Atezolizumab (Genetech/ Roche), another immunotherapy, is found effective in extending survival with favourable tolerability in selected patients with NSCLC, reported in 2 prospective phase II clinical trials.1,2
Targeting immune checkpoints such as PD-1 (programmed death protein 1) has achieved notable benefits, including overall survival, in multiple cancers through suppressing immunoinhibitory signals and, hence enabling patients’ self-immunity producing effective antitumor response. Currently, two PD-1 inhibitors, nivolumab (Opdivo, BMS) and pembrolizumab (Keytruda, MSD), have received regulatory approval to some difficult-to-treat cancers, such as pre-treated metastatic melanoma (in US/ Europe) and pre-treated metastatic non-small cell lung cancer (in US). Several more PD-1 inhibitors are under Phase III clinical evaluation.
Atezolizumab is a fully humanized monoclonal antibody targeting the ligand of PD-1: programmed death-ligand 1 (PD-L1). Disrupting PD-L1 from interacting with PD-1 can result in enhanced anti-tumor immunity across multiple cancer types, especially in patients whose tumor expressed high level of PD-L1.3
There may be potential advantage in targeting PD-L1. “Targeting PD-L1 leaves the PD-L2/PD-1 interaction intact, thereby potentially preserving peripheral immune homeostasis”, said Dr. Benjamin Besse, MD, PhD, the lead author of BIRCH study from the Institut Gustave Roussy, Villejuif France and Paris Sud University, France.
The safety and efficacy of atezolizumab is testing across several types of tumor in several phase 2/3 clinical trials. Atezolizumab has received breakthrough designation from the US FDA for use in treating patients with NSCLC whose tumor expresses high level of PD-1 an whose disease progressed on or during standard care.
Latest results of two prospective phase II trials, one RCT (POPLAR) and one large single-arm trial (BRICH), were presented in European Cancer Congress 2015.1,2
POPLAR: Atezolizumab versus docetaxel in pretreated NSCLC1
287 NSCLC patients with disease progression following platinum therapy, stratified by PD-L1 level on immune cells and histology, were randomized 1:1 to receive 1200mg IV atezolizumab q3w or 75mg/m2 IV docetaxel q3w under disease progression or unacceptable toxicity. The primary endpoint was OS.
Overall (in unselected setting), atezolizumab significantly improved OS compared with docetaxel (12.6m vs 9.7m, HR=0.73, 95%CI:0.53-0.99, p=0.04).
Consistent with previously reported interim data, better efficacy was observed with increasing PD-L1 expression. 105 Patients who were categorized to moderate-to-high PD-L1 level had median OS of 15+ months (15.1m vs 7.4m; HR=0.54, 95%CI:0.33-0.89, p=0.014)but patients with no detectable PD-L1 had no survival edge over docetaxel (9.7m vs 9.7m; HR=1.04, 95%CI:0.62-1.75, p=0.871).
Severe treatment-related adverse events (TEAE G3-4) occurred more frequently in docetaxel arm (39%) than atezolizumab arm (11%). The most common G3 TEAE for atezolizumab were pneumonia and elevated AST.
BRICH: single-arm trial in first line or subsequent use in PD-L1 selected NSCLC 2
667 patients with advanced/ metastatic NSCLC at various stages of treatment: No prior chemotherapy (1L), with 1 prior platinum-based chemotherapy (2L), and with ≥2 prior chemotherapies, were given IV 1200mg atezolizumab q3w until disease progression or unacceptable toxicity. These patients expressed moderate-to-high level PD-L1 in tumor and were screened from a large cohort of >3000 patients.
Primary endpoints were ORR, and the primary efficacy analyses compared the ORRs to historic controls at 2013 (1L, 2L and 3L+ were 15%, 7% and 5% respectively).
The primary endpoint was met in the interim analysis with 1L, 2L and 3L+ atezolizumab therapy. The ORRs were 19%, 17% and 17% respectively, all higher than historic controls. For patients with high level of PD-L1 expression, ORRs were even better, i.e., 26%, 24% and 27% respectively.
OS analysis was premature but 6-month survivals were 82%, 76% and 71% with median treatment duration of 4.2 months (range 0-15).
Severe TEAEs (G3-4) occurred in 11% of patients, and there was 1 G5 TEAE (pneumonia). The most common AEs were fatigue (18%) and nausea (10%). Discontinuation due to AE was 6%.
Both POPLAR and BRICH trials demonstrated clinically meaningful monotherapy efficacy of atezolizumab in patients with PD-L1 selected advanced NSCLC, with no unexpected toxicities, concluded the lead authors of both trials.
Discussion and comments
Dr. Luis Paz-Ares, the discussant for the papers4, MD, PhD, from the Hospital Universitario Virgen Del Roccio, in Seville, Spain, highlighted that survival benefits among atezolizumab and nivolumab over docetaxel in non-squamous NSCLC are very similar when respectively looking at OS data Phase II POPLAR trial and Phase III CheckMate 057 trial side-by-side, suggesting “one trial confirm the other even we are talking about different agents of the same class”.
He also noted that both PD-1/PD-L1 inhibitors give better response in patients with higher expression of PD-L1 and, conversely, offer no benefit in PD-L1 negative patents, although different positivity of PD-L1 and different assay kit were used.
He also pointed out issue of assay PD-L1 expression before prescription. “As there are so many assay kits out there with different cut-off values, definitions of positivity, etc, how to correspond one with the others is a practical issue”, “we are starting to learn a bit on that”, he said.
When discussing on the BRICH study, he acknowledged it is “a large single arm open-label phase II trial” enrolling nearly 700 patients. While it confirmed the activity and safety of atzeolizumab in selected patients with NSCLC, he was unable to see a definitive impact on clinical trial development except on registration strategy provided that “there is already a randomized phase II POPLAR trial comparing atezolizumab with docetaxel”.
Nevertheless, Dr. Martin Reck, Chief Oncology Physician in the Department of Thoracic Oncology, Hospital Grosshansdorf, Germany, commented in an ESMO statement that “Atezolizumab is set to substantially change treatment strategies for patients with refractory lung cancer”.
“First line treatment is also promising”, he added, “Treating patients with PD-L1 high expressing tumors remains an attractive option”.
Dr. Reck believed that atezolizumab will impact clinical practice. Yet, whether patients should be selected using a biomarker strategy still needs to be determined and remains a significant challenge based on the multiple different companion diagnostics that are in use for the particular agents”