Atezolizumab: Another Immunotherapy for Lung Cancer?

October 2015, Vol 6, No 9

Vienna, Austria—Immunotherapy is poised to become a game changer for patients with non–small-cell lung cancer (NSCLC). The first immunotherapy—­nivolumab (Opdivo), was approved by the FDA earlier this year for the treatment of patients with metastatic squamous NSCLC—and atezolizumab is the second checkpoint inhibitor to show promise as second-line or later therapy in this patient population.

The results of the POPLAR and BIRCH trials were presented separately at the European Cancer Congress 2015 and were very encouraging; in both trials, PD-1 ligand 1 (PD-L1) was found to be a predictive biomarker for response to therapy.

The POPLAR trial enrolled any patients with previously treated NSCLC; the BIRCH trial enrolled only patients with NSCLC who expressed PD-L1.

The POPLAR Trial

The randomized, phase 2 POPLAR trial compared atezolizumab, a PD-L1 antibody, to standard therapy with docetaxel (Taxotere) in 287 patients with advanced NSCLC that progressed with previous platinum therapy. Treatment with atezolizumab was continued until the loss of clinical benefit, and until disease progression in the docetaxel arm. The primary end points were efficacy, safety, and predictive biomarkers.

“POPLAR demonstrated significant improvements in overall survival for unselected patients treated with atezolizumab versus docetaxel, reflecting a 27% improvement. Higher PD-L1 expression was associated with improved overall survival,” said lead author Johan Vansteenkiste, MD, PhD, University Hospital Gasthuisberg, Leuven, Belgium.

PD-L1 expression was assessed by the SP142 assay that identifies tumor cells (TC) and immune cells (IC). The patients in POPLAR were stratified according to PD-L1 expression: patients with TC3 and/or IC3 were considered high expressors of PD-L1; TC2/3 and/or IC2/3, intermediate to high expressors; TC1/2/3 and/or IC1/2/3, any expressors; and TC0 and IC0 were considered nonexpressors.

At a minimum follow-up of 13 months, the overall survival (OS) was significantly improved in patients treated with atezolizumab; the median OS was 9.7 months with docetaxel versus 12.6 months with atezolizumab (P = .04).

The median OS was higher in patients categorized as TC3 or IC3 (ie, high expressors of PD-L1). The magnitude of the survival benefit correlated with the level of PD-L1 expression: a 41% improvement was seen with atezolizumab in patients who are high expressors of PD-L1 (ie, TC3 and IC3) versus no OS benefit in nonexpressors.

Progression-free survival also correlated with the intensity of PD-L1 expression.

The patients receiving atezolizumab exhibited fewer treatment-emergent grades 3 or 4 adverse events than those who received docetaxel (11% vs 39%, respectively). The rate of grade 5 adverse events was 4% in both treatment arms. Trial withdrawals that resulted from treatment-related adverse events were higher in the docetaxel arm than in the atezolizumab arm (22% vs 8%, respectively).

The BIRCH Trial

The BIRCH trial was a single-arm study of first-line or subsequent therapy that enrolled only patients with PD-L1 expression and advanced or metastatic NSCLC (brain metastasis was an exclusion criteria).

“The BIRCH trial found clinically meaningful results with atezolizumab monotherapy in PD-L1–selected patients with advanced NSCLC. The majority of responses are ongoing. Overall survival data are not mature. Six-month overall survival correlates with POPLAR results in second- and third-line therapy,” said lead investigator Benjamin Besse, MD, Institut Gustave Roissy, Paris, France.

Similar to the POPLAR trial, higher levels of PD-L1 correlated with higher response rates in BIRCH.

The BIRCH study enrolled 667 patients; patients in cohort 1 received first-line atezolizumab monotherapy until disease progression (N = 142), cohort 2 received second-line atezolizumab after 1 previous platinum-containing therapy (N = 271), and cohort 3 received third-line or later atezolizumab therapy (N = 254).

Using the SP142 assay for PD-L1 expression, the patients were classified as TC2/3 and/or IC2/3. Of the overall population, 46% of patients were classified as high PD-L1 expressors (ie, TC3 or IC3).

The overall response rate to atezolizumab was 17% in cohorts 2 and 3 and 19% in cohort 1. The response rates were higher among high PD-L1 expressors (ie, TC3 or IC3)—26%, 24%, and 27% in cohorts 1, 2, and 3, respectively. The majority of responses are ongoing.

The 6-month OS rates were 82%, 76%, and 71% in cohorts 1, 2 and 3, respectively, and were higher in patients categorized as TC3 and IC3—79%, 80%, and 75%, respectively—in the 3 cohorts.

Grades 3 or 4 adverse events were reported in 11% of patients enrolled in the trial. The rate of discontinuations because of treatment-related adverse events was 5%. The common adverse events included fatigue, diarrhea, nausea, pruritus, pyrexia, and decreased appetite.

Adverse events of special interest occurred in 26% of patients, but most were grades 1 and 2. The most common grades 3 or 4 adverse events of special interest were pneumonitis (1.5%, 1 fatal case), increased aspartate aminotransferase (0.8%), colitis (0.5%), hypothyroidism (0.3%), and rash (0.3%).

Ongoing Studies

More ongoing studies of atezolizumab are being conducted in the first-line and second-line settings, and the results are eagerly awaited.

PD-L1 needs to be validated in a phase 3 trial that enrolls unselected patients, according to Luis Paz-Ares, MD, PhD, Professor of Medicine at the Hospital Universitario Doce de Octubre, Madrid, Spain, who discussed these results.

The POPLAR and BIRCH studies are part of a large development program at the drug manufacturer (Roche). The results of the phase 3 OAK trial in unselected patients with NSCLC are expected within 1 year.

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