of multiple signal transduction pathways. In the LG1049 model, AFAT prompted limited but statistically significant tumor delay, with no additional benefit from CET. These experiments demonstrate the considerable potential of this PDX resource to assess therapeutic strategies in models representing individual patients. Supported by BJALCF.

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