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Chen Hu



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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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      OA12.01 - PCI for Radically Treated Non-Small Cell Lung Cancer: A Meta-Analysis Using Updated Individual Patient Data of Randomized Trials (Now Available) (ID 2624)

      15:45 - 17:15  |  Author(s): Chen Hu

      • Abstract
      • Presentation
      • Slides

      Background

      In localized non-small cell lung cancer (NSCLC), prophylactic cranial irradiation (PCI) reduced the incidence of brain metastases (BM) (relative risk 0.35), but without a demonstrated effect on overall survival (OS). This may be due to the small sample size in these individual randomized clinical trials (RCTs).

      Therefore, we aimed to assess the impact of PCI on long term OS for radically treated stage III NSCLC patients compared to observation using updated individual patient data (IPD) from RCTs.

      Method

      The main endpoint was OS and secondary endpoints were progression-free survival (PFS), BM-free survival (BMFS) and toxicity. All analyses were performed based on the intention-to-treat principle. The median follow-up was estimated using the inverse Kaplan-Meier method. The log-rank observed minus expected number of events and its variance were used to calculate individual and overall pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) with a fixed effects model. Heterogeneity was studied using the Cochrane test and I2. Survival curves and 5-year difference between arms were estimated using the Peto method. Interaction between prognostic factors (age, performance status, and histology) and treatment allocation were assessed using Cox proportional hazards models. Toxicities grade ≥ 3 were reported descriptively.

      Result

      Data on four of the seven eligible trials (SWOG 8300, RTOG 0214, Guangzhou 2005 and NVALT-11) were available for this IPD meta-analysis. In total, 924 patients were analyzed of which 68% was male, median age was 61 years, 94% of the patients had a performance status ≤ 1 and 37% had squamous histology. The median follow-up was 8.1 years. All trials provided sufficient IPD for the three endpoints, except for the SWOG 8300 trial (OS only). This trial explained inter-trial heterogeneity. Because of the qualitative interaction with the other trials (p=0.0062) it was separately analyzed (N=254). Compared to observation, OS was significantly lower for PCI in the SWOG 8300 trial (HR 1.38, 95% CI [1.07 to 1.79] p=0.013, 5-year absolute difference -0.9%, 95% CI [-5.9 to 4.1]). However, for the other trials (N=670) no significant OS difference was observed (HR 0.90, 95% CI [0.76 to 1.07] p=0.228, 5-year absolute difference 1.8%, 95% CI [-5.2 to 8.8]). PFS (HR 0.78, 95% CI [0.65 to 0.92] p=0.004, 5-year absolute difference 4.8%, 95% CI [-1.2 to 10.8]) and BMFS (0.38, 95% CI [0.27 to 0.53] p<0.001, 5-year absolute difference 20.7%, 95% CI [12.2 to 29.2]) were significantly higher in the PCI arm. There was no interaction between prognostic factors and treatment allocation for OS. Toxicity data for the PCI arm was available in all trials except the SWOG 8300 trial. The total number of patients with at least one grade ≥3 toxicity (for the adverse events pre-specified in the protocol) in the PCI arm was 19/456, including 11/86 in the NVALT-11 trial. Toxicity for the observation arm was only available in the NVALT-11 trial, including 4/88 patients with at least one grade ≥3 toxicity.

      Conclusion

      Although PFS and BM-free survival were improved for patients who received PCI, no significant PCI benefit for OS was observed.

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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  |  Presenting Author(s): Chen Hu

      • 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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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-04 - NCI-NRG Oncology ALK PROTOCOL (NRG-LU003): A Biomarker-Driven Protocol for Previously Treated ALK-Positive Non-Squamous NSCLC Patients      (ID 2021)

      10:15 - 18:15  |  Author(s): Chen Hu

      • Abstract

      Background

      Currently, the 1stgeneration ALK inhibitor crizotinib and 2ndgeneration ALK inhibitors ceritinib, alectinib and brigatinib are FDA-approved for the treatment of advanced ALK-positive NSCLC. The 3rdgeneration ALK inhibitor lorlatinibrecentlyreceived accelerated approval for patients after failure of a 2ndgeneration inhibitor.

      2ndgeneration ALK inhibitors are widely used in crizotinib-resistant patients and have recently replaced crizotinib as first-line therapy for newly diagnosed patients. There is an urgent need to define the optimal therapy for patients who have become resistant to a second-generation ALK inhibitor. Pre-clinical data and small case series suggest that the presence/absence of ALK resistance mutations or the specigic ALK mutation may serve as a critical biomarker to guide selection of therapy, particularly in the setting of relapse on a 2ndgeneration ALK inhibitor when ALK resistance mutations are more common,

      Method

      NRG-LU003 proposes to study ALK-positive non-squamous NSCLC patients who develop resistance to a second-generation ALK inhibitor, in order to establish a treatment algorithm for these patients based on resistance mechanisms.Patients will undergo tissue biopsy along with blood sampling for cfDNA analysis. One of the aims of the study is to establish the concordance between tissue and liquid biopsies; liquid biopsy may replace tissue biopsy after the first 200 patients enrolled, depending on the concordance and in consultation with CDRH/FDA. Treatments will be selected based on preclinical and clinical data demonstrating activity of treatment particular inhibitor against the specific ALK mutation or resistance mechanism identified. If no ALK resistance mutations are identified, patients will be randomized to receive either a next-generation ALK inhibitor they have not previously received or pemetrexed-based therapy with cisplatin or carboplatin.

      Target accrual is 660 patients and primary objective is to assess whether ALK kinase domain mutations (e.g., G1202/C1156/I1171/L1196/V1180/F1174 mutations) associated with drug resistance are predictive of objective response to subsequent ALK inhibitor therapy, to assess whether subsequent pemetrexed based chemotherapy improves objective response compared to ALK inhibitor therapy for patients with no ALK resistance mutations, and to evaluate objective responses of patients with specific genetic alterations (e.g., ALK L1198F, compound mutations, or high-level MET amplification) treated with crizotinib.

      Mutation

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      G1202, G1202del, G1202R

      lorlatinib

      brigatinib

      C1156Y

      lorlatinib

      alectinib

      brigatinib

      I1171

      lorlatinib

      ceritinib

      brigatinib

      L1196, L1196M

      lorlatinib

      ceritinib

      alectinib

      brigatinib

      ensartinib

      V1180

      lorlatinib

      ceritinib

      brigatinib

      F1174

      lorlatinib

      alectinib

      brigatinib

      Compound mutation

      lorlatinib

      ALK L1198F (alone/ in combination with another ALK mutation)

      crizotinib

      MET amplification

      crizotinib

      No ALK-resistance mutations*

      lorlatinib

      ceritinib

      alectinib

      brigatinib

      ensartinib

      Pemetrexed

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      Cisplatin or Carboplatin

      Result

      "Section not applicable"

      Conclusion

      This study has been approved and is open for enrollment through the National Clinical Trials Network (NCTN).

      This project is supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC) from the National Cancer Institute (NCI)

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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): Chen Hu

      • 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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