MPDL3280A Improves OS, PFS, ORR Versus Chemo in PD-L1+ NSCLC

Alexander Spira, MD, PhD

Alexander Spira, MD, PhD

MPDL3280A reduced the risk of death by 53% compared with docetaxel in previously treated patients with programmed death-ligand 1(PD-L1)—positive squamous and non-squamous non–small cell lung cancer (NSCLC). Data from the phase II study, labeled POPLAR, were released by Genentech, the company developing the drug, prior to a presentation of the results at the 2015 ASCO Annual Meeting.

In patients with the highest level of PD-L1 expression (TC/IC 3), the median overall survival (OS) with the PD-L1 inhibitor MPDL3280A was not yet reached compared with 11.1 months for docetaxel (HR, 0.47; 95% CI, 0.20-1.11). In this same group, the median progression-free survival (PFS) was 9.7 months versus 3.9 months for the MPDL3280A and docetaxel arms, respectively (HR, 0.56; 95% CI, 0.28-1.11). The objective response rate (ORR) was 38% with immunotherapy and 13% with chemotherapy.

Based on early-stage studies, MPDL3280A 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. Genentech is discussing findings from the POPLAR study with the FDA, for a potential regulatory filing.

“This is the first randomized study in non-squamous and squamous NSCLC to demonstrate that inhibition of the PD-L1/PD-1 pathway may lead to improved survival,” Alexander I. Spira, MD, PhD, et al wrote in the abstract. “Furthermore, these data showed that PD-L1 biomarker selection, using a highly sensitive and specific IHC assay measuring PD-L1 on both TC and IC, can identify both patients most likely to derive improved OS, PFS, and ORR and patients unlikely to benefit versus standard of care.”

In the phase II POPLAR study, 287 patients with previously treated NSCLC were randomized to receive MPDL3280A (n = 144) or docetaxel (n = 143). Intravenous MPDL3280A was administered at 1200 mg every 3 weeks and docetaxel was used at 75 mg/m²every 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 (TC/IC 1-3), there was a benefit seen with MPDL3280A. The median OS was not yet reached in the MPDL3280A arm (n = 93) compared with 9.1 months with docetaxel (n = 102; HR, 0.63; 95% CI, 0.42-0.95). The median PFS was similar between the two arms, at 3.3 months with MPDL3280A 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 MPDL3280A (n = 50), the median OS was 13 months compared with 7.4 months for patients treated with docetaxel (n = 55). Treatment with MPDL3280A 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). The median PFS was 4.0 months versus 2.8 months (HR, 0.70; 95% CI, 0.45-1.08), and the ORR was 22% versus 18% for MPDL3280A 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 MPDL3280A (n = 51) and docetaxel (n = 41). The median PFS was 1.9 months versus 4.1 months, and the ORR was 8% versus 10% for MPDL3280A and docetaxel, respectively.

MPDL3280A 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 to 5 adverse events (AEs) were experienced by patients treated with MPDL3280A compared with docetaxel (44% vs 56%). There was a higher incidence of respiratory side effects with immunotherapy versus chemotherapy. MPDL3280A was associated with aspartate and alanine aminotransferase increases (4% each), colitis (1%), hepatitis (1%), and pneumonitis (2%).

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Spira AI, Park K, Mazi&egrave;res J, et al. Efficacy, safety and predictive biomarker results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR).J Clin Oncol.2015;(suppl; abstr 8010).