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M. Ballas
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-082 - A Phase III Study of MEDI4736 (M) an Anti-PD-L1 Antibody ± Tremelimumab (T), vs Standard of Care (SoC), in Patients with Advanced NSCLC (ARCTIC) (ID 1237)
09:30 - 09:30 | Author(s): M. Ballas
- Abstract
Background:
M is a human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to programmed cell death-1 and CD-80 with high affinity and selectivity, and T is a selective human IgG2 mAb inhibitor of cytotoxic T-lymphocyte antigen-4 (CTLA-4). Both PD-L1 and CTLA-4 are regulators, or checkpoints, of T-cell activation. PD-L1 expression may be associated with greater clinical benefit of anti-PD-1/PD-L1 agents. Thus, the subset of patients with PD-L1-negative tumors represent a cohort with limited therapeutic options, and may benefit from the combination of M+T. Preclinical data, including mouse models of transplantable solid tumors, suggest that targeting both pathways may have synergistic antitumor activity. Emerging pharmacokinetics, pharmacodynamics, safety and efficacy data from a phase Ib study of M+T in advanced NSCLC (NCT02000947) has determined the appropriate dose for this combination.
Methods:
This randomized, open label, multi-center, phase III study (NCT02352948) is designed to evaluate the efficacy and safety of M (10mg/kg once every 2 weeks [Q2W] for up to 12 months) vs SoC (gemcitabine 1000 mg/m[2] iv Days 1, 8, and 15, vinorelbine 30 mg/m[2] iv on Days 1, 8, 15 and 22 or erlotinib 150 mg once daily, on a 4-weekly schedule until PD at the investigator’s discretion) in NSCLC patients with PD-L1-positive tumors (based on archival tumor sample or recent biopsy) (Sub-study A), and the combination of M+T (M 20mg/kg + T 1mg/kg Q4W for 12 weeks then M alone 10mg/kg Q2W for 34 weeks) vs M or T (10mg/kg Q4W for 24 weeks then Q12W for 24 weeks) vs SoC in NSCLC patients with PD-L1-negative tumors (Sub-study B). PD-L1-positive is defined as ≥25% of tumor cells with membrane staining based on central assessment. Approximately 300 patients will be randomized 1:1 in Sub-study A and approximately 600 patients in a 3:2:2:1 ratio (M+T or SoC or M or T) in Sub-study B. Retreatment with immune-therapy is allowed within the setting of PD. For both sub-studies, an interim analysis for OS (and also PFS for Sub-study B) will be performed. Eligible patients include patients (PS of 0-1) with locally advanced or metastatic NSCLC, who have received at least 2 prior treatment regimens including 1 platinum-based chemotherapy. Patients with brain metastases or spinal cord compression are excluded unless asymptomatic, treated and stable off steroids. Patients with known EGFR activating mutations or ALK rearrangements are not eligible, nor patients previously exposed to any anti-PD-1 or anti-PD-L1 antibody. The primary objective is to assess PFS (per RECIST 1.1 as assessed by the Blinded Independent Central Review) and OS of M (PD-L1-positive) and M+T (PD-L1-negative), compared with SoC, in sub-study A and B, respectively. Secondary objectives include proportion of patients alive at 12 months, objective response rate, duration of response, PFS at 6 and 12 months, safety, tolerability, pharmacokinetics, immunogenicity and health-related QoL. Tumor assessments are performed every 8 weeks (first 48 weeks) then every 12 weeks. A confirmatory scan is required following the initial demonstration of PD. Recruitment in the study is ongoing since January 2015.
Results:
Not applicable
Conclusion:
Not applicable
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-090 - Phase 3, Double-Blind, Placebo-Controlled Study of MEDI4736 after Chemoradiation in Stage III, Locally Advanced, Unresectable NSCLC (PACIFIC) (ID 1263)
09:30 - 09:30 | Author(s): M. Ballas
- Abstract
Background:
Non-small cell lung cancer (NSCLC) accounts for 85–90% of all lung cancer cases. Approximately 35% of patients with NSCLC have Stage III disease at the time of diagnosis. Platinum-based, concurrent chemoradiation therapy is the standard treatment for patients with locally advanced, unresectable NSCLC. However, most patients progress despite treatment, and 5-year overall survival (OS) is only ~15%. Therefore, there is a significant unmet need for novel, effective therapeutic approaches to prolong survival. Immunotherapies that block checkpoints used by tumor cells to dampen immune responses are a promising new treatment option. Encouraging clinical activity against several tumor types has been seen for anti-PD-L1/PD-1 monoclonal antibodies (mAbs). MEDI4736 is a human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to programmed cell death-1 and CD-80 with high affinity and selectivity, preventing PD-L1-mediated inhibition of T-cell activation. It has been engineered to harbor a triple mutation in the fragment crystallizable domain, which removes antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. Evidence of clinical activity for MEDI4736 in NSCLC has been observed in a Phase 1 study (Study 1108, NCT01693562), with initial data indicating that PD-L1 expression is associated with a higher objective response rate (ORR). Chemotherapy and radiotherapy upregulate the expression of tumor PD-L1, which could increase sensitivity to PD-L1-directed therapy. Based on this rationale, the PACIFIC study (NCT02125461) will evaluate the efficacy and safety of MEDI4736 in patients with locally advanced, unresectable NSCLC (Stage III) whose disease has not progressed following platinum-based, concurrent chemoradiation therapy.
Methods:
In this Phase 3, randomized, double-blind, multicenter, international study, ~700 patients will be randomized 2:1 to receive MEDI4736 (10 mg/kg IV) or placebo every 2 weeks for up to 12 months. Eligible patients must have previously received ≥2 cycles of platinum-based concurrent chemoradiation with no subsequent disease progression, have received a total dose of radiation of ≥60 Gy, and have archival tissue available. Patients treated with sequential chemoradiation therapy for locally advanced disease and those with metastatic disease are excluded. Randomization must occur within 42 days of radiation. Co-primary endpoints are OS and progression-free survival (PFS) (RECIST v1.1). Secondary endpoints include OS at 24 months, proportion of patients alive and progression-free at 12 and 18 months, time to second progression, objective response rate, duration of response, health-related quality of life, safety/tolerability, pharmacokinetics and immunogenicity of MEDI4736. Patients who achieve and maintain disease control up to 12 months will enter follow-up. Patients will be recruited at approximately 300 sites across Australia, Asia, Europe, North and South America and South Africa. Recruitment is ongoing.
Results:
Not applicable
Conclusion:
Not applicable
