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A. Santoro



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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): A. Santoro

      • 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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    MO10 - Molecular Pathology II (ID 127)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO10.10 - Detection of RET fusions by FISH in unselected NSCLC (ID 2434)

      16:15 - 17:45  |  Author(s): A. Santoro

      • Abstract
      • Presentation
      • Slides

      Background
      Activation of the RET gene by fusion has been described in 1-2% of unselected population of non-small-cell lung cancer (NSCLC) and there is early evidence suggesting that patients with RET activated tumors obtain clinical benefit from RET inhibitors. The major fusion partner is KIF5B, but CCDC6, NCOA4 and TRIM33 have also been reported. The prevalence of RET fusions in different lung cancer subtypes and clinicopathologic characteristics of remain unclear. In this study, we sought to identify RET rearrangements in NSCLC using FISH and to investigate the association with histology and clinical features.

      Methods
      A 3-target, 3-color FISH probe set [3’RET in red, 5’RET in green, 5’KIF5B in yellow] was developed to simultaneously detect (a) disruption between 3’ and 5’ RET and (b) specific fusion between 5’KIF5B-3’RET. This probe set was used to interrogate a cohort of Caucasian NSCLC patients using tumor microarray. Inclusion of specimens on the tissue microarray was independent of gender, age, smoking history, histology and any known molecular profile and was only based on patient informed consent and tissue availability.

      Results
      Among 348 evaluable NSCLC patients, 6 (1.7%) were found to be positive for RET rearrangement (RET+): 2 showed typical KIF5B:RET pattern, 2 showed patterns consistent with CCDC6: RET fusion; and 2 had split 3’-5’ without suggestion of the fusion partner identity. The histology was adenocarcinoma in 4, large cell carcinoma in 1 and squamous cell carcinoma in 1. All RET+ tumors were wild type for EGFR and negative for ALK and ROS1 rearrangements. The mean age of RET+ patients at the time of diagnosis was 62 years (49-74) and they were predominantly male (5) and former (4) or current smokers (1). The 10p11-q11 region displayed high level of genomic instability, with RET doublets, KIF5B and RET doublets, unbalanced KIF5B copy number gain, fusion KIF5B with 5’ and 3’RET, and abnormal separation between KIF5B and RET in 8.5%, 5.1%, 9.6%, 2.3%, and 2% of specimens, respectively. These atypical patterns will be further investigated by RT-PCR.

      Conclusion
      The customized 3-target, 3-color probe set successfully detected KIF5B:RET rearrangements and identified patterns suggestive of RET rearrangements with non-KIF5B partners in small subset of unselected NSCLC. Interestingly, only a minority of RET + patients were never smokers and 1/3 of them had non-adenocarcinoma histology. Despite the benefits of using enrichment strategies based on clinicopathologic variables for molecular testing of NSCLC in search for personalized therapy, these findings argue against using variables such as smoking status and histology for screening selection when the aim is to detect all potential RET+ patients.

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    O05 - Cancer Control (ID 130)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      O05.01 - The DANTE trial, a randomized study of lung cancer screening with spiral CT: 7-year results (ID 1428)

      10:30 - 12:00  |  Author(s): A. Santoro

      • Abstract
      • Presentation
      • Slides

      Background
      The purpose of this study was to explore the effect of screening with spiral CT on lung cancer mortality in comparison with no screening in a high-risk population. Secondary endpoints were incidence, stage and resectability.

      Methods
      Male subjects, aged 60-75, smokers of 20+ pack-years were randomized to screening with low-dose spiral CT or control. Prospective participants were pre-assessed for eligibility and randomized during a telephone interview, while formal enrolment took place at a later date. All enrolled participants underwent a structured medical interview and physical examination, a baseline, once-only chest X-ray (CXR) and sputum cytology examination. Screening-arm subjects had a LDCT upon accrual, which was repeated every year for four additional years (5 rounds), while controls had a yearly clinical review only, with further testing only if needed.

      Results
      Between March 2001 and February 2006, 2811 subjects were pre-assessed and randomized (CT arm: 1403, control arm:1408). 20 cases of double registration and two test records have been identified in the database, and 2540 subjects actually appeared for assessment (1229 CTR arm, 1299 CT arm), of whom 2450 (1264 CT arm and 1186 Controls) were eligible and enrolled. The two study groups are comparable for age, smoking exposure, and comorbid conditions. As per inclusion criteria, all subjects are males and 99.8 % are 60 or older. As of December 2012, median follow-up was 73.1 months in the control arm and 75.5 months in the screening arm. Altogether, 152 patients were detected during active follow-up with 161 lung cancers: 92 CT-arm subjects (7.27%) versus 60 controls (5.05%), p< 0,0237. 82% of CT-arm lung cancers were detected at scheduled CT examinations, and 55% were stage I disease at the time of diagnosis compared with 27% in the Control arm. The absolute number of lung cancer cases with stage II-IV disease was virtually the same as in the control arm. Resectability rate was similar in the two groups. After linkage with population registries, vital status information is now available for 2528 subjects (99.5%). Overall, 370 subjects have died, for 104 of whom we are currently investigating mortality causes.

      Conclusion
      While the number of participants is relatively small, smoking exposure and average age of participants are higher than in similar trials. A comparatively high number of events has been observed. To date, 28% of such events cannot yet be attributed to a specific cause. Health registry data necessary to complete mortality comparisons is expected to become available in the next few weeks. Merging of all European trials may yield robust data about this strategy in the future.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-004 - Addition of bevacuzimab (BEV) to pemetrexed (PEM) plus cisplatin (CIS) induction and PEM maintenance therapy in 1st line setting for treatment of advanced nonsquamous non small cell lung cancer (NS-NSCLC) - final results and safety update from a phase 2 study (ID 234)

      09:30 - 16:30  |  Author(s): A. Santoro

      • Abstract

      Background
      1st line PEM+CIS induction chemotherapy (CT) followed by PEM maintenance and 1st line BEV-based CT followed by BEV maintenance offer clinical benefit (progression-free and overall survival; PFS and OS) in NS-NSCLC. This study explored efficacy and safety of 1st line induction PEM+CIS+BEV followed by maintenance PEM+BEV.

      Methods
      Patients with advanced NS-NSCLC and ECOG performance status (PS) 0-1 were planned to receive 4 cycles PEM 500 mg/m[2], CIS 75 mg/m[2], BEV 7.5 mg/kg, given every 3 weeks. In the absence of progressive disease (PD) and in the case of ECOG PS 0-1, patients could continue on PEM+BEV until PD or unacceptable toxicity. All patients received vitamin supplementation as per PEM label. Primary endpoint was PFS; secondary endpoints included OS, response rate and toxicity. PFS without Grade (G)4 toxicity was additionally assessed.

      Results
      109 patients were enrolled in 5 countries. Characteristics: median age 61 years, males/females 59/41%, ECOG PS 0/1 54/46%, stage IIIB/IV 9/91%, adenocarcinoma 91%. 72 patients (66%) received maintenance CT. Overall median (maximum) number of cycles were 8(34) for PEM+BEV and 4(4) for CIS. Median PFS was 6.9 months (90% CI 5.7, 8.3). Table 1 summarizes efficacy data; Table 2 presents G1-4 adverse event (AE) data, including AEs of special interest regarding BEV. 2 patients died from study-drug related toxicity (GI hemorrhage, pneumonia aspiration; during induction CT). Figure 1 Figure 2

      Conclusion
      In this study of PEM+CIS+BEV induction CT followed by PEM+BEV maintenance, median PFS was 6.9 months. The addition of BEV to PEM-CIS induction and PEM maintenance was associated with acceptable and expected toxicities. Main G3/4 toxicities included neutropenia and fatigue, hypertension was less common.