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R. Salgia



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    MO07 - NSCLC - Targeted Therapies II (ID 114)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 2
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      MO07.03 - Crizotinib therapy for patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC) (ID 2777)

      16:25 - 16:30  |  Author(s): R. Salgia

      • Abstract
      • Presentation
      • Slides

      Background
      Rearrangements of the ROS1 receptor tyrosine kinase gene identify a subset of NSCLC sensitive to the small-molecule ALK and MET inhibitor crizotinib, approved multinationally for the treatment of advanced ALK-positive NSCLC. Here we present updated efficacy and safety data for crizotinib in an expanded cohort of patients with advanced ROS1-rearranged NSCLC.

      Methods
      ROS1 status was determined by break-apart FISH assays, and patients were enrolled into an expansion cohort of an ongoing phase I crizotinib study (PROFILE 1001; NCT00585195, Pfizer). Where available, samples were also tested for concurrent ALK rearrangement and MET amplification. Patients received crizotinib 250 mg BID, and responses were assessed using RECIST v1.0.

      Results
      At the data cut-off, 35 of 40 patients with ROS1-positive NSCLC were evaluable for response. Median age was 51 years (range 31–77), 80% of patients were never-smokers, and 98% had adenocarcinoma histology; 40% had received one prior regimen, and 45% had received 2–6 regimens for advanced/metastatic disease. 25 samples tested for concurrent ALK rearrangement (24 by FISH and 1 by PCR) and 12 samples tested for concurrent MET amplification (11 by FISH and 1 method not recorded) were all negative. The objective response rate (ORR) was 60% (95% CI: 42–76), with 2 complete responses, 19 partial responses, and 10 cases of stable disease. Median progression-free survival (PFS) had not been reached, with 25 patients (63%) still in follow-up for PFS; six patients (15%) experienced disease progression, and two (5%) died before progression occurred; 6-month PFS probability was 76% (95% CI: 55–88). The disease-control rate was 80% at 8 weeks and 66% at 16 weeks. The most common treatment-related adverse events (AEs) were visual impairment (80%), diarrhea (35%), and nausea (30%), with most patients (68%) reporting only AEs of grade 1 or 2 severity. Peripheral edema (28%) and elevated transaminases (18% AST, 15% ALT) were also reported, similar to previous experience with crizotinib. There were no treatment-related serious AEs and one patient discontinued treatment due to treatment-related nausea. Accrual of patients with ROS1-positive NSCLC is ongoing.

      Conclusion
      Similar to results obtained in ALK-positive NSCLC, crizotinib had marked antitumor activity with a high ORR (60%) in patients with ROS1-positive NSCLC, with a generally tolerable and manageable AE profile. These data suggest that crizotinib is an effective therapy for patients with advanced ROS1-positive NSCLC.

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      MO07.06 - Updated results of a first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies (ID 2400)

      16:45 - 16:50  |  Author(s): R. Salgia

      • Abstract
      • Presentation
      • Slides

      Background
      AP26113 is a novel tyrosine kinase inhibitor (TKI) that exhibits pan-ALK inhibitory activity against all 9 clinically-identified crizotinib-resistant mutants, including the L1196M gatekeeper, in preclinical experiments. AP26113 also inhibits ROS1 and selectively inhibits mutant EGFR (EGFRm) in preclinical experiments, including the T790M resistance mutation, without affecting the native receptor.

      Methods
      We report data from the dose finding component (3+3 design) of a phase 1/2 open-label, multicenter study in patients with advanced malignancies (except leukemia) refractory to available therapies or for whom no standard treatment exists. Dosing was once daily (QD) or twice daily.

      Results
      As of 17 April 2013, 55 patients were enrolled: 30mg (daily dose) n=3, 60mg n=3, 90mg n=8, 120 mg n=15, 180mg n=15, 240mg n=9, 300mg n=2; 62% female, median age 58 yrs; diagnoses: non-small cell lung cancer (NSCLC, n=47), other (n=8). 33 patients discontinued: 22 disease progression, 6 adverse event (AE), 4 deaths (2 possibly related: sudden death, hypoxia), 1 withdrawal by subject. The most common AEs included fatigue (40%), nausea (36%), and diarrhea (33%), which were generally grade 1/2 in severity. The most common grade 3/4 AE was pneumonia (5%). Two patients experienced dose limiting toxicities: grade 3 ALT increase in 1 patient (240mg QD); grade 4 dyspnea and grade 3 hypoxia in 1 patient (300mg QD). Twenty-eight patients had ALK+ history (24 NSCLC, 4 other). Among 24 evaluable ALK+ patients, 15 responded. Responses were observed in 2/4 (50%) ALK+ TKI-naïve patients and 13/17 (76%) ALK+ patients with prior crizotinib therapy and no other ALK inhibitor exposure. Among ALK+ NSCLC patients with prior crizotinib only, 12/16 (75%) responded. The longest response is 40+ weeks (ongoing). 4 of 5 ALK+ patients with untreated or progressing CNS lesions at baseline and with follow-up scans had evidence of radiographic improvement in CNS, including 1 patient resistant to crizotinib and LDK378 (overall response = stable disease). CNS lesion improvements in all 4 patients are ongoing, with durations ranging from 15+ to 28+ weeks. Twenty patients had EGFRm history (19 NSCLC, 1 SCLC); 18 had ≥1 prior EGFR TKI. Of 18 evaluable EGFRm patients, 1 patient (prior erlotinib) responded at 120mg QD (duration 26+ weeks, ongoing), 7 patients had stable disease, including 4 with T790M by history (1 ongoing at 240mg QD, duration 16+ weeks). The maximum tolerated dose has not been defined; however, based on safety, efficacy, and pharmacokinetics, the recommended phase 2 dose (RP2D) is 180mg QD. Updated data will be presented.

      Conclusion
      AP26113 has promising anti-tumor activity in patients with ALK+ NSCLC and other ALK+ tumors, with initial evidence of activity in EGFRm patients, and is generally well tolerated. Five phase 2 cohorts are enrolling at the RP2D (180mg QD): 1) ALK inhibitor-naïve ALK+ NSCLC, 2) crizotinib-resistant ALK+ NSCLC, 3) single EGFR TKI-resistant NSCLC with documented T790M, 4) other tumors with AP26113 targets, 5) crizotinib-naïve or –resistant ALK+ NSCLC with active CNS metastases. Further phase 1 testing at 240mg QD will occur in EGFRm patients with documented T790M. NCT01449461

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    O29 - Cancer Control & Epidemiology IV (ID 132)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      O29.06 - Prognostic Value of FDG-PET/CT Volumetric Prognostic Staging System in Non-small Cell Lung Caner (ID 2278)

      11:25 - 11:35  |  Author(s): R. Salgia

      • Abstract
      • Presentation
      • Slides

      Background
      Whole-body metabolic tumor volume (MTV~WB~) is a prognostic index independent of TNM staging, age, gender, performance status and treatment in non-small cell lung cancer (NSCLC). The current TNM staging system is also a prognostic index. However, it lacks advanced quantitative volumetric measurement in the 7[th] edition NSCLC TNM staging system. Integrating quantitative MTV~WB~ measurement into the current NSCLC staging system may make the staging system more quantitative and probably more prognostic. This study’s aim was to determine the utility of a FDG-PET volumetric prognostic (PVP) staging system based on univariate Cox regression models as a new prognostic index in NSCLC.

      Methods
      328 consecutive patients (156 males,172 females) with histologically proven NSCLC and median age of 68.3 years were identified for this retrospective analysis. The PET metabolic tumor volume in the whole body (MTV~WB~) was measured using a semi-automated 3D contouring program on baseline FDG PET/CT scans. The prognostic power for survival status of the PVP staging system was evaluated using the Kaplan–Meier method, Cox regression models, and compared with those of TNM staging system and ln(MTV~WB~) using C-statistic index (Gönen and Heller’s K concordance statistic).

      Results
      There were 46 cases with stage IA, 43 stage IB, 19 stage IIA, 18 stage IIB, 52 stage IIIA, 39 stage IIIB and 111 stage IV NSCLC. At the end of this investigation, 249 patients had died (88.4%). Median follow-up of 79 lost follow-up and known surviving patients was 58 months. On univariate survival analysis the HR of ln(MTV~WB~) was 1.56, and the HRs of TNM stages 2.25, 1.96, 2.89, 4.24, 4.93 and 7.63 for TNM stages IB, IIA, IIB, IIIA, IIIB and IV in reference to stage IA, respectively. These HRs were used for computing the PVP stage of each patient using following equation; PVP stage = [Hazard ratio of ln(MTV~WB~) × ln(MTV~WB~)] × [Hazard ratios of TNM stage]. There was a statistically significant association of better overall survival with lower PVP stage on both univariate [HR of 1.033 (95%CI =1.027 to1.039)] and multivariate [HR of 1.03 (95%CI =1.02 to1.04)] survival analyses. The range of the PVP stage were 0.06 to 87.57. For comparison with 7[th] edition of TNM stage and ln(MTV~WB~), the PVP stage and ln(MTV~WB~) were divided into 7 groups with similar numbers of patients. The C-statistic value of PVP staging system (mean±SE = 0.70±0.014) was statistically significantly higher than those of TNM stage (0.67 ±0.015, p=0.002) and ln(MTV~WB~) (0.67±0.015, p=0.02) on univariate survival analysis. In multivariate Cox regression models adjusted by patient’s age, gender, treatment types, tumor histology and tumor SUV~max~, the C-statistic value of PVP staging system (mean±SE=0.73±0.013) was also statistically significantly higher than that of TNM stage (0.71 ±0.015, p=0.036).

      Conclusion
      The PVP staging system from FDG-PET/CT has better prognostic ability and may prove to be a useful prognostic index in NSCLC. It can be treated as a complement to the TNM staging system.

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    P3.14 - Poster Session 3 - Mesothelioma (ID 197)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P3.14-011 - Genomic profiling of Epithelial Malignant Pleural Mesothelioma (MPM) using Massively Parallel Sequencing. (ID 2855)

      09:30 - 09:30  |  Author(s): R. Salgia

      • Abstract

      Background
      Development of targeted therapies in malignant pleural mesothelioma has been limited due to the incomplete understanding of genetic aberrations occurring in this disease. We determined mutational and copy number (CN) events in a comprehensive fashion in 12 patients with epithelial malignant pleural mesothelioma in order to identify characteristic genetic aberrations and new potential treatment targets.

      Methods
      Fresh frozen tumor (≥70% tumor content) and matched normal tissue from 12 patients with treatment-naïve epithelial malignant pleural mesothelioma were evaluated using targeted, massively parallel sequencing (Illumina HiSeq) for 580 cancer-relevant genes using hybrid capture target enrichment and an established bioinformatics analysis pipeline. CN analysis was performed using sequencing data (CONTRA) and validated on the NanoString nCounter. Mutations were modeled bioinformatically using the CHASM oncogenic driver prediction algorithm and reviewed for prior occurrence in COSMIC and evidence supporting usefulness as a treatment target.

      Results
      Loss of CDKN2A was the most common genetic event occurring in 80% of samples. INPP4B and TRAF6 were lost in 20-30% of tumors. No loss of PTEN was observed in any sample. Two BAP1 small frameshift deletions were observed. Copy number aberrations, in particular amplifications, were rare. The only gene with modest increase in copy number was MET (median CN=2.8). We identified multiple somatic missense mutations including: two APC mutations (K1245E, G2502D; both predicted to be damaging), one TSC1 (K587A) and one TSC2 (P952A, predicted driver) mutation, one KIT mutation (L799F; predicted driver), one JAK2 (P953A; predicted driver), as well as single mutations in NF1 (G849R), EPHA1 (P697S), EPHA4 (T532I), and mTOR (L2208P), all of which had driver character. Specific mutations have not been reported in COSMIC. No canonical PI3K or MAPK pathway aberrations were identified.

      Conclusion
      We identified several novel and known mutations and copy number events in epithelial malignant pleural mesothelioma: deletions in CDKN2A and INPP4B were the most common copy number events. Frameshift deletions in BAP1 were identified. Overall few copy number events were observed. Potentially targetable aberrations include missense mutations in NF1, JAK2, EPHA1, TSC2, mTOR and KIT, which are predicted to have driver character and additional experimental validation is indicated. Additional tumor and cell line samples are being processed and will be available at the time of presentation.