Atezolizumab Improves Survival in Second-Line NSCLC

Shirish Gadgeel MD

Treatment with the PD-L1 inhibitor atezolizumab (Tecentriq) significantly improved overall survival (OS) compared to standard chemotherapy in patients with non—small lung cancer (NSCLC) who progressed on platinum-based chemotherapy, according to results from the phase III OAK trial presented at the 17th World Lung Cancer Conference in Vienna.

OS in the intent-to-treat (ITT) population (a co-primary endpoint of the OAK study) was 13.8 months in patients treated with atezolizumab (n = 425) versus 9.6 months in patients who received docetaxel (n = 425) (HR = 0.73; 95% CI, 0.62-0.87; P = .0003).

Extentions in OS were also found in selected sub-groups of patients and also across subgroups of patients having differing levels of PD-L1 expression within squamous and nonsquamous histology. The trial has been touted as demonstrating improvement in OS for patients regardless of PD-L1 status, leading researchers to conclude that other biomarkers need to be looked at to help explain the activity in NSCLC seen with atezolizumab.

“PD-L1 may not be the best marker for atezolizumab or it may be that the biopsy sample may be insufficient to capture PD-L1 because of the high heterogeneity of these tumours,” said the presenter, Shirish Gadgeel MD, of the Molecular Therapeutics Program of the Karmanos Cancer Institute, at Wayne State University in Detroit, USA.

PD-L1 gene expression on tumor cell (TC) and immune cells (IC) was quantified by immunohistochemistry and by gene expression. Investigators found that PD-L1 gene expression was highly correlated with PD-L1 by immunohistochemistry.

Similar to OS in the ITT population, median OS in non—PD-L1 expressing patients treated with atezolizumab versus docetaxel was 12.6 months versus 8.9 months (HR = 0.73).

OAK also met the trial’s co-primary endpoint of OS in patients with PD-L1 expression of ≥1%. OS in patients at all levels of PD-L1 expression (TC 1/2/3 or IC 1/2/3) was 15.7 months versus 10.3 months, respectively, with atezolizumab versus docetaxel (HR 0.74). However, OS in the subgroup with the highest level of PD-L1 expression (TC3 or IC3) was 20.5 months with atezolizumab compared to 8.9 months with docetaxel (HR = 0.41).

“Two different PD-L1 biomarker assessments both demonstrate broad OS benefit with atezolizumab, including patients with no PD-L1 expression; and patients with high and low PD-L1 expression showed improved OS with atezolizumab,” said Gadgeel.

Atezolizumab, a Genentech drug, works by restoring tumor-specific T-cell immunity by inhibiting PD-L1 binding to the receptors PD-1 and B7.1. Atezolizumab was approved in October, 2016 by the US Food and Drug Administration for the treatment of patients with NSCLC whose disease progressed during or after chemotherapy.

Gadgeel’s presentation dealt specifically with the results from a subgroup analysis of the primary study population comprising the first 850 of 1225 randomized patients participating in the OAK phase III trial. “We wanted to see if there were subgroups that did not benefit more from atezolizumab than with docetaxel,” he explained.

Following stratification by PD-L1 expression, prior chemotherapy regimens, and tumor histology, patients were randomized 1:1 to intravenous atezolizumab at 1200 mg every 3 weeks or to intravenous docetaxel at 75 mg/m² every 3 weeks.

OS was longer with atezolizumab compared to docetaxel regardless of histology: In patients with nonsquamous NSCLC, median OS was 15.6 months versus 11.2 months (HR = 0.73; P = .0015), and in patients with squamous NSCLC, median OS was 8.9 versus 7.7 months (HR = 0.73; P = .0383) with atezolizumab versus docetaxel, respectively.

In patients with treated baseline brain metastases, median OS with atezolizumab versus docetaxel, respectively, was 20.1 months versus 11.9 months (HR = 0.54), and in never-smokers, median OS was 16.3 months versus 12.6 months (HR = 0.71).

“OAK subgroup analysis demonstrated broad clinically-relevant efficacy with atezolizumab regardless of PD-L1 expression levels or histology, and overall survival was improved across subgroups including all age ranges, never-smokers, and patients with baseline brain metastases,” Gadgeel summarized.

However, a lack of improved efficacy with atezolizumab relative to docetaxel was observed when efficacy was evaluated in terms of EGFR status. “Inpatients with EGFR mutations, the activity of atezolizumab was similar to other in-pathway agents,” Gadgeel said.

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