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J.R. Infante



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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)

      16:15 - 17:45  |  Author(s): J.R. Infante

      • 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)

      16:15 - 17:45  |  Author(s): J.R. Infante

      • 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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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-049 - TSR-011: A Potent Inhibitor of ALK Including Crizotinib-Resistant Mutations in Phase 1-2 Development for ALK+ NSCLC (ID 3466)

      09:30 - 16:30  |  Author(s): J.R. Infante

      • Abstract

      Background
      Significant progress has been made in the identification of subsets of non-small cell lung cancer (NSCLC) driven by tyrosine kinase gene fusions (including gene fusions of ALK, RET, ROS1 and NTRK1). Despite approval of crizotinib for ALK+ NSCLC there are still significant challenges and high unmet need to develop new agents with durable efficacy against these kinase gene fusions that initiate NSCLCs. In order to address limitations of crizotinib, and to provide treatment option with increased activity against crizotinib resistance mutations and amplified EML4-ALK, TSR-011, a potent, small molecule, second generation ALK inhibitor is undergoing clinical evaluation. TSR-011 was designed using X-ray structure based drug design, and hence has high affinity for the ALK kinase domain (Kd = 0.36 nanomolar, [nM]). TSR-011 inhibits wild type, recombinant ALK kinase activity with an IC50 value of 0.7 nM and exhibits sustained potent inhibition of EML4-ALK-dependent tumor growth in mice. ALK amplification and mutations that are important drivers of tumor cell growth or crizotinib resistance are inhibited by TSR-011 at low nM (IC50 values of 0.1 to 2.2 nM) concentrations. TSR-011 is a similarly potent inhibitor of recombinant TRK kinases including suppressing proliferation of a NTRK1-rearranged colorectal cancer cell line in vitro. Collectively, the selective and potent activity of TSR-011 against ALK, and clinically observed crizotinib resistance mutations, coupled with pharmacologic properties that predict a low clearance, minimal risk for drug interactions, wide distribution and long half life, make TSR-011 a promising 2[nd] generation ALK inhibitor.

      Methods
      A Phase 1-2a dose escalation and cohort expansion study is underway to evaluate safety, tolerability, PK, and preliminary efficacy of TSR-011. Phase 1 is evaluating unselected patients with advanced solid tumors and lymphomas. The recommended Phase 2 dose will be evaluated in Phase 2a in patients required to have ALK+ tumors (defined by immunohistochemistry or fluorescent in-situ hybridization) including those with NSCLC progressing on, or naïve to, ALK inhibitor therapy.

      Results
      As of June 2013, patients have been enrolled at oral doses between 30 and 480 mg. Pharmacokinetic parameters have been dose responsive and human drug exposures in excess of that associated with efficacy in murine xenograft models are maintained for the entire dosing interval. Two of the first five patients have SD. A patient with EML4-ALK+ NSCLC with metastatic pericardial thickening and symptomatic disease, who progressed on crizotinib showed clinical improvement in symptoms and thinning of the pericardium by 6 weeks of treatment and continues on study.

      Conclusion
      Based on tight binding to ALK, potency at inhibiting enzymatic activity, as well as activity against crizotinib resistant mutations and early clinical data, TSR-011 is a promising agent for both ALK-dependent and crizotinib resistant NSCLC.