Inhibition of PD-L1 with atezolizumab demonstrated significant clinical efficacy as monotherapy in patients with advanced non-small cell lung cancer.
Benjamin Besse, MD
Inhibition of PD-L1 with atezolizumab (MPDL3280A) demonstrated significant clinical efficacy as monotherapy in patients with advanced non-small cell lung cancer (NSCLC), according to findings from two phase II trials reported at 2015 European Cancer Congress (ECC).1,2
At a minimum follow-up of 6 months in the phase II BIRCH trial, more than 61% of responses were ongoing. Tumor shrinkage was observed in up to 27% of patients whose disease progressed following prior treatment and who expressed PD-L1 at the highest levels (P = .0001). In the phase II POPLAR study, patients with the highest level of PD-L1 expression experienced a median overall survival (OS) with atezolizumab of 15.5 months compared with 11.1 months for docetaxel (HR, 0.49; 95% CI, 0.22-1.07; P = .068).
Overall, the activity of atezolizumab correlated with the extent of PD-L1 expression on tumor cells (TC) and tumor infiltrating cells (IC), with the highest activity seen in patients demonstrating expression on both cell types, according to lead investigator of the BIRCH trial, Benjamin Besse, MD.
“Higher PD-L1 expression correlates with higher responses and may allow identification of patients most likely to benefit from atezolizumab,” said Besse, of the Institut Gustave Roussy, Villejuif, and the Paris Sud University. “The majority of responses are still ongoing.”
Atezolizumab is a humanized antibody that targets PD-L1 to inhibit the PD-1/PD-L1 interaction while preserving the PD-L2/PD-1 interaction, which potentially preserves peripheral immune homeostasis. BIRCH was an open-label, single-arm phase II study of atezolizumab administered either as first-line treatment or as subsequent second- or third-line treatment in patients with advanced NSCLC who were selected for high PD-L1 expression by immunohistochemistry (IHC) done on both archival and fresh tissue samples.
Of the 667 patients enrolled in the BIRCH trial, 659 patients were treated and evaluated for efficacy and safety. Patients with stage IIIB/IV or recurrent NSCLC but no active central nervous system metastases were enrolled. All enrolled patients showed PD-L1 expression at higher levels as TC2/3 or IC2/3 or on both cell types.
Atezolizumab was given at 1200 mg intravenously at 3-week intervals as first line to 142 patients who had received no prior chemotherapy (cohort 1) until disease progression or unacceptable toxicity, as second-line to 271 patients who had received one prior platinum therapy (cohort 2), and to 254 patients who had undergone 2 or more prior chemotherapy regimens (cohort 3) until loss of clinical benefit was seen. Patients in cohorts 2 and 3 had progressed after chemotherapy.
Patient characteristics were balanced across cohorts; the median age was 64 years, 35% were ECOG PS 0, 28% had squamous NSCLC and 17% of patients were never-smokers. EGFR and KRAS mutations were identified in 327 and 177 patients overall, respectively.
The primary objective of BIRCH was to determine the efficacy of atezolizumab by overall response rate (ORR) according to independent review facility (IRF) per RECIST v1.1 for defined subgroups. Key secondary endpoints were duration of response (DoR), progression-free survival (PFS) by IRF and investigator, ORR by investigator, OS, and safety.
The median treatment duration across all cohorts was 4.2 months (range, 0-15). The ORR in cohort 1 was 19% and 17% in cohorts 2 and 3 in patients with TC2/3 or IC2/3 expression. Stronger response was seen in patients with higher expression; ORR rates were 26%, 24%, and 27% in cohorts 1, 2, and 3 in patients with PD-L1 expression of level TC3 or IC3.
Besse also noted that OS data are not yet mature and that several trials of atezolizumab in patients with NSCLC are under way, including one phase III trial in heavily pretreated patients.
At a median follow-up of 8.8, 7.9, and 8.6 months, median OS was 14 months, not reached (NR), and NR, across cohorts 1, 2, and 3, respectively. Six-month OS was achieved by 76%, 75%, and 71% of patients in cohorts 1, 2, and 3, respectively, having TC2/3 or IC 2/3 expression levels and by 79%, 82%, and 80% of patients in cohorts 1, 2, and 3 having TC3 or IC 3 expression levels.
Improved PFS also mirrored higher PD-L1 expression: 6-month PFS rates were 29%, 39%, and 31% at the PD-L1 expression level of TC2/3 and IC 2/3 and 48%, 46%, and 34% in patients with TC3 or IC3 expression levels in cohorts 1, 2, and 3, respectively.
The safety profile was consistent with that demonstrated in other studies; grade 3/4 treatment-related adverse events (TRAEs) occurred in 11% of patients overall and TRAEs leading to study discontinuation occurred in 6% of patients. All-cause adverse events (AEs) grade 3/4 were reported in 38% of patients. The most commonly reported AEs were fatigue (18%) and nausea (10%).
Analysis of data according to EGFR mutation status is ongoing, according to Besse, who said the preliminary data suggested that the response rates for atezolizumab administered as second- and third-line may be quite different in patients with an EGFR mutation.
In the second- and third-line settings, findings were updated from the phase II POPLAR study at ECC.2 In this 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.
In high PD-L1 expressing tumors (TC/IC 3), the median PFS was 7.8 versus 3.9 months, for the anti-PD-L1 antibody and docetaxel, respectively (HR, 0.60; 95% CI, 0.31-1.16). The 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. Across the all expression levels, the ORR was 15% with both treatments. In this group, the median OS was 12.6 and 9.7 months and the median PFS was 2.7 and 3.0 months, for atezolizumab and docetaxel, respectively.
Atezolizumab was granted a breakthrough therapy designation for patients with PD-L1-positive NSCLC in February 2015. Building on this designation, the manufacturer of the drug, Genentech, is currently in discussions with the FDA on the submission of data from POPLAR and BIRCH.
“Results from both of our studies in non-small cell lung cancer showed that measuring PD-L1 may help identify people most likely to respond to atezolizumab, and the majority of responses continued when these data were assessed,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, said in a statement. “Durable responses are meaningful for people whose cancer has progressed on other medicines, and we plan to submit these results to global health authorities to bring this potential new option to people as soon as possible.”
Experts at ECC expressed their optimism that atezolizumab would soon be available for the treatment of patients with NSCLC. According to lung cancer expert Martin Reck MD, “atezolizumab is set to substantially change treatment strategies for patients with refractory lung cancer.”
“In the BIRCH trial, the PD-L1 antibody atezolizumab showed a remarkable activity in a large number of patients regardless of the line of treatment,” said Reck, chief oncology physician, Department of Thoracic Oncology, Hospital Grosshansdorf, Germany. “The profile of adverse events is in line with reported data from other PD-1/PD-L1 checkpoint inhibitors and overall tolerability looks quite favorable. The efficacy as shown by the response rate was in correlation with PD-L1 expression on tumor and immune cells favoring tumors with high PD-L1 expression.”
Reck also raised the possibility of combining atezolizumab with chemotherapy. In fact, in data presented at the 2015 World Conference on Lung Cancer, data demonstrated that almost two thirds of 41 evaluable patients had objective responses with atezolizumab plus different platinum-based chemotherapy doublets.3 The highest response rate occurred with the combination of atezolizumab, carboplatin, and pemetrexed, as 13 of 17 patients (76.5%) had partial responses. Four patients treated with the anti—PD-L1 inhibitor, carboplatin, and nab-paclitaxel had complete responses.
“While first-line treatment with atezolizumab in patients with PD-L1 high-expressing tumors is promising, the combination of atezolizumab with platinum-based chemotherapy remains an attractive option and is currently being investigated in large randomized phase III trials,” said Reck. “It is to be expected that atezolizumab, like other PD-1 and PD-L1 antibodies, will substantially change treatment strategies of patients with refractory lung cancer.”