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Thomas E. Stinchcombe



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    MS07 - Antibody-Drug Conjugates in Advanced NSCLC (ID 786)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 205 BD
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      MS07.03 - Clinical Data (ID 11430)

      14:10 - 14:30  |  Presenting Author(s): Thomas E. Stinchcombe

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA10 - Right Patient, Right Target & Right Drug - Novel Treatments and Research Partnerships (ID 910)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 106
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      OA10.04 - Afatinib With or Without Cetuximab for EGFR-Mutant Non-Small Cell Lung Cancer: Safety and Efficacy Results from SWOG S1403 (ID 14014)

      11:05 - 11:15  |  Author(s): Thomas E. Stinchcombe

      • Abstract
      • Presentation
      • Slides

      Background

      Several EGFR tyrosine kinase inhibitors (TKIs) are used for the treatment of EGFR-mutant non-small cell lung cancer (NSCLC), however resistance inevitably develops. The combination of the irreversible ErbB family TKI afatinib and the EGFR monoclonal antibody cetuximab was previously shown to overcome resistance to first-line EGFR TKIs. To attempt to delay resistance, we conducted a randomized trial of afatinib plus cetuximab versus afatinib alone in treatment-naïve patients with advanced EGFR-mutant NSCLC (NCT02438722).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with previously-untreated EGFR-mutant NSCLC were randomized to afatinib 40mg PO daily plus cetuximab 500mg/m2 IV every 2 weeks or afatinib 40mg PO daily. The study was designed to accrue a total of 212 patients, comparing progression-free survival (PFS) between the arms at the 1-sided 0.025 level when 134 PFS events had been observed. Secondary objectives included comparison of overall survival (OS), time to treatment discontinuation (TTD), and toxicity. An interim analysis evaluating early stopping for futility occurred when at least 64 PFS events were reported.

      4c3880bb027f159e801041b1021e88e8 Result

      Between March 26, 2015 and April 23, 2018, 170 eligible patients were accrued: 86 to afatinib/cetuximab and 84 to afatinib. Median age was 66.4 years, 66% were female, 64% had an EGFR exon 19 deletion mutation and 36% had an L858R point mutation. With 109 events observed, there was no improvement in PFS with the combination compared to single-agent (HR 1.17, 95% CI 0.80-1.73, P = 0.42, median 10.6 months vs 13.1 months). OS was also not improved with the addition of cetuximab (HR 1.23, 95% CI 0.62-2.44, P = 0.55, median 26.9 months vs not reached). TTD was similar between the two groups (HR 0.95, 95% CI 0.64-1.39, P = 0.79, median 12.5 months vs 12.2 months). Grade > 3 treatment-related adverse events (AEs) were more common among patients treated with afatinib/cetuximab, and more patients in the combination arm required at least 1 dose reduction of afatinib (57% vs 26%). However, treatment discontinuations due to AEs were similar between the two groups (11.6% vs 10.7%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      There was no difference in PFS, OS or TTD with the addition of cetuximab to afatinib for treatment-naïve patients with EGFR-mutant NSCLC. The trial was closed to accrual at the interim analysis having met the criteria for futility. Correlative analysis of tumor tissue and blood from patients is ongoing.

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    P1.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 948)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.16-47 - Adjuvant Targeted Therapy Following Standard Adjuvant Therapy for Resected NSCLC: An Initial Report from ALCHEMIST (Alliance A151216) (ID 12828)

      16:45 - 18:00  |  Author(s): Thomas E. Stinchcombe

      • Abstract
      • Slides

      Background

      The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) was launched in 2014 across the National Clinical Trials Network (NCTN) of the National Cancer Institute (NCI). This trial platform aims to enroll up to 8300 patients with resected high-risk non-small cell lung cancer (NSCLC) to facilitate enrollment to adjuvant targeted therapy trials following completion of standard adjuvant therapy, and to collect biospecimens for clinical and investigational genomics. On 5/1/2016, the study was expanded to include squamous NSCLC and PDL1 testing to facilitate enrollment to a new immunotherapy study.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eligible patients have completely resected NSCLC, stage IB (>4cm) to IIIA by AJCC 7. Eligibility window extends 75-285 days post-op depending upon receipt of adjuvant chemotherapy and/or radiation. Molecular testing of EGFR, ALK, PDL1 is performed centrally (depending on the histology and testing results) and results are returned to sites within 7-21 days. FFPE tissue and blood are collected by the NCI for genomic analysis. Appropriate patients may then enroll to one of three therapeutic trials studying single agent adjuvant targeted therapy (erlotinib NCT02193282, crizotinib NCT02201992, or nivolumab NCT02595944) versus observation.

      4c3880bb027f159e801041b1021e88e8 Result

      As of March 19, 2018, 2945 patients have been enrolled from 575 sites within the US, with a median enrollment of 98/month (range: 71-133) in 2017. Central molecular testing was completed in 83%-92% of appropriate patients: EGFR L858R/19del was detected in 395 of 2468 patients (16.0%), ALK FISH was positive in 106 of 2458 patients (4.3%), and PDL1 IHC was >1% in 902 of 1464 patients (61.6%). Adequate tissue and blood for whole exome sequencing (WES) was collected on 1928 patients (65.5%), and enrollment plasma (added January 2017) has been collected on 885 patients (30.1%). Of 1960 patients deemed to be eligible for the adjuvant treatment trials with sufficient follow-up, 560 (28.6%) were enrolled; those enrolled were younger (p=0.01) and had higher N stage (<0.01) than those not enrolled. The primary reason for eligible patients not enrolling to treatment trials was lack of interest in further adjuvant therapy (53%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      ALCHEMIST has achieved an enrollment of ~100 patients/month with resected high-risk NSCLC. This initial report demonstrates the feasibility of central molecular testing for enrollment to adjuvant targeted therapies. Efforts are ongoing to plan clinically-informed genomic analyses of tumor and plasma, as well as the planning of new treatment arms that leverage this ongoing trial platform.

      Support: U10CA180821, U10CA180882, U10CA180820, U10CA180868, U10CA180888; ClinicalTrials.gov Identifier: NCT02194738

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-35 - Predicting Risk of Chemotherapy-Induced Severe Neutropenia in Patients with Advanced Lung Cancer (ID 13500)

      16:45 - 18:00  |  Author(s): Thomas E. Stinchcombe

      • Abstract
      • Slides

      Background

      Neutropenia is associated with the risk of life-threatening infections, chemotherapy dose reductions and delays that may compromise treatment outcomes. The goal of this study was to develop simple prediction model for severe neutropenia in lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A lung cancer dataset was assembled using data from existing national cooperative group phase II/III trials conducted between 1991-2010. Chemotherapy trials in patients with stages III and IV non-small cell lung cancer (NSCLC) or extensive small-cell lung cancer (SCLC) were included. We randomly selected 2/3 patients to derive the model, and the remaining were used for validation. Models were built with stepwise logistic regression and lasso regression on imputed data sets. We fitted the model on the imputed training data sets individually to get 10 models with 10 sets of selected predictors. Next we picked the union set and the intersection set of predictors from the models. The variables in the final model were selected by lasso regression, and then fitted into a logistic model. The performance of the model was evaluated by receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC).

      4c3880bb027f159e801041b1021e88e8 Result

      The dataset was randomly separated into training [n=7606 (67%)] and testing sets [n=3746 (33%)]. The final predictive model included: Age (>65 years), gender (male), weight (kg), BMI, insurance status (yes/unknown), stage (IIIB/IV/ESSCLC), number of metastatic sites (1, 2 or ≥3), individual chemotherapy agents (gemcitabine, taxanes), number of chemotherapy agents (2 or ≥3), planned use of growth factors, associated radiation therapy, previous therapy (chemotherapy, radiation, surgery), duration of planned treatment, pleural effusion (yes/unknown), performance status (1, ≥2) and presence of symptoms (yes/unknown).

      wclc figure.jpg

      Figure: ROC Curve for Final model AUC=0.8306

      8eea62084ca7e541d918e823422bd82e Conclusion

      We have developed a relatively simple model with variables that are routinely available prior to treatment, to predict for neutropenia. This model should be validated prospectively.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.17 - Treatment of Locoregional Disease - NSCLC (Not CME Accredited Session) (ID 983)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.17-12 - Phase II Trial of Atezolizumab Before and After Chemoradiation for Unresectable Stage III NSCLC (AFT-16): Trial in Progress (ID 13929)

      12:00 - 13:30  |  Author(s): Thomas E. Stinchcombe

      • Abstract
      • Slides

      Background

      Cure is possible for a substantial minority of stage III NSCLC patients, but most will relapse after conventional chemoradiation (CRT). Combining checkpoint inhibition through PD-L1 blockade with CRT may attenuate tumor related immunosuppression via depletion of Tregs and clonal expansion of effector T-cells, thereby improving tumor immunogenicity. Further, CRT may reveal hidden antigens that can present additional targets to the reconstituting immune system. Whether anti-PD-L1 therapy before CRT will improve outcomes in this setting is the subject of this trial.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This phase II single arm Alliance Foundation Trials study (AFT-16, NCT03102242) explores safety and efficacy of atezolizumab before and after definitive CRT. 63 patients with stage III NSCLC, PS 0-1, no active autoimmune disease and no significant organ dysfunction will enroll at 15 Alliance sites. Participants receive 4 cycles of neoadjuvant atezolizumab 1200 mg IV q 21 days with restaging after cycles 2 and 4. Non-progressing patients undergo carboplatin and paclitaxel (C/P) weekly with 60 Gy RT followed by 2 cycles of C/P consolidation and adjuvant atezolizumab to complete one year of therapy. The primary endpoint is disease control rate (CR+PR+SD) after neoadjuvant atezolizumab. Secondary endpoints include ORR, PFS, OS, safety and QoL by the EORTC QLQ-30.

      aft-16 schema bw.pngCorrelatives include the role of PD-L1 and tumor mutation burden as predictive biomarkers. Tumor tissue is obtained at study entry, and plasma and immune cells are isolated at study entry, post neoadjuvant atezolizumab, post CRT, during adjuvant atezolizumab and at study end. Explorative endpoints include potential predictive biomarkers development that may define how atezolizumab affects the proportions of immunologic subtypes and immune activation using flow cytometry and T cell receptor immunophenotyping, multiplex immunohistochemistry and cytokine analysis.

      The trial was activated on 11/1/17. As of 5/4/18, the trial is open at 8 centers with 14 patients enrolled.

      4c3880bb027f159e801041b1021e88e8 Result

      Section not applicable

      8eea62084ca7e541d918e823422bd82e Conclusion

      Section not applicable

      6f8b794f3246b0c1e1780bb4d4d5dc53

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