Atezolizumab Doubles OS in PD-L1-Positive NSCLC

Alexander I. Spira, MD, PhD

Treatment with atezolizumab (MPDL3280A) doubled overall survival (OS) compared with docetaxel in previously treated patients with PD-L1-positive squamous and non-squamous non-small cell lung cancer (NSCLC), according to results from the phase II POPLAR study presented at the 2015 ASCO Annual Meeting.

In patients with the highest level of PD-L1 expression (tumor cells [TC]/immune cels [IC] 3), the median OS with atezolizumab was not yet reached compared with 11.1 months for docetaxel (HR = 0.46; 95% CI, 0.19-1.09). In this same group, the median progression-free survival (PFS) was 7.8 versus 3.9 months, for the anti-PD-L1 antibody and docetaxel, respectively (HR = 0.57). The objective response rate (ORR) was 38% with immunotherapy and 13% with chemotherapy. In patients without PD-L1 expression (TC/IC 0), a difference was not observed between the two groups.

"The POPLAR phase II randomized study demonstrated a pattern of improved survival that correlated with increasing PD-L1 expression," Alexander I. Spira, MD, PhD, medical oncology, hematology, Virginia Cancer Specialists, said during his presentation. "Atezolizumab was well tolerated with a safety profile consistent with previous studies and distinct from chemotherapy."

In the phase II POPLAR study, 287 patients with previously treated NSCLC were randomized to receive atezolizumab (n = 144) or docetaxel (n = 143). Intravenous atezolizumab was administered at 1200 mg every 3 weeks and docetaxel was used at 75 mg/m² every 3 weeks.

Patients were stratified based on prior lines of therapy and PD-L1 expression. PD-L1 was centrally evaluated by immunohistochemistry using the SP142 antibody assay.

Across all PD-L1-positive expression levels (m = 195; TC/IC 1-3), there was a benefit seen with atezolizumab. The median OS was not yet reached in the atezolizumab arm (n = 93) compared with 9.1 months with docetaxel (HR = 0.63; 95% CI, 0.42-0.94; P = .024). The median PFS was similar between the two arms, at 3.3 months with atezolizumab versus 3.0 months with docetaxel (HR = 0.87; 95% CI, 063-1.20). The ORR was 18% in both arms.

For patients with TC/IC 2 and 3 PD-L1 expression treated with atezolizumab (n = 50), the median OS was 13 months compared with 7.4 months for those treated with docetaxel (n = 55). Treatment with atezolizumab was associated with a 44% reduction in the risk of death for this group of patients (HR = 0.56; 95% CI, 0.33-0.95; P = .026). The median PFS was 4.0 versus 2.8 months (HR = 0.70; 95% CI, 0.45-1.08) and the ORR was 22% versus 18%, for atezolizumab and docetaxel, respectively.

In patients without PD-L1 expression (TC/IC 0), the median OS was 9.7 months in both arms, for patients treated with atezolizumab (n = 51) and docetaxel (n = 41). The median PFS was 1.9 versus 4.1 months and the ORR was 8% versus 10%, for atezolizumab and docetaxel, respectively.

Across all patients in the study (n = 287), the median OS was 11.4 months with atezolizumab versus 9.5 months with docetaxel (HR = 0.77; P = .11). For PFS, the median in the atezolizumab arm was 2.8 versus 3.4 months with docetaxel (HR = 0.98). The ORR was 15% in both treatment arms.

"The highly sensitive and specific IHC assay, using antibody SP142, was able to measures PD-L1 on both tumor cells and was immune cells and is a predictive diagnostic biomarker for atezolizumab in lung cancer," Spira said.

Atezolizumab is an engineered monoclonal antibody that binds to the ligand PD-L1, preventing the activation of PD-1. The antibody is modified to prevent the induction of antibody-dependent cytotoxicity or complement-dependent cytotoxicity. This design is meant to reduce toxicity seen with the agent.

In the study, fewer grade 3-5 adverse events were experienced by patients treated with atezolizumab compared with docetaxel (44% vs 56%). There was a higher incidence of respiratory side effects with immunotherapy versus chemotherapy. Atezolizumab was associated with aspartate and alanine aminotransferase increases (4% each), colitis (1%), hepatitis (1%), and pneumonitis (2%).

Based on early-stage studies, atezolizumab received a breakthrough therapy designation from the FDA as a potential treatment for patients with PD-L1—positive NSCLC following progression on prior therapy, including chemotherapy and targeted therapies. This designation is meant to expedite the approval of new therapies, through streamlined communication between the pharmaceutical company and the FDA.

Genentech, the developer of atezolizumab, is discussing findings from the POPLAR study with the FDA.

Spira AI, Park K, Mazières J, et al. Efficacy, safety and predictive biomarker results from a randomized phase II study comparing atezolizumab vs docetaxel in 2L/3L NSCLC (POPLAR). J Clin Oncol. 2015;(suppl; abstr 8010).

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