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F.R. Khuri



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    O03 - NSCLC - Targeted Therapies I (ID 113)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O03.01 - GALAXY-1: Randomized phase II study of docetaxel with or without ganetespib in advanced lung adenocarcinoma: Results in biomarker sub-groups and all adenocarcinoma patients. (ID 1715)

      10:30 - 10:40  |  Author(s): F.R. Khuri

      • Abstract
      • Presentation
      • Slides

      Background
      Ganetespib (G) is a highly potent 2[nd]-generation Hsp90 inhibitor showing synergistic activity with docetaxel (D) in NSCLC xenografts. G has a favorable clinical safety profile and has shown single-agent clinical activity in NSCLC patients with tumors harboring EML4-ALK translocations and KRAS mutations (mKRAS).

      Methods
      We conducted a randomized, international open-label Phase 2 study of D with or without G in patients with advanced lung adenocarcinoma, one prior systemic therapy, and ECOG PS 0/1. D was given at 75 mg/m[2] on Day 1 of a three-week cycle in both arms. In the combination arm, G was given at 150 mg/m[2] on Days 1 and 15. The co-primary endpoints were PFS in patients with elevated LDH (eLDH) levels, or tumors harboring KRAS mutation. Key secondary endpoints were OS and PFS in all adenocarcinoma patients. Target enrollment was 240 adenocarcinoma patients, including 120 eLDH and 80 mKRAS patients. The study was initiated in all NSCLC patients and amended to include only those with adenocarcinoma histology.

      Results
      Enrollment of 252 adenocarcinoma patients completed in November 2012; enrollment of eLDH (total N=112) and mKRAS (total N= 86) patients completed in May 2013. In all adenocarcinoma patients (N=252), baseline characteristics were balanced between the two arms (median age 60 years, males 56%, PS 0 41% and never-smokers 25%). Median numbers of cycles delivered were 6 and 4 for D+G and D, respectively. Grade 3/4 adverse events for the D+G and D alone arms were: neutropenia 37% vs. 38%; fatigue 6% vs. 3%; anemia 8% vs. 2%; diarrhea 3% vs. 0; fever with neutropenia 11% vs. 2%. A pre-specified analysis was conducted in May 2013. PFS HR for eLDH population (N=76) was 0.88 (90% CI: 0.57, 1.36, p=0.310); OS HR was 0.63 (90% CI: 0.40, 0.99, p=0.046). PFS HR for mKRAS population (N=63) was 0.83 (90% CI: 0.51, 1.37, p=0.271); and OS HR was 0.85 (90% CI: 0.48, 1.50, p=0.313). OS HR in the all adenocarcinoma population was 0.82 (90% CI: 0.62, 1.09, p=0.082), and the PFS HR was 0.84 (90% CI: 0.65, 1.07, p=0.038). For patients that were enrolled >6 months after diagnosis of advanced NSCLC (N=176), a pre-specified stratification factor, the OS HR was 0.61 (90% CI: 0.43, 0.87, p=0.0093), and the PFS HR was 0.61 (90% CI: 0.45, 0.83, p=0.0041). Final data analysis is expected by end of September 2013. Updated PFS and OS results for all populations will be presented at the meeting.

      Conclusion
      Survival improvement was noted in all adenocarcinoma patients with the addition of ganetespib to docetaxel. The maximal benefit was achieved in patients with eLDH and those diagnosed with advanced NSCLC >6 months prior to study entry.

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    P1.12 - Poster Session 1 - NSCLC Early Stage (ID 203)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.12-017 - A phase IB preoperative pharmacokinetic and pharmacodynamic study of everolimus in operable non small cell lung cancer (ID 2365)

      09:30 - 09:30  |  Author(s): F.R. Khuri

      • Abstract

      Background
      We conducted this ‘window- of-opportunity’ study to characterize the biologic activity of everolimus, an allosteric inhibitor of mTOR pathway, in patients with surgically resectable NSCLC.

      Methods
      Patients with surgically resectable NSCLC (Stage I-III) underwent baseline tumor biopsy and FDG PET/CT scan followed by treatment with everolimus (5 or 10mg daily for up to 28 days). A repeat PET/CT scan was obtained 24 hours prior to surgery. Blood samples for pharmacokinetic (PK) assay for drug levels were collected at 0.5, 1, 2, 5, 8 and 24 hours post drug ingestion on Days 1, 8 and 21. Control patients not treated with everolimus also had paired FDG PET/CT scans prior to surgery. Pharmacodynamic (PD) effect of everolimus was assessed in vivo by PET and ex vivo by immunohistochemical detection of total and phosphorylated mTOR, Akt, S6, eIF4e and 4EBP1 in pretreatment and posttreatment tissue samples. Alterations in common driver mutations in NSCLC were assessed using SnapShot multiplex minisequencing technique. Statistical comparisons by T-Test, ANOVA, Wilcoxon signed rank test or Kruskal-Wallis test were performed as appropriate using SAS statistical package V9.3. The significance level was set at 0.05 for all tests.

      Results
      We enrolled 33 patients; 23 on everolimus and 10 on the control arm. Median age: 64 yrs (range 36-77), gender: (14/19 -M/F), stage (I - 14; II - 13; IIIA - 6); histology (adenocarcinoma - 22; squamous - 7; others - 4). Treatment was tolerated well with mostly grade 1/2 anticipated toxicities (hyperglycemia, hypertriglyceridemia, stomatitis, anemia and fatigue) and 32 of 33 patients proceeded with surgery on schedule. Compared to controls, there was significant reduction in SUVmax and median anatomic tumor size in a dose-dependent manner in everolimus-treated patients (15.38 vs. -21.74 vs. -23.23; p=0.012 and 4.39 vs. 0 vs.-13.33; p=0.039 in the control, 5mg and 10mg cohorts respectively). There was a similar trend in reduced metabolic activity in Ras mutant tumors treated with 10mg everolimus compared to control (88% vs. -28%). Comparison of baseline biopsy samples and resected tumor specimens in control and everolimus-treated patients showed reduction of S6 (-27.38 vs. 0 vs. -78.95; p=0.0536), pS6 (-20 vs. -29.17 vs. -57.14 ; p=0.0233) and p4EBP1 (-45.83 vs. 0 vs. -75; p=0.057) with greatest reduction observed in patients treated with higher dose of everolimus.

      Conclusion
      Everolimus exerts a measurable, dose-dependent biologic activity in NSCLC. ‘Window of opportunity’ studies in early stage NSCLC can provide strong mechanistic insights to guide optimal development of novel targeted agents.

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    PL03 - Presidential Symposium Including Top Rated Abstracts (ID 85)

    • Event: WCLC 2013
    • Type: Plenary Session
    • Track:
    • Presentations: 1
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      PL03.07 - Treatment with Therapies Matched to Oncogenic Drivers Improves Survival in Patients with Lung Cancers: Results from The Lung Cancer Mutation Consortium (LCMC) (ID 2444)

      09:21 - 09:33  |  Author(s): F.R. Khuri

      • Abstract
      • Slides

      Background
      Detecting and targeting the oncogenic drivers EGFR and ALK have transformed the care of patients with lung adenocarcinomas. The LCMC was established to use multiplexed assays to test tumors for alterations in 10 genes and provide the results to clinicians to select treatments and clinical trials matched to the driver detected.

      Methods
      Fourteen LCMC sites enrolled patients with metastatic lung adenocarcinomas and tested their tumors in CLIA laboratories for activating mutations in 10 oncogenic driver genes.

      Results
      Tumors were tested from 1,007 patients for at least one gene and 733 for all 10 genes. An oncogenic driver was found in 466 (64%) of fully-genotyped cases. Among these 733 tumors, drivers found were: KRAS 182 (25%), sensitizing EGFR 122 (17%), ALK rearrangements 57 (8%), “other” EGFR 29 (4%), two genes 24 (3%), HER2 19 (3%), BRAF 16 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (<1%), AKT1 0. For cases with any genotyping, we used results to select a targeted therapy or trial in 275 (28%). Among 938 patients with follow-up, the median survivals were 3.5 years for the 264 with an oncogenic driver treated with genotype-directed therapy, 2.4 years for the 318 with an oncogenic driver with no genotype-directed therapy, and 2.1 years for the 360 with no driver identified (p<0.0001).

      Conclusion
      Individuals with lung cancers with oncogenic drivers receiving a corresponding targeted agent lived longer than similar patients who did not. An actionable driver was detected in 64% of tumors from patients with lung adenocarcinomas; more than one was present in 3%. Multiplexed testing aided physicians in choosing therapies and targeted trials in 28% of patients. This paradigm for care and research will expand as genotyping becomes more efficient with Next-Gen platforms, additional drivers are identified (i.e.ROS1 and RET), and more targeted drugs become available in the pharmacy and through clinical trials. Supported by HSS NIH NCI 1RC2CA148394-01. Trial Registered with Clinicaltrials.gov: NCT01014286.

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