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Jeffrey D Bradley



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    OA04 - Immuno Combinations and the Role of TMB (ID 126)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      OA04.01 - A Phase III Randomized Study of Nivolumab/Ipilimumab vs Nivolumab for Previously Treated Stage IV Squamous Cell Lung Cancer (Now Available) (ID 872)

      15:15 - 16:45  |  Author(s): Jeffrey D Bradley

      • Abstract
      • Presentation
      • Slides

      Background

      Lung-MAP is a master protocol for patients (pts) with stage IV previously treated SqNSCLC. S1400I enrolled pts who were not eligible for a biomarker-matched sub-study. (Lung-MAP Sub-Study S1400I, NCT02785952)

      Method

      S1400I is phase III randomized trial for immunotherapy-naïve patients with ECOG 0-1 not selected by PD-L1 expression. Pts were assigned 1:1 to nivolumab and ipilimumab (N+I) vs nivolumab (N). N was given at 3 mg/kg q 2w, I was given at 1 mg/kg q 6w. The primary endpoint was overall survival (OS). Secondary endpoints: investigator-assessed progression-free survival (IA-PFS), response by RECIST 1.1, and toxicity.

      Result

      From December 18, 2015 to April 23, 2018, 275 pts enrolled and 252 determined eligible (125 N+I and 127 N). Median follow up for patients still alive was 17.4 months. The study was closed for futility at an interim analysis. Baseline characteristics were similar across arms. mOS was 10.0 m (8.0-12.8) and 11.0 m (8.2-13.5) for N+I and N. HR 0.97 (0.71-1.31), p 0.82. mPFS was 3.8 m (2.3-4.2) and 2.9 m (1.8-3.9) for N+I and N. HR 0.84 (0.64-1.09), p 0.19. The response rate was 18% (12-25) in N+I and 17 % (11, 24) in N. Outcomes were similar across TMB subgroups and PD-L1 expression levels. Most AE were low grade. There were 5 grade 5 AE in N+I arm and 1 in N arm. Grade ≥3 treatment-related AEs occurred in 48(39%) of pts on N+I vs 38(31%) on N. irAE reported in 39% of pts on N+I and 34% of patients on N. Drug-related AEs led to discontinuation in 25% of pts on N+I and 16% of pts on N.

      OS and PFS based on TMB and PD-L1

      N+I

      Median in months

      N

      Median in months
      HR p
      OS PD-L1 ≥5 14.1 (5.8-17.5) 12.0 (8.2-19.8) 1.06 (0.58-1.92) 0.86
      OS PD-L1 <5 8.3 (6.0-10.7) 10.3 (6.3-13.5) 1.01 (0.62-1.65) 0.97
      OS TMB ≥10 13.1 (9.3-17.0) 11.4 (8.2-16.1) 0.86 (0.56-1.32) 0.48
      OS TMB <10 7.6 (5.7-10.2) 10.0 (6.3-15.2) 1.08 (0.68-1.71) 0.74
      PFS PD-L1 ≥ 5 3.9 (1.7-7.1) 2.9 (1.8-4.7) 0.65 (0.38-1.08) 0.10
      PFS PD-L1 <5 4.4 (2.1-6.0) 1.6 (1.5-3.0) 0.64 (0.41-1.01) 0.06
      PFS TMB ≥ 10 4.2 (3.4-5.9) 3.4 (1.8-5.3) 0.75 (0.52-1.10) 0.15
      PFS TMB < 10 1.9 (1.5-4.1) 2.7 (1.6-3.3) 0.92 (0.62-1.39) 0.70

      Conclusion

      S1400I failed to show improvement in outcomes with N+I. Study was closed for futility at interim analysis. Toxicities were not different between two arms. Molecular correlates will be presented at the meeting.

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    OA12 - Profiling the Multidisciplinary Management of Stage III NSCLC (ID 144)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
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      OA12.03 - Initial Reporting of NRG-LU001, Randomized Phase II Trial of Concurrent Chemoradiotherapy +/- Metformin HCL in Locally Advanced NSCLC (Now Available) (ID 1868)

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

      • Abstract
      • Presentation
      • Slides

      Background

      Preclinical and retrospective clinical data, have shown that metformin, an inexpensive diabetes drug, has the potential to improve response to chemotherapy and radiation in several solid tumors, including non-small cell lung cancer (NSCLC). These findings led to NRG-LU001, a multi-institutional, international randomized Phase II clinical trial to determine whether metformin can improve outcomes of curative chemoradiation (CRT) in locally advanced NSCLC (LA-NSCLC).

      Method

      Unresectable stage IIIA/B NSCLC patients were randomized to either concurrent chemoradiation to 60 Gy with weekly carboplatin-paclitaxel (CP), followed by consolidation CP (Control) or the same regimen combined with metformin (2000 mg/day) (Experimental). The primary endpoint was 1-year progression free survival (PFS). PFS and overall survival (OS) were estimated using the method of Kaplan-Meier. Time to loco-regional progression (TTLRP) or distant metastasis (TTDM) were estimated using the cumulative incidence method. Adverse events (AEs) were graded using CTCAE v4.0.

      Result

      170 patients were randomized between Aug. 2014-Dec. 2016, with planned analysis at 102 events. No significant difference in toxicity was observed between Control and Experimental arms. 1- and 2-year PFS was 60.4% (95% CI: 48.5, 70.4) and 40.1% (95% CI: 29.0, 51.0) in Control vs 51.3% (95% CI: 39.8, 61.7) and 34.5% (95% CI: 24.2, 45.1) in the Experimental arm (multivariable Cox proportional HR=1.20 (95% CI: 0.81, 1.78), p=0.36). On multivariable analysis including treatment arm, performance status, histology and stage, only higher stage (IIIA vs. IIIB) was associated with worse PFS (HR 1.79, 95% CI:1.19, 2.69, p=0.0054). OS at 2 years was 65.4% (95% CI: 53.5, 75.0) for Control vs 64.9% (95% CI: 53.1, 74.5) for the Metformin arm (HR=1.03 (95% CI: 0.64, 1.68)), while deaths due to disease were 90% vs 71%, respectively. No significant differences were found for TTLRP (HR 1.01, 95% CI: 0.57, 1.79, p=0.98) or TTDM (1.38, 95% CI: 0.76, 2.5, p=0.29). 63.4% of patients in the experimental arm received the complete course of metformin, with the most common cause of discontinuation being side effects or complications (13.4%).

      Conclusion

      In NRG-LU001, concurrent CRT and metformin presented no noticeable safety concerns. However, this combination failed to improve PFS at the hypothesized effect size. Additionally, no effect on OS or patterns of failure were identified. Blinded central review of imaging based PFS is ongoing. Somewhat unexpectedly, 37% of patients did not complete the prescribed course of metformin. Additionally, deaths due to disease were less in the experimental arm compared to control.

      Acknowledgements: This project was supported by National Cancer Institute (NCI) grants: U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG SDMC), UG1CA189867 (NCORP), U24CA180803 (IROC). HS and TT are Co-Principal Investigators in this trial.

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    P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.18-12 - PACIFIC-4/RTOG 3515: Phase III Study of Durvalumab Following SBRT for Unresected Stage I/II, Lymph-Node Negative NSCLC (ID 1363)

      09:45 - 18:00  |  Author(s): Jeffrey D Bradley

      • Abstract
      • Slides

      Background

      Approximately 20% of non-small-cell lung cancer (NSCLC) patients (pts) present with localized disease and this percentage is expected to increase with routine computerized tomography screening. While surgery remains standard of care (SoC) for operable pts, for unresected pts stereotactic body radiation therapy (SBRT) is now the standard. However, locoregional and distant failures occur in >30% of pts after SBRT, with higher failure rates associated with larger tumors. Durvalumab is a selective high-affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80. In the Phase 3 PACIFIC trial of durvalumab vs placebo in patients with unresected, Stage III NSCLC without progression on concurrent chemoradiotherapy (cCRT), durvalumab significantly improved both primary endpoints of progression-free survival (PFS) and overall survival (OS) versus placebo and the two treatment arms had similar safety profiles (Antonia et al, NEJM 2017; 2018). Accordingly, the PACIFIC regimen is becoming the SoC for Stage III NSCLC. Accumulating evidence suggests potential benefit with immunotherapy at early stage NSCLC. PACIFIC-4 will assess the efficacy and safety of durvalumab versus placebo following SBRT in pts with unresected Stage I/II lymph-node negative NSCLC.

      Method

      PACIFIC-4 is a Phase 3, randomized, placebo-controlled, double-blind, international study of durvalumab in pts with clinical Stage I/II node-negative (T1 to T3N0M0) NSCLC following definitive SBRT. Approximately 630 pts will be randomized 1:1 to receive durvalumab (1500 mg intravenously) or placebo every 4 weeks for 24 months, or until discontinuation due to disease progression, toxicity or withdrawal of consent. Eligible pts are adults with unresected Stage I/II NSCLC, are node-negative, ECOG PS 0–2, and have completed SoC SBRT. The primary endpoint is PFS using BICR assessments and the key secondary endpoint is OS. Other endpoints include health-related quality of life, lung cancer mortality, pharmacokinetics, immunogenicity, and safety. Recruitment for this trial is ongoing.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P2.12 - Small Cell Lung Cancer/NET (ID 180)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.12-20 - NRG Oncology/Alliance LU005:  A Phase II/III Randomized Study of Chemoradiation Versus Chemoradiation Plus Atezolizumab in LS-SCLC   (Now Available) (ID 2670)

      10:15 - 18:15  |  Author(s): Jeffrey D Bradley

      • Abstract
      • Slides

      Background

      Clinical outcomes for limited stage small cell lung cancer (LS-SCLC) remain suboptimal. Standard of care chemoradiation with platinum/etoposide and thoracic radiation to 45 Gy delivered twice daily followed by prophylactic cranial irradiation yields a median overall survival of 30 months. LU005 is a randomized phase II/III trial designed to test the addition of atezolizumab to concurrent chemoradiation (ClinicalTrials.gov Identifier: NCT03811002).

      Method

      Patients with LS-SCLC (Tx-T4, N0-N3, M0) are randomly assigned in a 1:1 ratio to either standard chemoradiation, consisting of thoracic radiation (45 Gy twice daily or 66 Gy daily) with concurrent platinum/etoposide chemotherapy, or the experimental arm, consisting of the same chemoradiation regimen plus the addition of atezolizumab beginning concurrently with thoracic radiation, and continued every 3 weeks for 12 months duration. Thoracic radiation begins with the second cycle of chemotherapy in both treatment arms. Stratification variables include radiation schedule (once daily vs. twice daily), chemotherapy (cisplatin vs. carboplatin), sex, and performance status (PS 0/1 vs. 2). Prophylactic cranial radiation is recommended for patients who have a response to treatment. The phase II primary endpoint is progression free survival (PFS) and the phase III primary endpoint is overall survival (OS). It is hypothesized that the addition of atezolizumab will yield a hazard ratio of 0.62 for PFS, for a sample size of 280 patients in the phase II portion of this study. The overall sample size for phase II/III will be 506, with the OS analysis designed to provide at least 85% power to detect a hazard ratio of 0.71 at a 1-sided significance level of 0.025. Secondary endpoints include objective response rates, local control, distant metastases free, and quality of life. This study includes a robust translational science component including blood and tissue based assays to further understand which patients may benefit most from immunotherapy.

      Result

      This study activated in May 2019 and is currently enrolling patients.

      Conclusion

      NRG Oncology/Alliance LU005 is a randomized II/III trial testing the addition of atezolizumab to standard chemoradiation for LS-SCLC. The estimated date of study completion is May 2024.

      *Authors Higgins and Ross are co-first authors and contributed equally to this work.

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