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F. Barlesi



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    Best of Posters - IASLC Selection - Part 2 (ID 263)

    • Event: WCLC 2013
    • Type: Exhibit Showcase Session
    • Track:
    • Presentations: 1
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      P2.11-024 - Efficacy Analysis for Molecular Subgroups in MARQUEE: a Randomized, Double-blind, Placebo-controlled, Phase 3 Trial of Tivantinib (ARQ 197) Plus Erlotinib versus Placebo plus Erlotinib in Previously Treated Patients with Locally Advanced or Metastatic, Non-squamous, Non- small Cell Lung Cancer (NSCLC) (ID 2909)

      09:55 - 10:25  |  Author(s): F. Barlesi

      • Abstract
      • Slides

      Background
      MARQUEE, a Phase 3 study which investigated the role of tivantinib, a c-MET inhibitor, in previously treated non-squamous NSCLC, collected EGFR and KRAS genotype on >90% of randomized patients, and MET expression was determined for 42%. In the ITT population, addition of tivantinib to erlotinib significantly improved PFS and ORR but did not show benefit in OS. Additional efficacy analyses in the pre-defined molecular subgroups are presented.

      Methods
      Patients with locally advanced or metastatic non-squamous, EGFR inhibitor naive NSCLC previously treated with 1 or 2 lines of systemic therapy, including a platinum-doublet, were stratified by number of prior therapies, sex, smoking history, and EGFR and KRAS mutation status, then randomized to oral tivantinib (360 mg twice daily) + erlotinib (150 mg once daily) or placebo + erlotinib until disease progression. Primary endpoint was OS with one interim analysis for futility/superiority. MET was assessed centrally by IHC using CONFIRM (SP44) antibody. Based upon a stability study, tumor tissue must have been sectioned within 90 days prior to MET immunostaining to be considered reliable. MET High was pre-specified as ≥50% of tumor cells staining with 2+ or 3+ intensity.

      Results
      From 1/2011 to 7/2012, 1048 patients were randomized to tivantinib + erlotinib (TE, n=526) or placebo + erlotinib (PE, n=522). Baseline characteristics were median age = 62 years (range, 24-89), prior therapies = 1 (66%) or 2 (34%), ECOG performance status = 0 (32%) or 1 (68%), EGFR mutant (10.4%), and KRAS mutant (27.1%). In 9/2012, the data monitoring committee recommended trial discontinuation because the pre-planned interim analysis of OS crossed the futility boundary. At the 12/2012 data cutoff, median OS was 8.5 months and 7.8 months for TE and PE, respectively (hazard ratio [HR] = 0.98; 95% CI, 0.84-1.15; p = 0.81). Median PFS was 3.6 months and 1.9 months, respectively (HR = 0.74; 95% CI, 0.62-0.89; p < 0.0001). Overall response rate (ORR) improved to 10.3% for TE compared with 6.5% for PE (p < 0.05). MET expression was obtained for 445 patients. In the pre-specified, MET High subgroup (n = 211), median OS improved to 9.3 months for TE vs 5.9 months for PE (HR = 0.70; 95% CI, 0.49-1.01; p = 0.03). In the MET Low subgroup (n = 234), median OS was 8.5 months for TE and 7.7 months for PE (HR=.90, 95% CI, 0.64-1.26, p=.53). OS did not differ between treatments in KRAS wildtype (n=702), KRAS mutant (n=284), and EGFR wildtype (n=937) subgroups; OS was immature for the EGFR mutant (n=109) subgroup at the cut-off time. Consistent with ITT, PFS was increased with TE vs PE across all molecular subgroups. Common adverse events (TE vs PE, respectively) included rash (33.1% vs 37.3%), diarrhea (34.6% vs 41.0%), and asthenia/fatigue (43.5% vs 38.1%), which occurred at similar rates between treatments; neutropenia (Grade 3/4: 10.0% vs 1.0%) was more common with TE.

      Conclusion
      Tivantinib significantly improved PFS and OS in the prospectively defined MET High subgroup. Further investigation of tivantinib in MET High selected, non-squamous NSCLC is warranted.

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    MO08 - NSCLC - Early Stage (ID 117)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO08.02 - Adjuvant pazopanib or placebo in resected stage I NSCLC patients: results of the NSCLC adjuvant randomized phase II trial (IFCT-0703) from the French collaborative Intergroup (ID 2274)

      16:15 - 17:45  |  Author(s): F. Barlesi

      • Abstract
      • Presentation
      • Slides

      Background
      Although UFT is approved in eastern countries, most guidelines do not recommend any adjuvant treatment in resected Stage I NSCLC. Pazopanib (P) is a potent, orally active multi-target receptor tyrosine kinase inhibitor of VEGFR-1, -2, -3, platelet derived growth factor (PDGFR) type-α and –β, approved in metastatic renal cell carcinoma and sarcoma. Neoadjuvant P demonstrated single-agent activity in patients with early stage NSCLC. We report the feasibility and tolerance of adjuvant P in stage I NSCLC.

      Methods
      In this double-blind randomized multicenter phase II/III trial, completely resected patients (pts) with stage I NSCLC (7[th] TNM edition) were randomized to receive either placebo or P 800 mg/d during 6 months. The Fleming’s two stage phase II primary endpoint was compliance (i.e. % of pts able to receive at least 3 months of P, whatever the dose). After 64 pts included (interim analysis), IDMC recommended to start with P 400 mg/d because of initial insufficient compliance. A one-step Fleming design was used with the new dose. Phase II design was not comparative.

      Results
      143 pts were randomized in 29 centers between March 2009 and August 2012, 71 and 72 in the placebo and P arms respectively. Most pts were male (61%) and smokers (91%), median age was 60. Pathological stage was IA in 111 pts (78%) and 16% were squamous cell carcinomas. Compliance for P800 was adequate in 38% (95% confidence interval [21-56]) vs. 87% [71-96] in placebo; for P400 in 69% [50-84] (p=0.01, compared to P800) vs. 93% [77-99] in placebo. Dose modifications were seen in 44% and 34% of P800 and P400 groups. The proportion of patient with at least one grade 3/4 toxicity was 53% [35-71] in P800 (13% [4-29] for placebo) and 38% [21-56] in P400 (27% [12-46] for placebo). No toxic deaths were observed. Only 2 pts has grade 4 toxicities in P800 (fatigue in P arm, GGT in the placebo arm). Most common toxicities G3 in P800 were diarrhea (9%), hypertension (9%), and increased transaminases (16% vs. 0% in P400); in P400 gastro-intestinal disorders (16%, 6% diarrhea) and hypertension (6%).

      Conclusion
      IFCT-0703 is the first feasibility study demonstrating that full dose of P is safe but not feasible in the adjuvant setting in NSCLC. Compliance and tolerance with reduced dose appeared acceptable for adjuvant settings.

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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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      MO18.10 - 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): F. Barlesi

      • 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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    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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      P1.11-037 - Phase II activity of the HSP90 inhibitor AUY922 in patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) (ID 2730)

      09:30 - 16:30  |  Author(s): F. Barlesi

      • Abstract

      Background
      AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor. HSP90 is a molecular chaperone of oncogenic client proteins relevant in NSCLC pathogenesis, including epidermal growth factor receptor (EGFR), which is mutated in 10% of NSCLC cases in the Western population, and in 30% of NSCLC cases in the Asian population. We report here a subgroup analysis of data from the 2 EGFR mutation strata of a Phase II study of AUY922 in patients with previously treated, advanced NSCLC stratified by molecular status.

      Methods
      Patients with advanced NSCLC who progressed following ≥1 prior line of therapy, received AUY922 (70 mg/m[2]) as a once-weekly, 1-hour infusion. Patients with EGFR-mutant NSCLC were divided into 2 strata: pretreated EGFR-mutant (>2 prior regimens), or less-heavily treated EGFR-mutant (≤2 prior regimens and documented response to an EGFR tyrosine kinase inhibitor [TKI]). The primary endpoint was confirmed response, stable disease at 18 weeks, or no clinical benefit. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety/tolerability.

      Results
      At the cut-off date of 14 March 2013, 66 patients with EGFR-mutant NSCLC had been treated (median age 58 years; 67% female; 94% adenocarcinoma; EGFR-initial stratum n=35; less-heavily pretreated EGFR-mutant stratum n=31); all patients had been pretreated with an EGFR TKI. Clinical activity of AUY922 was seen, with any responses (investigator assessed), in 12/66 (18.2%) patients. A total of 34/66 (51.5%) patients had a best overall response of stable disease or non-confirmed partial response; of these patients, 11 (32%) had stable disease for ≥18 weeks. The 18-week PFS rate was 39% in all patients with ≤2 prior lines of therapy (n=43), and 28% in all patients (n=21) who had received >2 lines of therapy. The most frequent adverse events (AEs; any grade, regardless of study drug relationship) were diarrhea (73%), nausea (47%), decreased appetite (38%), fatigue (35%), and headache and night blindness (both 29%). Most AEs were Grade 1 or 2; Grade 3 or 4 AEs included diarrhea (9%), and fatigue, decreased appetite, and hyponatremia (all 6%).

      Conclusion
      AUY922 had an acceptable safety profile. Strong evidence of clinical activity was demonstrated in EGFR TKI-pretreated patients with EGFR-mutant NSCLC. Median PFS, OS and biomarker data for the EGFR-mutant stratum will be presented.

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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P3.09-018 - IFCT-0803 Trial: a phase II study of cetuximab, pemetrexed, cisplatin and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non squamous, non-small cell lung cancer (NSCLC): preliminary safety analysis (ID 3281)

      09:30 - 16:30  |  Author(s): F. Barlesi

      • Abstract

      Background
      Cisplatin-based chemotherapy and concurrent radiotherapy are the standard treatments for locally advanced unresectable NSCLC. New therapeutic combinations using molecular targeted drugs are needed. IFCT-0803 Trial is a phase II study evaluating the benefit of adding cetuximab to a combination of concomitant radio-chemotherapy with cisplatin and pemetrexed in patients with stage III, non-squamous NSCLC. Data on safety and tolerance during the first 16 weeks of treatment, available after the inclusion of the first 62 eligible patients, are presented.

      Methods
      Based on a two-stage Simon approach, 106 patients will be included in IFCT-0803 trial. An interim analysis of the first 34 patients authorized the continuation of the study. Eligible patients receive conformal thoracic radiation with no elective nodal irradiation (66 Gy in 33 fractions, ICRU) along with cisplatin (75 mg/m[2]) and pemetrexed (500 mg/m[2]) on day 1 administered intravenously every 21 days for four cycles; weekly cetuximab (400 mg/m[2] for the first week, then 250 mg/m[2]) is added from the first week of therapy for a total of 12 doses. The primary objective is to assess the disease control rate at the 16[th] week, one month after treatment completion

      Results
      62 patients were included (37 male, 56 years mean age), PS 0 = 39 and PS 1 = 23, ever smoker = 57, stage IIIA = 31 and IIIB = 31, adenocarcinoma = 50. Compliance for the first 62 patients included was as follows: Day 1 chemotherapy was administered to 100% of patients on cycles 1 and 2, to 98.4% on cycle 3 and to 96.6% on cycle 4. Radiotherapy protocol was respected: median was 33 for number of fractions, 66 Gy for total dose, 46 days for duration of treatment, 39 patients had a maximal toxicity of grade 3 and 6 of grade 4. Table 1 lists the number of patients for the main categories of toxicity.

      n=62 grade 1/2 grade 3 grade 4
      anemia 32 4 0
      neutropenia 24 20 5
      thrombocytopenia 30 4 2*
      general toxicity 42 13 0
      skin toxicity 51 9 0
      digestive toxicity (nausea and vomiting) 42 6 0
      esophageal toxicity 43 10 0
      febrile neutropenia - 5 0
      renal toxicity 4 3 0
      neurologic toxicity 11 0 0
      * :One patient died consecutively to a subdural hematoma caused by a fall, he had a grade 4 thrombocytopenia

      Conclusion
      IFCT-0803 trial is ongoing, the end of the inclusions is scheduled for October 2013. This combination therapy is feasible without any unexpected side effects.