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P. Hegde



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    MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      MA 05.09 - Pre-Existing Immunity Measured by Teff Gene Expression in Tumor Tissue is Associated with Atezolizumad Efficacy in NSCLC (ID 10759)

      15:45 - 17:30  |  Author(s): P. Hegde

      • Abstract
      • Presentation
      • Slides

      Background:
      Association between T-effector (Teff) gene expression (GE), a marker of pre-existing immunity, and OS benefit with atezolizumab (anti–PD-L1) was demonstrated in the Phase II study POPLAR of atezolizumab vs docetaxel in 2L+ NSCLC. We analyzed Teff GE association with atezolizumab efficacy in a larger Phase III study, OAK.

      Method:
      Patients with 2L+ NSCLC were randomized to receive atezolizumab or docetaxel. Teff signature was defined by 3 genes (PD-L1, CXCL9, and IFNγ), and Teff GE was measured by averaging the normalized expression of each gene. Teff GE subgroups were defined by quartiles. PD-L1 expression was assessed using the SP142 IHC assay; the TC1/2/3 or IC1/2/3 subgroup had ≥ 1% PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC).

      Result:
      753 of 850 patients from the OAK primary analysis constituted the biomarker evaluable population (BEP) for Teff GE. Expression of the Teff signature was associated with PD-L1 expression by IHC (P = 7.3×10[−45]). Although no significant PFS benefit with atezolizumab vs docetaxel was observed in the BEP (HR, 0.94 [95% CI: 0.81, 1.10]) or the TC1/2/3 or IC1/2/3 subgroup (HR, 0.93 [95% CI: 0.76, 1.15]), a gradient of improved PFS benefit with atezolizumab was observed with increasing Teff GE. Significant PFS benefit occurred with ≥ median Teff GE cutoff (HR, 0.73 [95% CI: 0.58, 0.91]; Table). Teff GE also enriched for improved OS; however, a trend toward OS benefit was still observed in patients with low Teff GE (Table).

      Table. PFS and OS with atezolizumab vs docetaxel by PD-L1 IHC and Teff GE subgroups
      PFS, HR (95% CI) OS, HR (95% CI)
      OAK primary population (N = 850)[a]
      ITT[a] 0.95 (0.82, 1.10) 0.73 (0.62, 0.87)
      TC1/2/3 or IC1/2/3[a ](n = 463) 0.91 (0.74, 1.12) 0.74 (0.58, 0.93)
      TC2/3 or IC2/3[a] (n = 265) 0.76 (0.58, 0.99) 0.67 (0.49, 0.90)
      OAK BEP for Teff GE (N = 753)
      BEP 0.94 (0.81, 1.10) 0.71 (0.59, 0.85)
      TC1/2/3 or IC1/2/3 (n = 420) 0.93 (0.76, 1.15) 0.74 (0.58, 0.95)
      Teff GE subgroups
      ≥ 25% (n = 570) 0.91 (0.76, 1.09) 0.67 (0.54, 0.83)
      < 25% (n = 183) 1.11 (0.82, 1.49) 0.87 (0.63, 1.21)
      ≥ 50% (n = 379) 0.73 (0.58, 0.91) 0.59 (0.46, 0.76)
      < 50% (n = 374) 1.30 (1.05, 1.61) 0.87 (0.68, 1.11)
      ≥ 75% (n = 190) 0.66 (0.48, 0.91) 0.60 (0.42, 0.87)
      < 75% (n = 563) 1.10 (0.92, 1.31) 0.76 (0.62, 0.92)
      [a]Rittmeyer A. et al. Lancet, 2017;389:255-265. NCT02008227.


      Conclusion:
      This is the first demonstration of the association between markers of Teff biology and clinical outcomes with cancer immunotherapy in a randomized Phase III trial. Teff GE may reflect pre-existing immunity and be a more sensitive biomarker compared with PD-L1 IHC, identifying more patients (50% prevalence) likely to experience PFS benefit with atezolizumab.

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