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D. Waterkamp
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OA20 - Immunotherapy and Markers (ID 401)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:M. Früh, C.S. Baldotto
- Coordinates: 12/07/2016, 11:00 - 12:30, Stolz 2
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OA20.01 - Tumor Mutation Burden (TMB) is Associated with Improved Efficacy of Atezolizumab in 1L and 2L+ NSCLC Patients (ID 6149)
11:00 - 11:10 | Author(s): D. Waterkamp
- Abstract
- Presentation
Background:
In NSCLC, atezolizumab (anti-PDL1) efficacy correlates with PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC). Here we examined the association between atezolizumab efficacy and TMB assessed by FoundationOne (F1) sequencing panel.
Methods:
Pretreatment tumor specimens from 102 1L and 465 2L+ NSCLC patients enrolled on three Ph 2 atezolizumab monotherapy trials (POPLAR: randomized 2/3L trial comparing atezolizumab vs docetaxel; BIRCH/FIR: single-arm, 1L/2L+ PD-L1‒selected trials) were available for targeted genetic sequencing using the F1 panel of 315 cancer-related genes. TMB was quantified using an updated TMB algorithm and efficacy was assessed in groups defined by the 75th (high) and 50th (median) percentile of each study-specific TMB. Atezolizumab efficacy was examined at Dec 1, 2015 (POPLAR and BIRCH); and Jan 7, 2015 (FIR) data cutoffs.
Results:
Across samples, median TMB was similar in 1L and 2L+ patients (9/MB and 9.9/MB, respectively). In 1L and 2L+ PD-L1–selected patients, atezolizumab benefit was increased in those with ≥ TMB cut-offs (Table). In unselected 2L+ patients from POPLAR, the OS, PFS, and ORR benefits of atezolizumab vs docetaxel were also enhanced in patients with increased TMB. TMB and PD-L1 expression were independently associated with improved atezolizumab efficacy. TMB associations with PD-L1 expression, tumor-infiltrating lymphocyte infiltration and T-effector cell gene expression will be presented.
Conclusion:
For the first time, we demonstrate that TMB assessed with F1 targeted sequencing is associated with improved atezolizumab outcomes in 1L and 2L+ NSCLC. Moreover, this is the first study demonstrating the association of TMB with improved anti-PD-L1/PD-1 efficacy in a randomized trial. Importantly, the association between TMB and atezolizumab efficacy occurred in both unselected and PD-L1-selected patients. Therefore, in addition to PD-L1, TMB may be an independent predictor of improved responsiveness to atezolizumab in advanced NSCLC.Atezolizumab efficacy by TMB subgroups PD-L1‒selected BIRCH+FIR 1L n=102 2L+n=371 Median (≥9/MB) High (≥13.5/MB) Median (≥9.9/MB) High (≥17.1/MB) OS,HR[a] (95% CI) 0.79 (0.39-1.58) 0.45 (0.17-1.16) 0.87 (0.65-1.16) 0.7 (0.49-1.00) PFS,HR[a] (95% CI) 0.58 (0.36-0.94) 0.54 (0.3-0.97) 0.64 (0.5-0.8) 0.5 (0.38-0.67) ORR,above/below cutoff 28%/13% 25%/20% 25%/14% 29%/16% POPLAR 2L+ unselected n=92 Biomarker- evaluable population Median (≥9.9/MB) High (≥15.8/MB) OS,HR[b ] (95% CI) 0.65 (0.38-1.12) 0.48 (0.23-1.04) 0.5 (0.15-1.67) PFS,HR[b] (95% CI) 0.98 (0.63-1.53) 0.49 (0.25-0.93) 0.49 (0.19-1.3) ORR,atezolizumab/docetaxel 13%/15% 20%/4% 20%/8% [a]HR:efficacy-evaluable patients, atezolizumab at/above cutoff vs below.[b]HR:efficacy-evaluable patients, atezolizumab vs docetaxel at/above cutoff.
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PL04a - Plenary Session: Immune Checkpoint Inhibitors in Advanced NSCLC (ID 430)
- Event: WCLC 2016
- Type: Plenary
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:J. Soria, C. Zhou
- Coordinates: 12/07/2016, 08:45 - 09:40, Hall D (Plenary Hall)
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PL04a.02 - OAK, a Randomized Ph III Study of Atezolizumab vs Docetaxel in Patients with Advanced NSCLC: Results from Subgroup Analyses (Abstract under Embargo until December 7, 7:00 CET) (ID 5822)
08:55 - 09:05 | Author(s): D. Waterkamp
- Abstract
- Presentation
Background:
Atezolizumab inhibits PD-L1 binding to its receptors PD-1 and B7.1, thereby restoring tumor-specific T-cell immunity. Primary analysis of the Phase III OAK study in previously-treated NSCLC revealed superior survival for atezolizumab vs docetaxel in the ITT population (mOS, 13.8 vs 9.6 months; HR, 0.73) and in patients expressing ≥1% PD-L1 on TC or IC (TC1/2/3 or IC1/2/3; mOS, 15.7 vs 10.3; HR, 0.74). Here we present further subgroup analyses.
Methods:
OAK evaluated atezolizumab vs docetaxel in an unselected NSCLC population who had failed prior platinum-containing chemotherapy. Patients were stratified by PD-L1 expression, prior chemotherapy regimens and histology, and randomized 1:1 to atezolizumab (1200 mg) or docetaxel (75 mg/m[2]) IV q3w. PD-L1 expression by IHC and mRNA was centrally evaluated by VENTANA SP142 IHC assay and Fluidigm, respectively. Data cutoff, July 7, 2016.
Results:
For the first 850 of 1225 randomized patients (primary study population), OS was improved with atezolizumab vs docetaxel regardless of histology and this benefit was observed across PD-L1 subgroups within each histology (Table). PD-L1 gene expression showed a similar association with OS as PD-L1 IHC. In nonsquamous patients ORR was 14.4% vs 15.2%; in squamous patients ORR was 11.6% vs 8.2% (atezolizumab vs docetaxel). OS benefit vs docetaxel was seen across subgroups including patients with treated baseline brain metastases (n=85; mOS 20.1 vs 11.9 mo; HR 0.54, 95% CI 0.63-0.89) and never smokers (n=156; mOS 16.3 vs 12.6 mo, HR 0.71, 95% CI 0.47-1.08). Further secondary endpoints and exploratory biomarker analyses for these subgroups and by age and EGFR/KRAS status will be presented.
Conclusion:
OAK demonstrated clinically relevant improvements with atezolizumab in the ITT population, including in both histology subgroups regardless of PD-L1 expression (measured by IHC or tumor gene expression), and among other subgroups including never smokers and in patients with baseline brain metastases.OS Atezolizumab Docetaxel HR[a]95% CI n Median, mo n Median, mo Nonsquamous TC3 or IC3 49 22.5 47 8.7 0.35(0.21-0.61) TC2/3 or IC2/3 89 18.7 99 11.3 0.61(0.42-0.88) TC1/2/3 or IC1/2/3 171 17.6 162 11.3 0.72(0.55-0.95) TC0 and IC0 140 14.0 150 11.2 0.75(0.57-1.00) All 313 15.6 315 11.2 0.73(0.60-0.89) Squamous TC3 or IC3 23 17.5 18 11.6 0.57(0.27-1.20) TC2/3 or IC2/3 40 10.4 37 9.7 0.76(0.45-1.29) TC1/2/3 or IC1/2/3 70 9.9 60 8.7 0.71(0.48-1.06) TC0 and IC0 40 7.6 49 7.1 0.82(0.51-1.32) All 112 8.9 110 7.7 0.73(0.54-0.98) [a]Unstratified HRs. TC=tumor cell, IC=tumor-infiltrating immune cell
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