Atezolizumab Makes Inroads in Non–Small Cell Lung Cancer

David R. Spigel, MD

David R. Spigel, MD

Single-agent atezolizumab (formerly MPDL3280A) had excellent clinical activity in both chemotherapy-naïve and previously treated patients with metastatic non—small cell lung cancer (NSCLC) in the phase II FIR study, and higher expression of PD-L1 was associated with improved response. Results were presented at the 2015  American Society of Clinical Oncology (ASCO) Annual Meeting.

“This is a great study. We took all comers, so the results are applicable to any patient with advanced NSCLC,” explained lead author David R. Spigel, MD, Sarah Cannon Cancer Center at Vanderbilt University in Nashville, Tennessee. “This study shows us that atezolizumab is active in NSCLC and that response rates are correlated with PD-L1 expression. In this study, the response rates in chemotherapy-naïve patients are as good as we see with chemotherapy. This suggests it is safe to consider an anti-PD-L1 strategy alone as upfront treatment without chemotherapy, but this needs to be shown in large randomized trials,” Spigel said.

Study Details

More than 1000 patients were screened for PD-L1 expression by central testing using a proprietary assay (SP142, by Spring Bioscience) in both archived and fresh tumor specimens, scored as IC0, IC1, IC2, or IC3, and TC0, TC1, TC2, or TC3.

The trial was designed to be enriched for PD-L1 expression (ie, TC2/3 and/or IC2/3). In all, 137 patients were enrolled and treated with atezolizumab 1200 mg intravenously every 3 weeks.

Median age was 66 years, and 58% were male. Patients were assigned to one of three cohorts.

Cohort 1 included 31 patients who were chemotherapy-naïve; cohort 2 patients received at least 1 prior line of chemotherapy and had no brain metastases (n = 92); cohort 3 patients received at least 2 prior lines of therapy for asymptomatic brain metastases (n = 13).

The highest overall response rates (ORR) were observed in the highest PD-L1 expressors (either TC3 or IC3). In cohort 1 (n = 31 patients), ORR was 26%; in cohort 2 ORR was 16%; and in cohort 3 ORR was 23%. Among TC3 or IC3 patients (ie, highest level of PD-L1 expression), response rate in cohort 1 was 29%, in cohort 2 was 24%, and in cohort 3 was 25%. Median duration of response had not yet been reached at the time of ASCO.

Median progression-free survival (PFS) was 4.5 months in cohort 1, 2.7 months in cohort 2, and 2.3 months in cohort 3. Among TC3 or IC3 patients, median PFS was 5.4 months for cohort 1, 4.1 months for cohort 2, and 2.3 months for cohort 3.

The adverse events (AEs) profile of atezolizumab was similar in all three cohorts. Two-thirds of patients had treatment-related AEs, most commonly fatigue (26%), nausea (15%), and decreased appetite (14%). Treatment-related grade 3 and 4 AEs were reported in 15% of patients; one treatment-related death occurred from constrictive pericarditis.

PD-L1 status

In commenting on the usefulness of PD-L1 expression as a biomarker for selection of therapy, Spigel said, “There is a catch. To get on the study, patients had to have a certain level of PD-L1 expression. Of more than 1000 people screened, only about 20% expressed PD-L1 at the level required. The problem is that we know some non-PD-L1 expressors respond, so this enriched population leaves out some people who could benefit.”

“It could be that the assay we are using is not the right one or that PD-L1 is not the right biomarker to select for benefit. Other biomarkers are being studied, and so far none has uniformly showed that it is the best way to identify responders. We have other studies showing that PD-L1 status does not matter [in terms of response],” Spigel stated.

The Future

“Anti-PD-L1 drugs are coming fast on the heels of anti-PD-1 agents. All of them target the ligand instead of the receptor. At least three are under development, and none is approved yet. We did this study to further define patients most likely to respond to our anti-PD-L1 drug by enriching the population for PD-L1 expression,” said Roel Funke, PhD, of Genentech, coauthor of the abstract presented at ASCO.

Funke said another phase II study, POPLAR, enrolled all comers with NSCLC and stratified them for PD-L1 expression to compare atezolizumab with docetaxel. In that study, an overall survival (OS) benefit was observed in patients who expressed any level of PD-L1.

Several phase III trials are studying atezolizumab as front-line treatment of metastatic NSCLC. One trial has enrolled an enriched population of PD-L1 expressors to compare single-agent therapy with a platinum doublet. Two other studies are looking at the combination of atezolizumab and chemotherapy in all comers—that is, unselected patients regarding PD-L1 expression.

Spigel DR, Chaft JE, Gettinger SN, et al. Clinical activity and safety from a phase II study (FIR) of MPDL3280A (anti-PDL1) in PD-L1—selected patients with non-small cell lung cancer (NSCLC). Presented at the ASCO Annual Meeting, Chicago: June 1, 2015. Abstract 8028.