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Jeffrey Bradley



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    MA 13 - New Insights of Diagnosis and Update of Treatment (ID 674)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Early Stage NSCLC
    • Presentations: 1
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      MA 13.08 - Long Term Follow-up on NRG Oncology RTOG 0915 (NCCTG N0927): a Randomized Phase II Study of 2 SBRT Schedules for Lung Cancer (ID 7390)

      15:45 - 17:30  |  Author(s): Jeffrey Bradley

      • Abstract
      • Presentation
      • Slides

      Background:
      NRG Oncology RTOG 0915/NCCTG N0927 was a randomized lung stereotactic body radiotherapy (SBRT) trial of 34 Gy in 1 fraction (arm 1) versus 48 Gy in 4 fractions (arm 2) designed to select the better of the 2 regimens by comparing them at 1 year (yr): first by rates of pre-specified protocol-specified adverse events (psAEs), then by primary tumor control for each arm. 34 Gy emerged as the least toxic yet equally efficacious regimen. Herein, we update those results with long-term follow-up.

      Method:
      This phase II North American multicenter study of patients aged 18 yrs or older with medically inoperable non-small cell lung cancer with biopsy-proven peripheral (≥2 cm from the central bronchial tree) T1 or T2, N0 (clinically node negative by positron emission tomography), M0 tumors was designed to detect 1-yr psAEs rates >17% as primary endpoint. Primary tumor failure (PTF) (either infield or marginal failure) and local failure (either infield, marginal, or involved lobe failure) [with death without failure considered as a competing event]; overall survival (OS); disease-free survival (DFS) and progression-free survival (PFS) were secondary endpoints, but the study was not designed for statistical comparisons of these outcomes. The study opened in September 2009 and closed in March 2011. Updated data were analyzed through November 14, 2016.

      Result:
      Ninety four patients were accrued, with 86 eligible for analysis: 41 in arm 1 and 45 in arm 2, after 8 cases were excluded. Median follow-up time was 3.8 yrs for all patients, and 5.1 yrs for those alive at analysis. The grade 3 and higher treatment-related toxicity profile was unchanged since previous report, with specifically no new high grade chest wall or grade 5 events. Four of 48 Gy patients had subsequent grade 3 changes in spirometry since meeting the primary endpoint. Medians (in yrs) for 34 Gy and 48 Gy were: 4.1 vs. 4.0 for OS, and 2.6 vs. 2.8 for DFS, respectively. Five-yr outcomes as % (95% CI) for 34 Gy and 48 Gy were: PTF rate of 7.9 (2.0, 19.5) vs. 6.8 (1.7, 16.9); OS of 28.8 (15.4, 43.8) vs. 40.2 (24.9, 55.0); PFS of 19.1 (8.5, 33.0) vs. 31.8 (18.6, 45.9); and second primary rate of 15.5 (6.1, 28.9) vs. 13.3 (5.3, 25.1), respectively. Distant failure as the sole failure or a component of first failure was numerically higher in the 34 Gy arm (7 (46.7%)), but in the 48 Gy arm, rate of second primary development was higher (7 (43.8%)). Approximately 1/3 of patients’ causes of death was unknown, and another 1/3 was related to causes other than cancer or treatment.

      Conclusion:
      No excess in late-appearing toxicity was seen in either arm. Primary tumor control rates at 5 yrs were similar by arm. Median survival times of 4 yrs for each arm suggest similar efficacy pending any larger studies appropriately powered to detect survival differences.

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    MA 18 - Global Tobacco Control and Epidemiology II (ID 676)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Epidemiology/Primary Prevention/Tobacco Control and Cessation
    • Presentations: 1
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      MA 18.06 - Clinical Prognostic Model for Older Patients with Advanced Non-Small Cell Lung Cancer (ID 8113)

      15:45 - 17:30  |  Author(s): Jeffrey Bradley

      • Abstract
      • Presentation
      • Slides

      Background:
      The median age at diagnosis of lung cancer is 70 years. Older patients are often not prescribed standard therapy. Due to multiple competing causes of death, older patients often do not demonstrate a benefit in overall survival (OS). It is important to know which older patients would actually be candidates for aggressive therapy based on their prognosis, and to develop a simple prognostic model that can help clinicians determine individual prognosis.

      Method:
      Data on patients enrolled on 38 NCI-sponsored cooperative group clinical trials of advanced non-small cell lung cancer (NSCLC) from 1991 to 2011 were analyzed. Multivariable Cox PH model was built with a stepwise procedure with all potential predictors: age, sex, race, ethnicity (Hispanic or non-Hispanic), performance status, initial stage, BMI, and weight loss in the past 3/6 months. We derived a prognostic score using the estimated Cox PH regression coefficient in the training set. To assess the performance of our prognostic model, we calculated the area under receiver operating characteristic (ROC) curve of 1- and 2-year survival in the testing set.

      Result:
      The final analysis included 1454 NSCLC patients ≥70 years of age. These patients were randomly divided into a training set (n=962) and a testing set (n=492). The prognostic risk score was calculated as: 3 (if male) + 3 (if PS=1) + 8 (if PS=2) + 11 (if initial stage=IV) + 4 (if weight loss). Patients were classified into three prognostic groups by tertiles: good (0-6), intermediate (7-14) and poor (≥15). The median OS in the three groups in the testing set were: 14.6 months (95% CI, 12.2-18.5); 12.2 months (95% CI, 10.7-14.4) and 7.0 months (95% CI, 5.6-8.9), respectively. Despite its simplicity, the present model had area under the 1-year and 2-year ROCs (0.63 and 0.68, respectively) that were higher than existing models.

      Conclusion:
      Male gender, poor performance status, distant metastases and weight loss immediately prior to diagnosis predict for poor OS in older patients with advanced NSCLC. This study proposes a simple prognostic model for older adults with advanced NSCLC based on basic clinical characteristics that are part of the routine evaluation process for every patient with NSCLC.

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    MS 16 - Future Direction of Chemoradiotherapy for Inoperable Non-small Cell Lung Cancer (ID 538)

    • Event: WCLC 2017
    • Type: Mini Symposium
    • Track: Radiotherapy
    • Presentations: 1
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      MS 16.01 - Is the Dose Escalation Possible? (ID 7716)

      15:45 - 17:30  |  Presenting Author(s): Jeffrey Bradley

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA 14 - New Paradigms in Clinical Trials (ID 681)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      OA 14.07 - Progress in Lung Squamous Cell Carcinoma from the Lung-MAP Master Protocol (S1400) Sub-Studies S1400A, S1400B, S1400C and S1400D (ID 9593)

      11:00 - 12:30  |  Author(s): Jeffrey Bradley

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung-MAP (S1400) is a master umbrella protocol designed to establish genomic screening for previously treated squamous cell lung cancer patients (SqCCA), and independently evaluate targeted therapies with matching biomarkers and alternative therapies (designated non-match therapy) in patients without putative markers. The protocol opened June 16, 2014 with four biomarker-driven sub-studies and one non-match sub-study.

      Method:
      Eligibility stipulated advanced SqCCA, progressing after at least one prior platinum-based chemotherapy, PS 0–2, and EGFR/ALK wild-type. Tumor samples were required and analyzed for gene alterations by FoundationOne NGS assay (Foundation Medicine). The original biomarker and non-match studies were: S1400B evaluating taselisib for PI3K mutations, S1400C evaluating palbociclib for cell cycle gene alterations (CCGA), S1400D evaluating AZD4547 for FGFR mutations, S1400E evaluating rilotumumab and erlotinib for c-MET positive tumors, and S1400A evaluating durvalumab in patients with no matching biomarkers. The original design included randomization to a control arm, but was amended to a single-arm phase 2 design. The primary endpoint for each modified sub-study was response.

      Result:
      As of June 16, 2017 all original sub-studies have been closed to accrual; 1298 patients registered to the screening component of the trial and 486 patients have registered to a sub-study. Two new sub-studies have been launched and are currently accruing. Details of the completed sub-studies are included in the table.

      Sub-study Final Accrual Biomarker prevalence/% of sub-study registrations Closure Date Response to investigational therapy N (%) Status
      S1400A (non-match) Total: 116 Durvalumab: 78 Docetaxel: 38 NA/59% 12/18/15 Docetaxel arm closed: 4/22/15 11 (16%) Administratively closed to enable activation of new non-match study.
      S1400B PI3K Total: 39 taselisib: 31 Docetaxel: 8 8%/9% 12/12/16 Docetaxel arm closed: 12/18/15 1 (4%) Closed at interim futility analysis.
      S1400C (CCGA+) Total: 54 Palbociclib: 37 Docetaxel: 17 19%/15% 09/01/16 Docetaxel arm closed: 12/18/15 2 (6%) Closed at interim futility analysis.
      S1400D (FGFR+) Total: 45 AZD4547: 35 Docetaxel: 10 16%/12% 10/31/16 Docetaxel arm closed: 12/18/15 2 (7%) Closed at interim futility analysis.
      S1400E (MET+) Total: 9 R+E: 4 E: 5 N/A (closed too early) 11/26/2014 N/A Closed d/t discontinuation of development of rilotumumab


      Conclusion:
      Lung-MAP as a master genomic screening protocol has demonstrated feasibility with respect to accrual and evaluation of targeted therapies in lower prevalence patient populations. This dynamic, centralized, single-IRB platform is well positioned to efficiently assess multiple novel therapeutics for advanced SqCCA patients.

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    P1.08 - Locally Advanced NSCLC (ID 694)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      P1.08-003 - Concomitant Chemotherapy and Radiotherapy with SBRT Boost for Unresectable, Stage III Non-Small Cell Lung Cancer: A Phase I Study (ID 8181)

      09:30 - 16:00  |  Author(s): Jeffrey Bradley

      • Abstract

      Background:
      Stereotactic Body Radiation Therapy (SBRT) is now the standard of care in medically inoperable stage I non-small cell lung cancer, yielding high rates of local control. It is unknown if SBRT can be safely utilized in the locally advanced NSCLC setting. This multi-institution phase I study evaluated the safety of 44 Gy conventionally fractionated thoracic radiation with concurrent chemotherapy plus a dose escalated SBRT boost to both the primary tumor and involved mediastinal lymph nodes. The primary endpoint of this study was to establish the maximum tolerated dose (MTD) of the SBRT boost.

      Method:
      Inclusion criteria included unresectable stage IIIA or IIIB disease, primary tumor ≤8 cm, and N1 or N2 lymph nodes ≤5 cm. Tumors were staged with PET/CT while four dimensional CT simulation was employed for radiation planning. The treatment schema was 44 Gy thoracic radiation (2 Gy/day) with weekly carboplatin and paclitaxel chemotherapy. A second CT simulation was obtained after 40 Gy was delivered, and a SBRT boost was planned to the remaining gross disease at the primary site and involved lymph nodes. Four SBRT boost dose cohorts were tested: Cohort 1 (9 Gy x 2); cohort 2 (10 Gy x 2); cohort 3 (6 Gy x 5); and cohort 4 (7 Gy x 5). Patients were treated in cohorts of three patients and using Bayesian Escalation with Overdose Control (EWOC) method to determine Maximum tolerated dose of the SBRT boost. Dose limiting toxicities (DLT) were defined as any grade 3 or higher toxicities within 30 days of treatment attributed to treatment, not including hematologic toxicity, or any grade 5 toxicity attributed to treatment.

      Result:
      The study enrolled 19 patients from 11/2012-12/2016. There were 4 screen failures and 15 patients were treated on study. There were no DLTs in dose cohort 1 (n = 3) and 2 (n = 6). One patient in dose cohort 3 (n = 3) developed a DLT, and 2 patients in dose cohort 4 (n = 3) developed a DLT. The calculated MTD was 6 Gy x 5. The DLT observed at this dose level was a tracheoesophageal fistula; given this substantial toxicity, there was investigator reluctance to enroll further patients in this dose level. Thus the calculated MTD is 6 Gy x5, however 10 Gy x 2 is felt to be a reasonable dose as well given no grade 5 toxicities occurred with this dose.

      Conclusion:
      The MTD of a SBRT boost combined with 44 Gy thoracic chemoradiation is 6 Gy x 5. A SBRT boost dose of 10 Gy x 2 could be considered very safe with no grade 3 or higher toxicities observed at this dose level.