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A. Rittmeyer



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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): A. Rittmeyer

      • 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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    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): A. Rittmeyer

      • 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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    P1.01 - Advanced NSCLC (ID 757)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P1.01-052 - Patient-Reported Outcomes (PROs) in OAK: A Phase III Study of Atezolizumab vs Docetaxel in Non-Small-Cell Lung Cancer (NSCLC) (ID 9903)

      09:30 - 16:00  |  Author(s): A. Rittmeyer

      • Abstract
      • Slides

      Background:
      The phase III OAK study in NSCLC (NCT02008227) demonstrated prolonged overall survival with atezolizumab (an anti-programmed death-ligand 1 antibody) versus docetaxel (median 13.8 vs 9.6 months; HR:0.73, 95% CI 0.62–0.87; p=0.0003). PROs were collected to support documentation of clinical benefit. We report data regarding symptom burden, functioning, and health-related quality of life (HRQoL).

      Method:
      Patients (n=850) with squamous/non-squamous, previously treated NSCLC, ≥18 years, with measurable disease (RECIST), and ECOG PS 0–1 were randomized to receive atezolizumab 1200mg or docetaxel 75mg/m[2] q3w. PROs were collected using two questionnaires: EORTC QLQ-C30 and its lung module, QLQ-LC13. Analyses included time-to-confirmed-deterioration (TTD) in lung cancer symptoms, physical and role function, HRQoL, longitudinal analyses of mean scores change from baseline to Cycles 5 and 6, proportion of patients with clinically meaningful worsening (≥10-point change from baseline) by Cycles 5 and 6.

      Result:
      High completion rates were observed throughout treatment (>80% for most cycles). Atezolizumab delayed TTD in physical (HR:0.75, 95% CI 0.58–0.98) and role function (HR:0.79, 95% CI 0.62–1.00). Prolonged TTD in chest pain (HR:0.71, 95% CI 0.49–1.05) was observed with atezolizumab; no differences in TTD were seen for other lung cancer symptoms and HRQoL. Longitudinal analyses demonstrated average changes from baseline in favor of atezolizumab for lung cancer symptoms (Cycle 6: dyspnea, fatigue), domains of functioning (Cycle 6: physical function, social function), HRQoL (Cycle 5); see Table. Fewer atezolizumab-treated patients experienced clinically meaningful worsening in possible treatment-related symptoms during treatment (Cycle 6: diarrhea [OR:0.51, p<0.0001], sore mouth [OR:0.40, p<0.0001], dysphagia [OR:0.61; p=0.0052], peripheral neuropathy [OR:0.50, p<0.0001], alopecia [OR:0.02; p<0.0001]).

      Conclusion:
      In OAK, atezolizumab delayed the time until NSCLC patients experience limitations in physical and role functioning versus docetaxel. Patient-reported data indicate atezolizumab maintained/improved lung cancer symptom burden and HRQoL compared with baseline, while demonstrating improved tolerability, versus docetaxel.

      By Cycle 5 By Cycle 6
      LS means difference between treatment arms (average change from baseline) P value LS means difference between treatment arms (average change from baseline) P value
      EORTC QLQ-C30 Global Health Status and Function Scales (positive values indicate greater improvement with atezolizumab over docetaxel)
      Global Health Status 4.32* p=0.0151 3.08 p=0.1257
      Physical Function 3.33* p=0.0290 6.64* p<0.0001
      Role Function 2.93 p=0.1959 4.72 p=0.0542
      Emotional Function 2.66 p=0.1110 1.92 p=0.2868
      Cognitive Function -0.67 p=0.6790 -1.08 p=0.5309
      Social Function 3.25 p=0.1159 4.68* p=0.0319
      EORTC QLQ-C30 Symptom Scales (negative values indicate greater improvement with atezolizumab over docetaxel)
      Fatigue -6.27* p=0.0015 -7.66* p=0.0003
      Nausea/Vomiting -0.37 p=0.7824 -0.18 p=0.9040
      Pain 1.44 p=0.5132 -1.67 p=0.4727
      Dyspnea -4.70* p=0.0317 -5.92* p=0.0138
      Insomnia 3.50 p=0.1675 0.83 p=0.7564
      Appetite Loss -2.94 p=0.1994 -4.49 p=0.0586
      Constipation -0.31 p=0.8772 -0.33 p=0.8816
      Diarrhea -3.14* p=0.0482 -2.05 p=0.1748
      EORTC QLQ-LC13 Symptom Scales (negative values indicate greater improvement with atezolizumab over docetaxel)
      Dyspnea -1.66 p=0.3146 -4.80* p=0.0140
      Coughing -2.60 p=0.2572 -1.38 p=0.5772
      Sore Mouth -7.29* p<0.0001 -9.23* p<0.0001
      Dysphagia -0.08 p=0.9595 -2.01 p=0.1575
      Peripheral Neuropathy -12.98* p<0.0001 -15.71* p<0.0001
      Hemoptysis -0.24 p=0.7365 -0.91 p=0.2080
      Alopecia -50.59* p<0.0001 -47.04* p<0.0001
      Chest Pain -0.91 p=0.6064 -0.58 p=0.7779
      Arm/Shoulder Pain -2.27 p=0.3177 -0.58 p=0.8109
      Pain in Other Parts 0.94 p=0.7197 -1.05 p=0.7034
      *Values that are significantly in favor of atezolizumab versus docetaxel


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    P1.03 - Chemotherapy/Targeted Therapy (ID 689)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P1.03-050 - Clinical Consequences, Quality of Life, and Management of Neutropenic NSCLC Patients in the REVEL Trial (ID 8279)

      09:30 - 16:00  |  Author(s): A. Rittmeyer

      • Abstract
      • Slides

      Background:
      Ramucirumab is a human IgG1 monoclonal antibody antagonist of VEGFR-2 approved as a post-platinum progression therapy in non-small cell lung cancer (NSCLC). Chemotherapy-induced neutropenia is a major risk during cancer treatment and can be potentially dose-limiting, as well as play a significant role in infection-related morbidity and mortality. In the REVEL phase 3 global, placebo-controlled study of Stage IV NSCLC patients (NCT01168973), ramucirumab plus docetaxel treatment improved patient survival versus docetaxel monotherapy independent of histology; however, all grade and high-grade (Grade ≥3) neutropenia was numerically increased with ramucirumab versus placebo (Table 1). A post-hoc analysis was performed on the REVEL data to characterize neutropenia: clinical consequences, quality of life (QoL), and clinical management.

      Method:
      The duration of neutropenia, as well as the course and incidence of complications and their severity and related consequences associated with neutropenia were summarized. Time to deterioration in ECOG performance status (PS) was analyzed using Kaplan-Meier method, and stratified hazard ratios and 95% confidence intervals (CI, Wald) were estimated for average symptom burden index and lung cancer symptom scale items using Cox model. Clinical management summary data will be presented at the meeting.

      Result:
      Neutropenia events from the REVEL trial are summarized in terms of duration, course, incidence of complications, severity and resolution status in Table 1. All-grade neutropenia risk ratio is 1.197 (95% CI 1.072, 1.338) and Grade ≥3 is 1.226 (95% CI 1.081, 1.390). Figure 1



      Conclusion:
      Despite numerically increased rates of neutropenia observed in the ramucirumab plus docetaxel arm of the REVEL trial, the clinical consequences (resolution) of neutropenia, rate of hospitalization, and duration/incidence of Grade ≥3 infection were similar to placebo. In addition, the quality of life results do not indicate any significant differences between placebo and ramucirumab. Therefore, neutropenia in the NSCLC population is considered to be manageable during ramucirumab treatment.

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