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S.S. Ramalingam



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    HOD4 - Tuesdays Highlights of the Day - Medical Oncology, Biology, Radiotherapy and Combined Modality (ID 228)

    • Event: WCLC 2013
    • Type: Highlight of the Day Session
    • Track: Biology
    • Presentations: 1
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      HOD4.1 - Medical Oncology and Biology (ID 4044)

      07:00 - 07:20  |  Author(s): S.S. Ramalingam

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.12 - Efficacy and safety of paclitaxel and carboplatin with bevacizumab for the first-line treatment of patients with nonsquamous non-small cell lung cancer (NSCLC): analyses based on age in the phase 3 PointBreak and E4599 trials (ID 2879)

      17:20 - 17:25  |  Author(s): S.S. Ramalingam

      • Abstract
      • Presentation
      • Slides

      Background
      A post hoc analysis of NSCLC patients (pts) aged ≥70 y in the pivotal E4599 trial found increased adverse events (AEs) and numerically decreased overall survival (OS) benefit associated with bevacizumab (BEV) compared with pts <70 y. We evaluated the efficacy and safety of BEV by age in pts in a pooled dataset from the E4599 and PointBreak (PB) trials.

      Methods
      Pts randomized to the PC (paclitaxel and carboplatin ) + BEV arms of E4599 and PB received P 200 mg/m[2], C AUC 6, and BEV 15 mg/kg q3w for 6 (E4599) or 4 (PB) cycles; Eligible pts received maintenance BEV alone q3w until disease progression or unacceptable toxicity. OS, progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and safety were assessed in pts grouped according to age (<65 y, 65–74 y, 70–74 y, <75 y, and ≥75 y). Pt-level data from the PC + BEV arms of E4599 and PB were pooled and compared with data from pts in the PC-alone arm of E4599.

      Results
      PB and E4599 randomized 467 pts and 434 pts to PC + BEV, respectively, while 444 were randomized to receive PC alone on E4599. Baseline characteristics were balanced between age groups. OS and PFS hazard ratios (HRs) and increases in grade ≥3 AEs for the pooled pt cohort relative to E4599 PC-alone arm are shown (Table). Outcomes were similar in pts <70 y and ≥70 y, and data from the pooled population were similar to those seen in each individual trial (data not shown). ORR for pts <75 y was 39% with PC + BEV vs 26% with PC (P<.01). For pts ≥75 y, ORR was 33% vs 30% (P=.71). DCR in pts <75 y was 70% with PC + BEV vs 53% with PC (P<.01). For pts ≥75 y, DCR was 60% vs 67% (P=.37).

      Conclusion
      In a pooled exploratory analysis of pt data from E4599 and PB, the statistically significant benefit associated with the addition of BEV to PC appeared consistent across all age groups <75y, while pts ≥75 y receiving PC + BEV had no statistically significant survival benefit. Pts receiving PC + BEV had an increase in grade ≥3 AEs compared with pts receiving PC-alone in all age groups.

      PB + E4599 <65 y n=735 65–74 y n=453 70–74 y n=203 <75 y n=1188 ≥75 y n=157
      HR for OS 95% CI P 0.75 0.62–0.89 <.01 0.80 0.64–1.00 .05 0.68 0.48–0.96 .03 0.78 0.68–0.89 <.01 1.05 0.70–1.57 .83
      HR for PFS 95% CI P 0.71 0.60–0.85 <.01 0.62 0.49–0.78 <.01 0.68 0.48–0.96 .03 0.69 0.60–0.79 <.01 0.95 0.62–1.44 .80
      E4599 n=499 n=277 n=129 n=776 n=102
      Δ Grade ≥3 AEs,[a ]% P 13 <.01 21 <.01 23 <.01 15 <.01 25 <.01
      [a]Relative to PC-alone arm.

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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): S.S. Ramalingam

      • 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): S.S. Ramalingam

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-036 - Overall Survival and Hospitalization Rates in Medicare Patients Diagnosed with Advanced NSCLC Treated With Bevacizumab- Paclitaxel-Carboplatin vs Paclitaxel-Carboplatin: A Retrospective Cohort Study (ID 2419)

      09:30 - 09:30  |  Author(s): S.S. Ramalingam

      • Abstract

      Background
      The study aimed to compare overall survival and hospitalization rates for Medicare patients diagnosed with advanced nonsquamous non-small cell lung cancer (NSCLC) and treated with first-line bevacizumab-carboplatin-paclitaxel (BCP) vs. carboplatin-paclitaxel (CP).

      Methods
      Patients aged ≥65years first diagnosed with nonsquamous NSCLC stage IIIB/ IV between 2006 and 2009 and treated with first-line BCP or CP therapy were identified in the SEER-Medicare database that links cancer registry and Medicare claims data from United States. Outcomes were measured from the treatment initiation date to the end of data availability on 12/31/2010 for hospitalizations and 12/31/2011 for survival. Survival and hospitalization rates are reported from Kaplan-Meier analyses over the follow-up period. Bootstrap methodology was used to test treatment groups differences in median time to death and first hospitalization. Age-stratified survival analyses were conducted using age 75 as a cut point. Inpatient utilization rates are also reported per 100 patient-days for each treatment group and compared in terms of incidence rate ratios (IRR) estimated from negative binomial models adjusted for potential confounders.

      Results
      Of 1,706 patients, 592 (34.7%) received BCP and 1,114 (65.3%) received CP by inclusion criteria, while 692 (40.6%) were ≥75 years of age. Patient characteristics were balanced between arms for age, sex, disease stage. The BCP group had fewer pre-treatment comorbidities, greater proportion of adenocarcinoma histology, and differences in ethnicity, SEER region, and income compared to the CP group. The median survival time was 10.5 months in the BCP group vs. 8.4 months in the CP group (2.1 months difference, p=0.0007). The difference in median overall survival favoring BCP over CP groups was 1.3 months for patients aged 65-74 years (p=0.11), and 3.3 months for those aged ≥75years (p=0.006). At 6-months and 1 year of follow-up, survival rates for all subjects were, respectively, 70.3% and 43.8% of BCP patients vs. 60.6% and 37.0% of CP patients. After 1 year of follow-up, 69.5% of BCP vs. 75.1% of CP had ≥ 1 hospital admission. Hospitalization rates were significantly lower for BCP patients (adjusted IRRs: 0.82, p=0.003 and 0.77, p=0.002 for hospital admission and hospitalization days). The difference in median time to first hospitalization was 2.1 months (p <.0001). Additional statistics are presented in the Table. Figure 1

      Conclusion
      In this retrospective analysis of updated SEER-Medicare data, first-line therapy with BCP was associated with longer median survival and reduced hospitalizations compared to CP in patients > 65 years of age.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-032 - Patient Report of Dacomitinib (PF-00299804)-Associated Symptom and HRQoL Benefit in Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 2293)

      09:30 - 09:30  |  Author(s): S.S. Ramalingam

      • Abstract

      Background
      Decreasing tumor burden may reduce/delay cancer-related symptoms experienced by patients with NSCLC and favorably impact global health-related quality of life (HRQoL). Dacomitinib is an irreversible small-molecule inhibitor of all catalytically active members of the human epidermal growth factor receptor (HER) family of tyrosine kinases (EGFR/HER1, HER2, and HER4), and has shown anticancer activity and manageable toxicity in NSCLC clinical trials [Janne et al 2009; Park et al 2010; Ramalingam et al 2012; Mok et al 2012]. Qualitative assessment of the adverse event (AE) burden from the patient’s perspective helps to provide a greater understanding of the overall impact of treatment-related AEs than grading of AEs alone. Here we report the impact of dacomitinib on core lung cancer symptoms in patients with previously treated, advanced NSCLC in three phase II clinical trials [Janne et al 2009; Park et al 2010; Ramalingam et al 2012].

      Methods
      Dacomitinib was evaluated in advanced NSCLC, in patients who had received prior chemotherapy and erlotinib (study 1002; n=66) [Janne et al 2009], in Korean patients who had received prior chemotherapy and erlotinib or gefitinib (study 1003; n=43 in phase II) [Park et al 2010], and in comparison with erlotinib in patients who had received prior chemotherapy (study 1028; n=188) [Ramalingam et al 2012]. In each of the trials, HRQoL was evaluated using validated patient-reported outcome (PRO) measures. Disease/treatment‑related symptoms were recorded using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core module (EORTC QLQ-C30) and its lung cancer module (LC13). Scores were summarized using the mean (and 95% CI) for each group and plotted over time. Mean changes from baseline were also reported.

      Results
      On-study questionnaire mean completion rates were high (>90% of patients answered at least 1 question across treatment cycles) in each of the studies. Across the three trials, patients reported a rapid onset (typically ≤3 weeks of starting therapy) of improvement in key lung cancer symptoms (e.g. cough, pain in chest, and pain in arm/shoulder) relative to baseline scores, with symptomatic improvements remaining durable over the course of therapy. Diarrhea and sore mouth were the most commonly reported class-related AEs (for dacomitinib in studies 1002 and 1003, and for both dacomitinib and erlotinib in study 1028). These AEs peaked at weeks 3–6, were manageable, and remained stable or improved over time with intervention. Compared with erlotinib in study 1028, clinically meaningful improvements from baseline (>10 points difference on a 0–100-point scale) in key NSCLC symptoms (cough, dyspnea, pain in chest, pain in arm/shoulder, fatigue, and physical function) were reported by patients receiving dacomitinib. The difference in mean change from baseline was more favorable with dacomitinib at most time-points.

      Conclusion
      Dacomitinib demonstrated consistent improvements in common NSCLC symptoms across three clinical trials in pretreated patients with advanced NSCLC. PROs such as cough and pain improved within 3 weeks of initiating treatment, with benefits sustained throughout the course of therapy. Dacomitinib also demonstrated greater improvements in key NSCLC symptoms than erlotinib.