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Marcin Kowanetz



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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  |  Presenting Author(s): Marcin Kowanetz

      • 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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    OA 17 - Immunotherapy II (ID 683)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      OA 17.07 - Long-Term Survival in Atezolizumab-Treated Patients with 2L+ NSCLC from Ph III Randomized OAK Study (ID 8663)

      14:30 - 16:15  |  Author(s): Marcin Kowanetz

      • Abstract
      • Presentation
      • Slides

      Background:
      Atezolizumab (anti–PD-L1) inhibits PD-L1 binding to PD-1 and B7.1, restoring anti-cancer immunity. OAK, a Phase III study of atezolizumab vs docetaxel demonstrated superior OS of atezolizumab. The characteristics of the long-term survivors (LTS) in the OAK primary population (n = 850) are evaluated and describe the largest cohort of cancer immunotherapy-treated NSCLC LTS yet reported.

      Method:
      Patients received IV q3w atezolizumab (1200 mg) until PD / loss of clinical benefit or docetaxel (75 mg/m[2]) until PD / unacceptable toxicity. No crossover was allowed. LTS were defined as patients with OS ≥ 24 months and non-LTS as those who died within 24 months of randomization. Patients with OS censored prior to 24 months were not included. Data cutoff, January 23, 2017.

      Result:
      A higher 2-year survival rate was observed for the atezolizumab-arm (31%) vs docetaxel-arm (21%). After a minimum follow-up of 26 months, there were 119 LTS vs 279 non-LTS in the atezolizumab-arm and 77 LTS vs 299 non-LTS in the docetaxel-arm. Characteristics of atezolizumab-arm LTS and non-LTS are shown (Table). Atezolizumab-arm LTS were enriched for non-squamous histology and high PD-L1–expressing tumors, but also included low/no PD-L1–expressing tumors (40.3%). Atezolizumab-arm LTS had higher ORR (39.5%) than non-LTS (5.0%) but included LTS subjects with PD. 52.9% atezolizumab-arm vs 71.4% docetaxel-arm LTS received anti-cancer non-protocol therapy (NPT) after discontinuation of protocol-defined therapy. 51.9% of docetaxel-arm LTS vs 12.7% non-LTS received non-protocol immunotherapy. Median treatment exposure in atezolizumab-arm LTS was 18.0 months. Atezolizumab-arm LTS had a comparable safety profile to all atezolizumab-treated population.

      Conclusion:
      Atezolizumab provides superior 2-year OS benefit vs docetaxel and is well tolerated. The majority of docetaxel-arm LTS received a checkpoint inhibitor as NPT. Atezolizumab LTS appeared to have favorable prognostic factors, including non-squamous histology, but notably were not limited to patients with RECIST v1.1 response or with PD-L1 expression.

      Table. Characteristics of Atezolizumab-Arm Long-Term Survivors (LTS) vs Non-Long Term Survivors (Non-LTS)
      Atezolizumab LTS (n = 119) n (%) Atezolizumab Non-LTS (n = 279) n (%)
      Sex
      Male 61 (51.3) 183 (65.6)
      Female 58 (48.7) 96 (34.4)
      Tobacco use history
      Never smoker 29 (24.4) 47 (16.8)
      Current/previous smoker 90 (75.6) 232 (83.2)
      Histology
      Non-squamous 101 (84.9) 195 (69.9)
      Squamous 18 (15.1) 84 (30.1)
      No. of prior therapies, 1 89 (74.8) 209 (74.9)
      ECOG performance status at baseline
      0 60 (50.4) 89 (31.9)
      1 59 (49.6) 190 (68.1)
      EGFR mutation status, positive 11 (9.2) 26 (9.3)
      PD-L1 IHC subgroup
      TC3 or IC3 28 (23.5) 39 (14.0)
      TC1/2/3 or IC1/2/3 71 (59.7) 156 (55.9)
      TC0 and IC0 48 (40.3) 119 (42.7)
      Best overall response
      Complete response 5 (4.2) 0 (0)
      Partial response 42 (35.3) 14 (5.0)
      Stable disease 47 (39.5) 97 (34.8)
      Progressive disease 25 (21.0) 142 (50.9)
      IC, tumor-infiltrating immune cell; TC, tumor cell. TC3 or IC3 = PD-L1 ≥ 50% TC or 10% IC; TC1/2/3 or IC1/2/3 = PD-L1 ≥ 1% on TC or IC; TC0 and IC0 = PD-L1 < 1% on TC and IC. NCT02008227.


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