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M. Gandhi



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    MA 10 - Immunotherapy I (ID 664)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      MA 10.03 - 3-Year Survival and Duration of Response in Randomized Phase II Study of Atezolizumab vs Docetaxel in 2L/3L NSCLC (POPLAR) (ID 8703)

      11:00 - 12:30  |  Author(s): M. Gandhi

      • Abstract
      • Presentation
      • Slides

      Background:
      Atezolizumab (anti–PD-L1) has demonstrated OS benefit over docetaxel in a randomized Phase II study, POPLAR, in patients with advanced NSCLC. This benefit has been confirmed in the randomized Phase III study OAK (Rittmeyer, 2017). The 3-year survival analysis of the POPLAR study presented here describes the longest survival follow-up reported to date of an all-comer randomized PD-L1/PD-1 immunotherapy trial in 2L+ NSCLC.

      Method:
      Patients were randomized 1:1 to receive atezolizumab (1200 mg) or docetaxel (75 mg/m[2]) IV q3w. Tumors were prospectively evaluated for tumor cell (TC) or tumor-infiltrating immune cell (IC) PD-L1 expression using the VENTANA SP142 IHC assay. Landmark OS was estimated using the Kaplan-Meier method. Data cutoff, April 7, 2017; minimum follow-up, 3 years.

      Result:
      The 2-year and 3-year survival with atezolizumab vs docetaxel were 32.2% vs 16.6% and 18.7% vs 10.0%, respectively. The long-term OS benefit of atezolizumab vs docetaxel was observed across histology and PD-L1 expression subgroups (Table). While the TC3 or IC3 subgroup derived the greatest OS benefit, the TC0 and IC0 subgroup also had improved long-term OS with atezolizumab vs docetaxel. The ITT ORR was 15% in both atezolizumab and docetaxel arms, but the median duration of response was 3 times longer with atezolizumab (22.3 months [95% CI: 11.6, 31.1] vs 7.2 months [95% CI: 5.8, 12.2] with docetaxel). Seven of the 11 docetaxel-arm 3-year survivors received subsequent non-protocol therapy with anti–PD-L1/PD-1 agents. Atezolizumab had a favorable safety profile compared with docetaxel that was consistent with previous reports.

      Conclusion:
      Atezolizumab demonstrates superior 2-year and 3-year OS benefit compared with docetaxel, and this benefit is observed across histology and PD-L1 expression subgroups (including TC0 and IC0). Atezolizumab is well tolerated, and responses are highly durable. These results are consistent with long-term OS results from OAK, presented separately.

      Table. Landmark OS in the ITT, PD-L1 expression, and histology subgroups in POPLAR
      Population (n, atezolizumab vs docetaxel) 2-year OS rate, % 3-year OS rate, %
      Atezolizumab Docetaxel P value[a] Atezolizumab Docetaxel P value[a]
      ITT (144 vs 143) 32.2% 16.6% 0.0027 18.7% 10.0% 0.0419
      PD-L1 Expression Subgroups
      TC3 or IC3 (24 vs 23) 41.7% 19.9% 0.1003 37.5% 14.9% 0.0724
      TC2/3 or IC2/3 (50 vs 55) 36.1% 13.8% 0.0082 21.2% 9.9% 0.1166
      TC1/2/3 or IC1/2/3 (93 vs 102) 36.0% 19.8% 0.0124 18.0% 11.0% 0.1759
      TC0 and IC0 (51 vs 41) 25.0% 6.8% 0.0202 20.5% 6.8% 0.0693
      Histology Subgroups
      Non-squamous (95 vs 95) 32.2% 21.1% 0.0960 23.3% 12.4% 0.0585
      Squamous (49 vs 48) 32.7% 7.8% 0.0020 9.4% 5.2% 0.4603
      [a ]For descriptive purpose only. TC3 or IC3 = PD-L1 ≥ 50% TC or 10% IC; TC2/3 or IC2/3 = PD-L1 ≥ 5% TC or 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. NCT01903993.


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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): M. Gandhi

      • 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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    P3.04 - Clinical Design, Statistics and Clinical Trials (ID 720)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      P3.04-003 - Phase II Trial of Atezolizumab Before and After Definitive Chemoradiation for Patients with Unresectable Stage III NSCLC (ID 9662)

      09:30 - 16:00  |  Author(s): M. Gandhi

      • Abstract
      • Slides

      Background:
      More than 40,000 US patients per year present with stage III NSCLC. These patients are of particular interest in that most are not resectable and while they can be treated with curative intent with excellent initial responses, only approximately 25% will be cured by conventional chemoradiotherapy. This, together with the generally better health of this cohort compared to patients with metastatic NSCLC, makes these patients ideal candidates for studies of immunotherapy to increase cure rates. The combination of checkpoint inhibition to counter tumor related immunosuppression along with standard chemoradiotherapy that depletes T-regulatory cells should create immunologic “space” to facilitate clonal expansion of effector T-cells in an environment that fosters improved tumor immunogenicity by blocking PD-L1. Responses to immunotherapy seem to be higher in patients for whom significant cytoreduction can be achieved, such as with radiation of all known disease. Further, both chemotherapy and radiation may expose otherwise hidden antigens that can present additional targets to the reconstituting immune system.

      Method:
      This phase II single arm Alliance Foundation study (NCT03102242) will evaluate safety and efficacy of atezolizumab before and after definitive chemoradiotherapy. 63 patients with stage III NSCLC, PS 0-1, no active autoimmune disease, adequate cardiopulmonary function and no underlying organ dysfunction will be enrolled at 15 Alliance sites in the US. Treatment consists of 4 cycles of neoadjuvant atezolizumab 1200 mg IV q 21 days before chemoradiotherapy with restaging after cycles 2 and 4. Nonprogressing patients undergo weekly carboplatin and paclitaxel concurrent with 60 Gy thoracic radiotherapy followed by 2 cycles of carboplatin and paclitaxel consolidation followed by completion of one year of atezolizumab. The primary endpoint of this pilot study is disease control (CR+PR+SD) after neoadjuvant atezolizumab. Secondary endpoints include ORR, PFS and OS, safety and QoL assessed by the EORTC QLQ-30. Translational endpoints seek to define the role of PD-L1 biomarker testing in selecting the population most likely to respond to neoadjuvant and adjuvant immunotherapy together with standard chemoradiotherapy and to study the association of biomarkers, including immunologic signatures, with response and survival. Tumor tissue will be assessed at study entry and, where possible, at progression. Plasma and immune cells will be assessed at baseline, post neoadjuvant atezolizumab, post chemoradiotherapy, during adjuvant atezolizumab and at study completion or progression. Analyses may include multipanel immunohistochemistry, gene expression profiling, whole exome and T cell receptor sequencing, cytokine/chemokine analysis, flow cytometry immunophenotyping, and T cell function.

      Result:
      Section not applicable

      Conclusion:
      Section not applicable

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