Simonetta Mocci

Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients With Programmed Death-Ligand 1–Selected Advanced Non–Small-Cell Lung Cancer (BIRCH)

Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced non-small-cell lung cancer (NSCLC) across lines of therapy. Patients were selected on the basis of PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior chemotherapy. Patients whose tumors expressed PD-L1 using the SP142 immunohistochemistry assay on ≥ 5% of TC or IC (TC2/3 or IC2/3 [TC or IC ≥ 5% PD-L1-expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659) comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n = 268); and third line or higher (cohort 3; n = 252). The primary end point was independent review facility-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points included median duration of response, progression-free survival, and overall survival (OS). Results BIRCH met its primary objective of demonstrating a significant ORR versus historical controls. With a minimum of 12 months of follow-up, the independent review facility-assessed ORR was 18% to 22% for the three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The median OS from an updated survival analysis (minimum of 20 month follow up) for cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials. Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status may serve as a predictive biomarker for identifying patients most likely to benefit from atezolizumab.

Results From the Phase III Randomized Trial of Onartuzumab Plus Erlotinib Versus Erlotinib in Previously Treated Stage IIIB or IV Non–Small-Cell Lung Cancer: METLung

Purpose The phase III OAM4971g study (METLung) examined the efficacy and safety of onartuzumab plus erlotinib in patients with locally advanced or metastatic non-small-cell lung cancer selected by MET immunohistochemistry whose disease had progressed after treatment with a platinum-based chemotherapy regimen. Patients and Methods Patients were randomly assigned at a one-to-one ratio to receive onartuzumab (15 mg/kg intravenously on day 1 of each 21-day cycle) plus daily oral erlotinib 150 mg or intravenous placebo plus daily oral erlotinib 150 mg. The primary end point was overall survival (OS) in the intent-to-treat population. Secondary end points included median progression-free survival, overall response rate, biomarker analysis, and safety. Results A total of 499 patients were enrolled (onartuzumab, n = 250; placebo, n = 249). Median OS was 6.8 versus 9.1 months for onartuzumab versus placebo (stratified hazard ratio [HR], 1.27; 95% CI, 0.98 to 1.65; P = .067), with a greater number of deaths in the onartuzumab arm (130 [52%] v 114 [46%]). Median progression-free survival was 2.7 versus 2.6 months (stratified HR, 0.99; 95% CI, 0.81 to 1.20; P = .92), and overall response rate was 8.4% and 9.6% for onartuzumab versus placebo, respectively. Exploratory analyses using MET fluorescence in situ hybridization status and gene expression showed no benefit for onartuzumab; patients with EGFR mutations showed a trend toward shorter OS with onartuzumab treatment (HR, 4.68; 95% CI, 0.97 to 22.63). Grade 3 to 5 adverse events were reported by 56.0% and 51.2% of patients, with serious AEs in 33.9% and 30.7%, for experimental versus control arms, respectively. Conclusion Onartuzumab plus erlotinib did not improve clinical outcomes, with shorter OS in the onartuzumab arm, compared with erlotinib in patients with MET-positive non-small-cell lung cancer.

ORAL01.04: Phase II Trial of Atezolizumab for Patients with PD-L1–Selected Advanced NSCLC (BIRCH): Updated Efficacy and Exploratory Biomarker Results: Topic: Medical Oncology

47% and 39% in the two cohorts in unselected patients (Table) and median duration of response was not reached after a median follow-up of 12.8 months and 11.8 months. Responses were seen across all PD-L1 subgroups, and were enriched among those with greater PD-L1, up to 100% and 86% among those with 50% PD-L1 expression (Table). Responses were achieved in patients with EGFR mutations and in never smokers. Conclusion: First-line therapy with nivolumab plus ipilimumab demonstrates pronounced and durable clinical activity and a manageable safety profile. The nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q6W schedule is being evaluated in a phase III clinical trial in first-line advanced NSCLC.

Abstract B001: Development of a PD-L1 companion diagnostic IHC assay (SP142) for atezolizumab

Background: Understanding of immune tolerance mechanisms of cancer has prompted the development of cancer immunotherapies such as atezolizumab (anti-PD-L1, MPDL3280A). Robust, durable responses have been observed, leading to Breakthrough status designation by the FDA for atezolizumab for previously treated NSCLC and bladder cancer (UBC) patients. Roche/Ventana have developed a companion diagnostic (CDx) for atezoliziumab using a robust immunohistochemistry (IHC) assay and antibody clone (SP142), optimized to detect PD-L1 expression in both tumor cells (TC) and tumor-infiltrating immune cells (IC). Here we describe the characteristics of the SP142 assay, PD-L1 expression patterns observed by immunohistochemistry in TC and IC compartments, and their association with clinical efficacy for NSCLC and UBC patients. Methods: The anti-human PD-L1 rabbit monoclonal antibody SP142 was optimized for detection of both TC and IC expression of PD-L1 with the Ventana OptiView DAB IHC Detection Kit on the automated BenchMark ULTRA platform. The VENTANA PD-L1 (SP142) CDx assay was validated for use in formalin-fixed, paraffin-embedded samples of NSCLC and UBC in a series of studies addressing sensitivity, specificity, robustness, and precision. Formalin fixed, paraffin embedded tumor specimens were obtained from patients prescreened and/or enrolled into Genentech Ph I study PCD4989g, and PD-L1 expression was measured using the SP142 assay and PCR gene expression assays. Results: The SP142 assay met pre-defined acceptance criteria for TC and IC assessment of PD-L1 expression in NSCLC and UBC tumors, including >90% inter-reader concordance between pathologist readers. Rapid and durable responses were observed in the Ph I study (PCD4989g), and correlated with PD-L1 expression patterns observed by immunohistochemistry in TC and IC. In the same Ph I study (PCD4989g), PD-L1 expression as measured by PCR did not demonstrate the same predictive value as observed for IHC. Conclusions: The PD-L1 IHC (SP142) CDx is a robust assay to measure PD-L1 expression in both IC and TC. Further, the high reproducibility of results between pathologists shows that the scoring algorithms in UBC and NSCLC are precise, reproducible, and practical in the diagnostic setting. The results indicate that favorable atezolizumab efficacy for UBC is strongly associated with higher IC levels as assessed by the sensitive and specific PD-L1 IHC (SP142) CDx assay. In NSCLC, favorable atezolizumab efficacy is associated with tumors expressing either high TC or high IC levels by the PD-L1 IHC (SP142) CDx assay. These data support the predictive value of tumor PD-L1 levels by IHC for NSCLC and UBC patients receiving atezoliziumab. Citation Format: Zachary S. Boyd, Dustin Smith, Brian Baker, Bharathi Vennapusa, Hartmut Koeppen, Marcin Kowanetz, Sanjeev Mariathasan, Jean-Marie Bruey, Howard Mackey, Gregg Fine, Simonetta Mocci, Priti Hegde, J. Andrew Williams, Ian McCaffery. Development of a PD-L1 companion diagnostic IHC assay (SP142) for atezolizumab. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B001.

PS01.56: IMpower110: Phase III Trial Comparing 1L Atezolizumab with Chemotherapy in PD-L1–Selected Chemotherapy-Naive NSCLC Patients: Topic: Medical Oncology

Eric Vallieres, Enriqueta Felip, Nasser Altorki, Caicun Zhou, Yunxia Zuo, Michael Howland, Fan Xia, Tien Hoang, Alan Sandler, Heather Wakelee Swedish Cancer Institute, Seattle, WA/United States of America, Vall d’Hebron University Hospital, Barcelona/Spain, New YorkePresbyterian Hospital, Weill Cornell Medicine, New York, NY/United States of America, Tongji University Affiliated Shanghai Pulmonary Hospital, Shanghai/China, Roche (China) Holding Ltd, Shanghai/China, Genentech, Inc., South San Francisco, CA/United States of America, Stanford Cancer Institute, Stanford/United States of America

Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti–PD-L1)

Significance Programmed death-ligand 1 (PD-L1) expression on tumor cells and tumor-infiltrating immune cells is regulated by distinct mechanisms and has nonredundant roles in regulating anticancer immunity, and PD-L1 on both cell types is important for predicting best response to atezolizumab in non-small cell lung cancer. Programmed death-ligand 1 (PD-L1) expression on tumor cells (TCs) by immunohistochemistry is rapidly gaining importance as a diagnostic for the selection or stratification of patients with non-small cell lung cancer (NSCLC) most likely to respond to single-agent checkpoint inhibitors. However, at least two distinct patterns of PD-L1 expression have been observed with potential biological and clinical relevance in NSCLC: expression on TC or on tumor-infiltrating immune cells (ICs). We investigated the molecular and cellular characteristics associated with PD-L1 expression in these distinct cell compartments in 4,549 cases of NSCLC. PD-L1 expression on IC was more prevalent and likely reflected IFN-γ–induced adaptive regulation accompanied by increased tumor-infiltrating lymphocytes and effector T cells. High PD-L1 expression on TC, however, reflected an epigenetic dysregulation of the PD-L1 gene and was associated with a distinct histology described by poor immune infiltration, sclerotic/desmoplastic stroma, and mesenchymal molecular features. Importantly, durable clinical responses to atezolizumab (anti–PD-L1) were observed in patients with tumors expressing high PD-L1 levels on either TC alone [40% objective response rate (ORR)] or IC alone (22% ORR). Thus, PD-L1 expression on TC or IC can independently attenuate anticancer immunity and emphasizes the functional importance of IC in regulating the antitumor T cell response.