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J. Soria
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ORAL 06 - Next Generation Sequencing and Testing Implications (ID 90)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:G. De Lima Lopes, V. Miller
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 1a-1f
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ORAL06.05 - Molecular Tumor Board (MTB) in Non-Small Cell Lung Cancers (NSCLC) to Optimize Targeted Therapies: 4 Years' Experience at Gustave Roussy (ID 2563)
10:45 - 12:15 | Author(s): J. Soria
- Abstract
- Presentation
Background:
Molecular biology has changed the treatment of advanced NSCLC, leading to many small subgroups of patients (pts) eligible for targeted therapies, many of them being not approved. Since 2010 we created a monthly MTB dedicated to NSCLC pts with potential driving molecular abnormalitie(s). MTB includes expert physicians from the lung tumor board and phase I unit, radiation therapists, researchers, geneticists, pathologists and biologists. A medical report summarizes the findings and treatment recommendations for each pts. We report 4 years of activity of MTB at Gustave-Roussy.
Methods:
All consecutive files discussed in MTB for a NSCLC were reviewed. MTB included pts with at least one molecular alteration based on a 75 gene panel (NGS analysis and FISH for ALK, HER2, MET, FGFR1, ROS1 and RET). Tumor and pts characteristics were collected as well as treatments. Pts outcome was calculated from the MTB date. Kaplan-Meier methods, and Cox proportional hazards models were used for survival analysis, adjusting for sex, histology, smoking status, metastasis at diagnosis, number of line(s) before MTB.
Results:
502 files were discussed between 02/2010 and 09/2014. Median age was 60 yrs (25–88 yrs), 53% were male, 86% Caucasian, 26% never-smokers, and 93% had PS ≤1. Initial clinical stage was III-IV in 417 pts (84%) and 79%/10%/11% were adenocarcinomas/squamous cell carcinomas/others NSCLC. Median number of treatment-lines before MTB was 1 (0-10), 86% were previously treated by a platinum-based chemotherapy regimen, 17% in a therapeutic trial, and median time from diagnosis to MTB was 5 months. Biopsy for Molecular Analysis (MoA) mostly came from CT guided biopsies (62%), surgery (21%) or endoscopy (16%). Biopsy was repeated in 19% of pts to get enough material for MoA. The MoA results were ALK rearrangement in 11%, exon 18/19/20/21 EGFR mutation (mut) in 2/14/4/7% respectively, KRAS mut in 32%, PI3KCA mut in 3%, BRAF mut in 5%, HER2 mut (Exon 20) in 2%, HER2 amplification in 2%, FGFR1 amplification in 3%, MET amplification in 3% and other rare mutations in 27%. MTB recommended a targeted therapy in 344 pts (68%) either within clinical trials (57%), EMA approved therapy (23%), an off label drug (9%), or an expanded access program (11%). 162pts (47%) actually received the recommended therapy, 141 (41%) did not and 41 (12%) might receive it at the time of progression. Median follow-up was 24 months (1-24; follow-up censored after 24 months). Median OS was 13.1 months [95%CI: 8.8; 18.2] for non-oriented pts, and 14.3 months [11.5; 16.7] for oriented pts (p=0.39). We observed a significant difference between EGFR/ALK/ROS1 mutated/rearranged pts (median 23.8 months) vs. pts with KRAS (8.6 months) or others mutations (11.1 months) or non-oriented pts (13.1 m; p=0.0008, HR=0.56, 1.15 and 0.97 respectively compared to non-oriented).
Conclusion:
MTB is feasible in daily practice with treatment recommendations in a majority of NSCLC pts (68%), enrichment in clinical trials or expanded access programs, and limitation of off-label drugs use. Benefit on survival for all oriented pts has to be clarified based on the type of molecular abnormality. Update results will be presented at the meeting.
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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 - 17:00 | Author(s): J. Soria
- 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
