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)

Abstract

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.

Fig 1.

Atezolizumab was administered at a fixed dose of 1,200 mg intravenously on day 1 every 3 weeks in all cohorts. TC3 or IC3 = TC ≥ 50% or IC ≥ 10% PD-L1–expressing cells, respectively; TC2/3 or IC2/3 = TC or IC ≥ 5% PD-L1–expressing cells, respectively. 1L, first line; 2L, second line; 3L, third line; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; IC, tumor-infiltrating immune cells; IHC, immunohistochemistry; INV, investigator; IRF, independent review facility; NSCLC, non–small-cell lung cancer; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-L1, programmed death-ligand 1; PFS, progression-free survival; PS, performance status; RECIST, Response Evaluation Criteria in Solid Tumors; TC, tumor cells.

Fig 2.

Estimated Kaplan-Meier overall survival for patients with advanced non–small-cell lung cancer treated with atezolizumab in the BIRCH trial, by cohort. (A) TC2/3 or IC2/3 group (intent-to-treat population), and (B) TC3 or IC3 subgroup. TC3 or IC3 = TC ≥ 50% or IC ≥ 10% PD-L1–expressing cells, respectively; TC2/3 or IC2/3 = TC or IC ≥ 5% PD-L1–expressing cells, respectively. Cohort 1 = 1L; cohort 2 = 2L; cohort 3 = ≥ 3L. On the basis of an updated data cutoff of August 1, 2016. IC, tumor-infiltrating immune cells; NE, not estimable; TC, tumor cells.

Fig A1.

Best change in sum of the longest diameters (SLD) from baseline by cohort, on the basis of an independent review facility assessment. (A) Cohort 1 (1L), (B) cohort 2 (2L), and (C) cohort 3 (≥ 3L). Complete responders are indicated in blue, partial responders in gold, patients with stable disease in red, and patients experiencing disease progression in gray. ^aPatients with TC3 or IC3 PD-L1 immunohistochemistry status. On the basis of a data cutoff of December 1, 2015. 1L, first line; 2L, second line; 3L, third line; IC, tumor-infiltrating immune cells; PD-L1, programmed death-ligand 1; TC, tumor cells; TC3 or IC3 = TC ≥ 50% or IC ≥ 10% PD-L1–expressing cells, respectively.

Fig A2.

Objective response rates (ORR) for tobacco use and histology patient subgroups shown by cohort as determined by an independent review facility (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Error bars represent 95% CIs. On the basis of a data cutoff of December 1, 2015.

Fig A3.

Estimated Kaplan-Meier progression-free survival (by independent review facility) curves by PD-L1 status for patients with advanced non–small-cell lung cancer treated with atezolizumab in the BIRCH trial. TC2 or IC2 patients were determined by excluding TC3 or IC3 patients from TC2/3 or IC2/3 patients. (A) Cohort 1 (1L), (B) cohort 2 (2L), and (C) cohort 3 (≥ 3L). On the basis of a data cutoff of December 1, 2015. 1L, first line; 2L, second line, 3L, third line; IC, tumor-infiltrating immune cells; PD-L1, programmed death-ligand 1; TC, tumor cells; TC2/3 or IC2/3 = TC or IC ≥ 5% PD-L1–expressing cells, respectively; TC3 or IC3 = TC ≥ 50% or IC ≥ 10% PD-L1–expressing cells, respectively.