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D. Kozono



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    MA 17 - Locally Advanced NSCLC (ID 671)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      MA 17.07 - Veliparib in Combination with Paclitaxel/Carboplatin (P/C)-Based Chemoradiotherapy (CRT) in Patients with Stage III NSCLC (ID 10210)

      15:45 - 17:30  |  Author(s): D. Kozono

      • Abstract
      • Presentation
      • Slides

      Background:
      CRT is a standard for patients with Stage III non-small cell lung cancer (NSCLC). Veliparib (V) is a potent, orally bioavailable PARP1/2 inhibitor that can delay DNA repair following chemotherapy or radiation induced damage. A phase 2 study indicated favorable efficacy of V vs placebo when added to P/C in advanced NSCLC (Ramalingam et al. Clin Cancer Res. 2016). Based on these results, a phase 1/2 trial was initiated to study the safety and efficacy of V/P/C-based CRT in the treatment of Stage III NSCLC.

      Method:
      Patients without prior NSCLC therapy suitable for definitive CRT received V plus C AUC 2 + P 45 mg/m[2] weekly + 60 Gy over 6-9 weeks. V was escalated from 60 mg BID to a maximum planned dose based on prior studies of 240 mg BID via 3+3 design with over-enrollment allowed followed by consolidation therapy of V 120 mg BID + C AUC 6 + P 200 mg/m[2] for up to two 21-day cycles.

      Result:
      Thirty-nine patients (median age 66; 14 male) have been enrolled to date into dosing cohorts at 60 mg (7), 80 mg (9), 120 mg (7), 200 mg (8), and a maximum planned dose of 240 mg (8). Median tumor volume at screening was 81 cc (16-555 cc). PK of V was dose proportional. CRT or V required dose reduction for 0 or 1 patient, respectively. Four (10%) patients discontinued study during CRT. No DLTs were observed and an MTD has not been identified. The most common any-grade AEs were esophagitis (23), nausea (22), fatigue (20), neutropenia (19), and thrombocytopenia (19). 27 SAEs occurred including 12 SAEs with reasonable attribution to V but outside the DLT window including G3/4 febrile neutropenia (2), G3 dehydration (1), G3 vomiting (1), G3 esophagitis (1), G3 radiation esophagitis (1), G3 esophageal stricture (1), G3 intractable N/V (1), G3 aspiration pneumonia (1), G3 radiation pneumonitis (1), G4 sepsis (1), and G5 sepsis during consolidation (1). Of 29 patients evaluable for tumor assessment, best response was CR (2), PR (22), SD (3), and PD (2).

      Conclusion:
      V/P/C-based CRT followed by V/P/C consolidation therapy is a tolerable regimen for the treatment of Stage III NSCLC. The RPTD for V during CRT is 240mg BID. A randomized placebo-controlled phase 2 extension of this study is planned. Clinical trial information: NCT02412371

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    P3.04 - Clinical Design, Statistics and Clinical Trials (ID 720)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      P3.04-003 - Phase II Trial of Atezolizumab Before and After Definitive Chemoradiation for Patients with Unresectable Stage III NSCLC (ID 9662)

      09:30 - 16:00  |  Author(s): D. Kozono

      • Abstract
      • Slides

      Background:
      More than 40,000 US patients per year present with stage III NSCLC. These patients are of particular interest in that most are not resectable and while they can be treated with curative intent with excellent initial responses, only approximately 25% will be cured by conventional chemoradiotherapy. This, together with the generally better health of this cohort compared to patients with metastatic NSCLC, makes these patients ideal candidates for studies of immunotherapy to increase cure rates. The combination of checkpoint inhibition to counter tumor related immunosuppression along with standard chemoradiotherapy that depletes T-regulatory cells should create immunologic “space” to facilitate clonal expansion of effector T-cells in an environment that fosters improved tumor immunogenicity by blocking PD-L1. Responses to immunotherapy seem to be higher in patients for whom significant cytoreduction can be achieved, such as with radiation of all known disease. Further, both chemotherapy and radiation may expose otherwise hidden antigens that can present additional targets to the reconstituting immune system.

      Method:
      This phase II single arm Alliance Foundation study (NCT03102242) will evaluate safety and efficacy of atezolizumab before and after definitive chemoradiotherapy. 63 patients with stage III NSCLC, PS 0-1, no active autoimmune disease, adequate cardiopulmonary function and no underlying organ dysfunction will be enrolled at 15 Alliance sites in the US. Treatment consists of 4 cycles of neoadjuvant atezolizumab 1200 mg IV q 21 days before chemoradiotherapy with restaging after cycles 2 and 4. Nonprogressing patients undergo weekly carboplatin and paclitaxel concurrent with 60 Gy thoracic radiotherapy followed by 2 cycles of carboplatin and paclitaxel consolidation followed by completion of one year of atezolizumab. The primary endpoint of this pilot study is disease control (CR+PR+SD) after neoadjuvant atezolizumab. Secondary endpoints include ORR, PFS and OS, safety and QoL assessed by the EORTC QLQ-30. Translational endpoints seek to define the role of PD-L1 biomarker testing in selecting the population most likely to respond to neoadjuvant and adjuvant immunotherapy together with standard chemoradiotherapy and to study the association of biomarkers, including immunologic signatures, with response and survival. Tumor tissue will be assessed at study entry and, where possible, at progression. Plasma and immune cells will be assessed at baseline, post neoadjuvant atezolizumab, post chemoradiotherapy, during adjuvant atezolizumab and at study completion or progression. Analyses may include multipanel immunohistochemistry, gene expression profiling, whole exome and T cell receptor sequencing, cytokine/chemokine analysis, flow cytometry immunophenotyping, and T cell function.

      Result:
      Section not applicable

      Conclusion:
      Section not applicable

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