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T.E. Stinchcombe



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    MA06 - Locally Advanced NSCLC: Risk Groups, Biological Factors and Treatment Choices (ID 379)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      MA06.10 - A Pooled Analysis Comparing the Outcomes of Elderly to Younger Patients on NCTN Trials of Concurrent CCRT for Stage 3 NSCLC  (ID 4219)

      17:06 - 17:12  |  Author(s): T.E. Stinchcombe

      • Abstract
      • Presentation
      • Slides

      Background:
      Concurrent chemoradiotherapy (CCRT) is the standard treatment (TRT) for stage 3 NSCLC. Elderly patients (pts) are common, may have increased toxicity,& poorer results from CCRT

      Methods:
      Individual patient data (IPD) from NCTN phase 2/3 trials of CCRT for stage 3 NSCLC from 1990-2012 was collected. We compared the overall survival (OS), progression-free survival (PFS), & adverse events (AE’s) for pts age ≥70 years (yrs) (elderly) vs. <70 yrs (younger). Unadjusted & adjusted Hazard Ratios (HRs) for survival time & their confidence intervals (CIs) were estimated by single-predictor & multivariable Cox models. Unadjusted & adjusted Odds Ratio (OR) for AE’s & their CIs were obtained from single-predictor & multivariable logistic regression models

      Results:
      IPD from 16 trials were analyzed; 2,768 pts were younger & 832 were elderly. Median OS & PFS for elderly & younger pts are in the table. In the unadjusted & multivariable models elderly pts had worse OS (HR=1.23; 95%CI =1.13-1.35, and 1.20; 95%CI=1.10-1.32, respectively). In the unadjusted & multivariable models, elderly & younger pts had a similar PFS (HR=1.02; 95% CI=0.94-1.11 and 1.01, 95% CI=0.92-1.10, respectively). Elderly pts had a higher rate of grade ≥3 AE’s in the unadjusted & multivariable models (OR=1.25; 95% CI=1.00-1.57 and 1.30; 95%CI=1.03-1.62, respectively). A lower percentage of elderly pts compared to younger completed TRT (47% and 57%, respectively; P<0.0001) & higher percentage stopped due to AE’s (20% and 13%; P<0.0001). Grade ≥ 3 AE’s (occurring at a rate ≥ 2.5%) with a higher rate in the elderly: neutropenia, dyspnea, fatigue, anorexia, vomiting, dehydration, hypoxia, hypotension, & pneumonitis (P<0.05).

      Age ≥ 70yrs Age < 70 yrs P-value[a]
      Median OS (months) 17.0 20.7 < 0.01
      Median PFS (months) 8.7 9.1 0.68
      All toxicities grade ≥3 86% 84% 0.04
      Hematologic AE’s grade ≥3 65% 61% 0.04
      Non-hematologic AE’s ≥3 68% 62% <0.01
      Grade 5 AE’s 9.0% 4.4% <0.01
      TRT related deaths[b] 3.2% 2.0% 0.12
      a: Log-rank test for survival times, chi-square test for AE’s, and Fisher’s exact test for deaths. The P-values from these tests are unadjusted. b: Data available on 2,091 patients

      Conclusion:
      Elderly pts in CCRT trials had worse OS, similar PFS, & a higher rate of severe AE's.

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    P2.03a - Poster Session with Presenters Present (ID 464)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 2
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      P2.03a-040 - Safety and Efficacy of Nab-Paclitaxel for 2nd Line Treatment of Elderly Patients with Stage IV Non-Small Cell Lung Cancer (ID 4209)

      14:30 - 14:30  |  Author(s): T.E. Stinchcombe

      • Abstract

      Background:
      Retrospective analyses suggest benefit to 2[nd] line therapy in the fit elderly, but prospective data are lacking. Subgroup analysis of a phase III study of carboplatin and nab-paclitaxel for 1[st] line treatment of NSCLC showed superior survival in elderly patients.

      Methods:
      This is a phase II study for patients > 70 years of age with progression on a non-taxane 1[st] line doublet. Nab-paclitaxel 100mg/m[2] is administered intravenously, 3/4 weeks per cycle until progressive disease or intolerance. The primary endpoint is occurrence of ≥grade 3 treatment-related toxicities after 6 cycles or within 3 weeks if early treatment discontinuation occurred. Null hypothesis is a rate of 60% and alternative hypothesis is < 40%.

      Results:
      As of June 2016, 35/42 patients started treatment, and 31 completed. Median age is 75 (range 70 to 83). 51.4% are female. 8.6% have PS0, 68.6% PS1 and 22.9% PS2. 82.9% have adenocarcinoma, 14.3% SqCC, and 2.9% adenosquamous. 5.7% had EGFR, 28.6% kRAS. 33 patients had one prior treatment and 2 also received nivolumab. Of the 31 patients off treatment, median cycles received was 3 (range 1-22). 11/30 (37%) experienced the primary endpoint. When expanded to >=grade 3 toxicity at any time, this rose to 43% (13/30). The most common ≥G3 toxicities at any time point were fatigue (6/30), peripheral sensory neuropathy (4/30) and neutropenia (3/30). RR was 21% (1CR, 5PR, 16SD and 7PD of 29 patients evaluable). With a median FU of ongoing survivors (n=9) of 7.8 months, median progression free survival (PFS) was 5.2 months and median overall survival (OS) was 10.1 months. Figure 1



      Conclusion:
      These results demonstrate efficacy and safety of nab-paclitaxel for the 2[nd] line treatment of NSCLC in elderly patients and provide prospective data to support the treatment of fit elderly in 2[nd] line. Updated PFS, OS, geriatric assessment and quality of life data will be presented.

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      P2.03a-055 - Predicting Risk of Chemotherapy-Induced Severe Neutropenia in Lung Patients: A Pooled Analysis of US Cooperative Group Trials (ID 3975)

      14:30 - 14:30  |  Author(s): T.E. Stinchcombe

      • Abstract

      Background:
      Neutropenia is the most serious hematologic toxicity associated with the use of chemotherapy. Severe neutropenia (SN) may result in dose delays and/or reductions, and the use of growth colony stimulating factors (CSFs) increases the cost of therapy. Lyman et al. (2011) published a risk model to predict individual risk of neutropenia in patients receiving chemotherapy for multiple types of cancer. The Lyman model (LM) has not been validated by external datasets. We investigated the LM with a large external lung cancer dataset based on clinical criteria of SN and investigated new risk prediction models for SN.

      Methods:
      Stage IIIA/IIIB/IV non-small cell lung cancer (NSCLC) and extensive small cell lung cancer (SCLC) chemotherapy phase II/III trials completed in 1990-2012 were assembled from U.S. cancer cooperative groups. SN was defined as any neutropenic complications grade ≥ 3 according to CTCAE. A risk score was calculated as a weighted sum of regression coefficients of the LM for all patients in the database. The performance of risk models was evaluated by the area under the ROC curve (AUC) with a good model defined as AUC ≥ 0.7. To develop new risk models, a random split was used to divide the database into training cohort (2/3) and testing cohort (1/3). Multivariable logistic regression models with stepwise selection and lasso selection (Tibshirani, 1996) were built in training cohort and validated in testing cohort. Candidate predictors included patient-level and treatment-level variables. The patients with complete data were used for validation and all patients, including those with imputed predictors, were used to develop new risk models.

      Results:
      Eighty seven trials with 14,829 patients were included. The LM had a good performance in SCLC patients (AUC=0.86), but it had poor performance in NSCLC patients (AUC=0.47), and an overall unsatisfactory performance in all patients (AUC=0.56). The stepwise model had superior performance than the lasso model (AUC: 0.84 vs. 0.76) in training, while the lasso model had smaller shrinkage in testing. A parsimonious model, based on histology, prior chemo, platinum-based, taxanes, gemcitabine, CSFs, age as continuous variable, relative dose intensity, and white blood cell (WBC), performed slightly worse (AUC=0.71) in testing than the stepwise model and the lasso model.

      Conclusion:
      The U.S. cooperative group data failed to validate the LM in predicting the risk for severe neutropenia in lung cancer patients receiving chemotherapy. The parsimonious model involving nine predictors showed good performance in predicting severe neutropenia. Prospective validation is warranted.

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02b-052 - Afatinib with or without Cetuximab for First-Line Treatment of EGFR-Mutant NSCLC: Interim Safety Results of SWOG S1403 (ID 5798)

      14:30 - 14:30  |  Author(s): T.E. Stinchcombe

      • Abstract

      Background:
      Afatinib is used as first-line therapy for EGFR-mutant non-small cell lung cancer (NSCLC), however resistance invariably develops. To attempt to delay resistance and improve survival, we are conducting a randomized Phase II/III trial of afatinib plus cetuximab versus afatinib alone in treatment-naïve patients with advanced EGFR-mutant NSCLC (NCT02438722).

      Methods:
      Previously untreated patients with EGFR exon 19 deletion or L858R point mutation are randomized to afatinib 40mg PO daily plus cetuximab 500mg/m2 IV every 2 weeks (afat/cetux) or afatinib 40mg PO daily (afat). Dose reductions are performed for grade 3-4 or intolerable or medically concerning grade 2 adverse events (AEs) per CTCAE v4.0. The Phase II primary endpoint is progression-free survival and the Phase III primary endpoint is overall survival. Here we review the safety data after enrollment of the first 53 patients.

      Results:
      53 patients were registered as of June 30, 2016, and safety has been assessed in 47 (23 treated with afat/cetux and 24 with afat, see Table). Grade 1-2 rash occurred in 71% of patients receiving afat/cetux and 63% of patients on afat. Grade 3 rash was noted in 22% of patients on afat/cetux. Fatigue was more common in the combination arm; all occurrences were grade 1-2. Grade 1-2 diarrhea and other gastrointestinal AEs were comparable between the two arms. There were similar numbers of dose reductions for AEs on each arm. Three patients discontinued treatment due to AEs: 2 on the afat/cetux arm due to hyperglycemia and accumulated side effects and 1 on the afat arm due to weight loss and diarrhea. Figure 1



      Conclusion:
      In this randomized trial of afat/cetux versus afat, treatment was tolerable in both arms of the study. Skin toxicity appears to be worse with the combination however other AEs are similar between the two groups. Enrollment to this trial is ongoing.

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    P3.03 - Poster Session with Presenters Present (ID 473)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      P3.03-036 - Prognostic Model for Mesothelioma Based on Cancer and Leukemia Group B (CALGB) Trials (Alliance) (ID 3976)

      14:30 - 14:30  |  Author(s): T.E. Stinchcombe

      • Abstract

      Background:
      Prognostic models play an important role in the design and analysis of mesothelioma treatment trials. The European Organisation for Research and Treatment of Cancer (EORTC) developed a well-known tool in 1998 to predict overall survival (OS) in patients with malignant mesothelioma. In this study, we built and assessed the performance of a new mesothelioma prognostic model OS using data from multiple CALGB clinical trials data.

      Methods:
      This study included 595 mesothelioma patients from fifteen completed CALGB treatment trials accrued between June 1984 and August 2009. We split the cohort of patients into two parts - 67% of patients as training and 33% as testing. We developed a Cox model using the training set with PS, age, WBC count, and platelet count as prognostic variables. To compare the EORTC and our new models, the concordance of predicted survival times and risk scores were estimated by concordance C (c-index) (Harrell et al. 1996) and AUC score at 6-months (Patrick et al. 2000). 95% confidence intervals were calculated for the c-index. Based on the prediction model fit from training set, we partitioned testing set patients into high-risk and low-risk groups using the median for their risk score values for the new model. For the EORTC model, the cut off of 1.27 from the original paper was used to assign the high-risk and low-risk groups. A Log-rank test was used to compare the survival curves of these two groups. We also compared our results with a model using PS alone.

      Results:
      For OS, the EORTC model c-index was 0.55 (0.52, 0.58) and P = 0.0007 comparing high- and low- risk patients for testing set. The new model c-index was 0.60 (0.56, 0.64), with P < 0.000001 for testing set. Using the new model, the median OS in the high-risk and low-risk groups in the testing set were 5.16 (4.70, 6.37) and 10.41 (7.95, 14.32) months, respectively. PS alone produced c-index of 0.55 (0.53, 0.57) and P = 0.0002 for testing set. The AUC scores at 6-months for testing set generated by EORTC and PS alone models are 0.62 and 0.66. The new model generated AUC scores at 6-months of 0.70.

      Conclusion:
      Our new model performs better than the EORTC model or PS alone for survival prognostication in patients with mesothelioma.