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K. Kelly



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    E03 - Chemotherapy for NSCLC (ID 3)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Medical Oncology
    • Presentations: 1
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      E03.3 - Optimal Adjuvant Chemotherapy: Selection of Patients and Agents (ID 384)

      K. Kelly

      • Abstract
      • Presentation
      • Slides

      Abstract
      Optimal adjuvant chemotherapy: selection of patients and agents Patients with early stage, resectable non-small cell lung cancer (NSCLC) have the best chance to be cured with 5 year survival rates ranging from 73% for patients with pathological stage IA disease to 24% for patients with pathological stage IIIA disease. However, the presence of micro-metastases will lead to the development of systemic relapse and death in the majority of patients. To improve survival of these patients adjuvant chemotherapy following complete tumor resection has been studied. Three phase III trials with cisplatin-based regimens and the LACE meta-analysis demonstrated increased cure rates by adjuvant chemotherapy and established adjuvant chemotherapy as the standard of care. Randomized Trials The first trial to demonstrate a survival advantage for adjuvant chemotherapy was the International Adjuvant Lung Cancer Trial Cooperative Group (IALT) study. This trial enrolled 1867 patients; 932 patients were randomized to receive chemotherapy (cisplatin plus etoposide, vinorelbine, vinblastine, or vindesine for 3-4 cycles) and 935 patients were randomized to observation. The 5 year overall survival rate significantly favored the chemotherapy arm (Hazard Ratio [HR] 0.86; 95% CI 0.76-0.98; P <0.03). Disease free survival (DFS) was also superior in the treated arm (HR 0.83; 95% CI 0.74-0.94; P=0.003). With longer follow up of 8 years, the HR for overall survival was not significant (HR 91; 95% CI 0.81-1.02; P=0.10) while the HR for DFS retained significance (HR 0.88; 95% CI 0.78-0.98; P=0.02). In 2005, the National Cancer Institute of Canada Cancer Treatment Group (NCIC CTG) reported the results of JBR10. Patients with completely resected stage IB or stage II NSCLC were randomized to receive cisplatin plus vinorelbine (242 patients) or observation (240 patients). An impressive overall survival benefit was observed for the treated group (HR 0.69; 95% CI 0.52-0.91; P=0.04) corresponding to an absolute survival improvement of 15%. In a subgroup analysis, the survival benefit was restricted to patients with Stage II disease. An update of this study, with > 9 years of follow up continued to show a survival benefit for the treated group with an absolute improvement in the 5 year overall survival (OS) rate of 11% (67% versus 56%, respectively) with a HR of .78; 95% CI 0.62-0.99; P=0.04 (11). Subsequently, the results from the ANITA trial (Adjuvant Navelbine International Trialist Association) solidify the role of adjuvant systemic treatment. A total of 840 patients with Stage IB, II, and IIIA NSCLC were randomized to cisplatin plus vinorelbine versus observation. The HR for death was significantly lower for the chemotherapy group (HR= 0.80, 95% CI 0.66-0.96; P=0.017). The 5 and 7 year overall survival was improved by 8.6% and 8.4% in the chemotherapy group, respectively. No benefit was seen in the subset of patients with Stage IB disease (HR 1.10; 95% CI 0.76-1.57; P=NS). To identify which patients might have the greatest benefit from adjuvant chemotherapy, the LACE (Lung Adjuvant Cisplatin Evaluation) meta-analysis was conducted. Individual patient data was collected and pooled from 4,584 patients in 5 trials (BLT, ALPI, IALT, JBR10 and ANITA). The HR of death was 0.89; 95% CI 0.82-0.96; P=0.005, which corresponded to a 5-year absolute survival benefit of 5.4% with chemotherapy. This benefit varied with stage of disease and was not seen for stage IA patients. A positive chemotherapy effect was seen in patients with performance status (PS) 0-1 whereas chemotherapy was potentially harmful for patients with a PS of 2. Other subgroups analyzed including age, sex, histology, type of surgical resection, planned radiation, dose of cisplatin or the second agent used did not affect overall or disease free survival. Elderly patients Since the majority of patients diagnosed with lung cancer are 70 years old or greater, an additional analysis of the LACE data set by age was conducted. Elderly patients (age > 70 years) accounted for 9% of the patients. Their HR of death was better with treatment at .90 (95% CI 0.74-1.16) and was similar to the HR of death for treated patients < 65 years old at .86 (95% CI 0.78-.94). Elderly patients achieved a survival benefit despite having received lower cisplatin doses and fewer number of chemotherapy cycles than their younger counterparts. Tumor size The Cancer and Leukemia Group B (CALGB) trial 9633 evaluated four cycles of adjuvant paclitaxel and carboplatin versus observation in stage IB patients. With mature follow up of 74 months, overall survival was not significantly different between the two groups (HR 0.83; 95% CI 0.64-1.08; P=0.12). No significant improvement in DFS was observed. In an unplanned subgroup analysis based on tumor size a survival advantage for paclitaxel and carboplatin was seen in patients who had tumors >4 cm (HR, 0.69; 95% CI 0.48-0.99; P = .043). In support of this finding, a retrospective analysis of patients with stage IB disease on JBR 10 was conducted according to tumor size of < or > 4 cms. Patients with smaller tumors did not benefit from adjuvant therapy while treated patients with tumors > 4 cm had a favorable 5 year OS rate of 79% compared to 59% for untreated patients (HR .66; 95% CI 0.39-1.14; P=0.13). It is important to remember that in the 7[th] TNM staging system, patients with tumors of > 4 cm could be Stage IB, IIA or IIB. Chemotherapy regimen In the clinical trials described above vinorelbine plus cisplatin was the most commonly used regimen. In a subgroup analysis of LACE, adjuvant cisplatin plus vinorelbine improved survival at 5 years by 8.9% in the vinorelbine cohort and this outcome was superior to the “other” cohort. Today more modern regimens are frequently used based on their activity in advanced disease including cisplatin and gemcitabine, cisplatin and docetaxel and cisplatin and pemetrexed. In summary, adjuvant cisplatin based chemotherapy is the standard of care for patients with resectable Stage II-III NSCLC with a good performance status and should be considered for patients with tumor size > 4 cm. Current strategies to improve outcome of adjuvant chemotherapy focuses on the integration of targeted therapies, tumor vaccines and the identification of prognostic and predictive biomarkers.

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    MO13 - SCLC I (ID 118)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO13.01 - Disease control rate at 8 weeks predicts subsequent survival in platinum-treated extensive stage small cell lung cancer (ES-SCLC): a patient level analysis of SWOG trials (ID 967)

      K. Kelly

      • Abstract
      • Presentation
      • Slides

      Background
      Disease control rate (DCR) – the sum of partial (PR) and complete response (CR) plus stable disease (SD) – is a significant predictor of subsequent survival following platinum-based chemotherapy in patients with advanced non-small cell lung cancer (Lara, et al. JCO 2008). We evaluated whether this observation is also relevant in patients with platinum-treated ES-SCLC on investigational systemic therapy.

      Methods
      Updated patient-level data from recent SWOG trials in 2[nd] and/or 3[rd] line ES-SCLC (S0802: topotecan + aflibercept; S0435: sorafenib; and S0327: PS-341) were pooled. Landmark analysis was performed among patients still alive at 8 weeks for overall survival (OS) measured from the 8-week landmark. Association of clinical prognostic factors (including age, sex, platinum sensitivity status, number of prior chemo, weight loss, and LDH, among others) with DCR was assessed using logistic regression. A Cox proportional hazards model was used to assess the associations between DCR at the landmark time and subsequent OS, adjusted for prognostic factors.

      Results
      319 patients were included: median age = 63 years; male sex = 51%; PS 1 = 68%; weight loss > 5% = 29%; > 2 prior chemo = 16%; and elevated LDH = 43%. Only 8 patients had PR by RECIST for an overall response rate of 2.5%. Disease control at 8 weeks was observed in 74 patients (8 PR + 64 SD), for a DCR of 23.2%. Bivariate analysis of OS from the 8-week landmark revealed that only DCR (Hazard Ratio [HR] 0.53, p<0.0001) and elevated LDH (HR 1.69, p=0.001) were significantly associated with OS. Multivariable analysis showed that only DCR remained as an independent predictor of subsequent survival from the 8-week landmark (HR=0.58, p=0.002).

      Conclusion
      In this large 2[nd]- and 3[rd]-line ES-SCLC database, DCR at 8 weeks was found to be the strongest predictor of subsequent survival in patients receiving investigational therapy. Thus, DCR at 8 weeks should be considered for use as a surrogate clinical trial endpoint to screen for drug activity against ES-SCLC. These results have critical implications in the design of future prospective trials in ES-SCLC.

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    O21 - SCLC II (ID 119)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 2
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      O21.07 - A new prognostic model for relapsed/refractory extensive stage small cell lung cancer (ES-SCLC) derived from prospective SWOG trials: implications for study design (ID 966)

      K. Kelly

      • Abstract
      • Presentation
      • Slides

      Background
      ES-SCLC patients (pts) with progressive disease (PD) following plat-based chemo have traditionally been categorized as plat-sensitive (PD >/= 90 days from last plat dose) or refractory (PD < 90 days). Plat-sensitivity status has previously been strongly associated with response and survival in the 2[nd]/3[rd] line treatment setting. However, in a recent pooled analysis of SWOG trials in 2[nd]/3[rd] line SCLC pts, plat-sensitivity status was found to no longer be a significant independent variable for survival (Lara, ASCO 2013). We subsequently developed a new SCLC prognostic model for overall survival (OS) for potential clinical trial and bedside application.

      Methods
      Updated data from recent SWOG trials in 2nd and/or 3rd line ES-SCLC (S0802: topotecan + aflibercept: S0435: sorafenib; and S0327: PS-341) were pooled. Accrual goals were specified for sensitive and refractory in each trial. Hazard ratios (HRs) for OS were calculated using Cox Proportional Hazard (PH) models [unadjusted and adjusted]. To investigate a predictive model for OS, recursive partitioning was performed using the likelihood tree model of LeBlanc and Crowley. The minimum node size was set at 20.

      Results
      Of 329 pts, 151 were classified as sensitive, 178 refractory; median age = 63 years; males = 52%; Performance Status (PS) 1 = 67%; weight loss >5% = 28%; > 2 prior chemo = 16%; and elevated LDH = 43%. HRs from unadjusted Cox models for OS for refractory vs. sensitive were 1.0 (95% CI 0.81-1.25, p=0.98) and 1.24 (95% CI 0.99, 1.57; p=0.06). Cox PH models adjusted for baseline prognostic factors showed that plat-sensitivity status was not significantly associated with OS. Elevated LDH was significantly associated with PFS while LDH, PS, weight loss, and male sex were independently associated with OS. Clinically relevant prognostic risk groups (High, Intermediate, and Low) were identified by recursive partitioning analysis, as shown below (MST= median survival time). High Risk (MST = 2 months: Elevated LDH And > 5% Weight Loss Or PS >0) Intermediate Risk (MST = 5 months: Elevated LDH but not High Risk Or Male) Low Risk (MST=8 months: Normal LDH And Female)

      Conclusion
      In this large database analysis, clinically relevant prognostic risk groups were identified, categorized as low, intermediate, and high risk, with differential survival outcomes observed for each group. Validation of these risk groups in an independent SCLC dataset is warranted. If validated, these risk groups will have important implications for individualized patient counseling in clinic and stratification of patients in prospective trials in the second and third line setting.

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      O21.08 - DISCUSSANT (ID 3965)

      K. Kelly

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    Y - Young Investigator & First Time Attendee Session (ID 77)

    • Event: WCLC 2013
    • Type: Other Sessions
    • Track: Other Topics
    • Presentations: 1
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      Y.3 - How to Write a Grant Application for the IASLC (ID 644)

      K. Kelly

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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