Patients with advanced non-small-cell lung cancer survive four months longer with fewer side effects on the immunotherapy drug atezolizumab, compared to chemotherapy, according to a phase-3 clinical trial.
The trial enrolled 1225 advanced non-small-cell lung cancer patients who have no more treatment options, but this study used an early analysis of the first 850 patients from the trial. Half of the group were given atezolizumab and the other half were given docetaxel chemotherapy, which is the standard treatment for advanced non-small-cell lung cancer.
Patients given atezolizumab – a drug that blocks the programmed death ligand 1 (PD-L1) protein – survived for an average of 13.8 months, compared with 9.6 months for those on chemotherapy.
As well as the benefits in survival, atezolizumab also had fewer side effects than chemotherapy with 14.8% (90 of 609) of those given the drug having grade three or four side effects compared with 42.7% (247 of 578) of those given chemotherapy. However, 46 (of 609, 7.6%) of the patients given atezolizumab still gave up treatment due to side effects, as well as 108 (of 578 patients, 18.7%) of those on chemotherapy.
"Lung cancer is the most common cancer affecting 1.8 million people each year worldwide. It is also the leading cause of cancer death worldwide and survival remains stubbornly low. Recently, important advances in the treatment of the disease have come from immunotherapies that target the PD-L1 and PD-1 pathway," said Dr Achim Rittmeyer, lead author, University Goettingen, Germany. "Atezolizumab reinvigorates patients' immune systems against cancer, and our trial has shown that this has significant results for their survival."
In the trial the researchers also studied the amount of PD-L1 protein on the patients' cancer and immune cells and how long patients survived for on each treatment. They found that the drug worked best for patients with the highest levels of the PD-L1 protein on their cells – more than doubling survival compared with those given chemotherapy (20.5 months compared with 8.9 months overall survival) – but still increased survival for those with little to no levels of the protein by three and a half months (12.6 compared with 8.9 months overall survival).
"This is the first phase 3 trial of a PD-L1-directed immunotherapy in lung cancer. The fact that it improves survival in patients with all categories of PD-L1 expression is highly encouraging and adds to the already known benefits of immunotherapy in lung cancer," said Dr David Gandara, senior author, University of California – Davis Comprehensive Cancer Centre.
Other immunotherapies for non-small-cell lung cancer, such as nivolumab and pembrolizumab, are designed to block PD-L1's counterpart, the programmed cell death protein 1 (PD-1) which is located on the immune cell surface. Normally the PD-L1 and PD-1 proteins signal to one another to activate the immune system to attack tumours.
It's thought that the extra PD-L1 protein on some cancer cells' surfaces helps them hide from the immune system, meaning it cannot find and kill cancer cells as usual. But by blocking the extra PD-L1 protein, atezolizumab may unveil the cells to the immune system so they can be attacked and destroyed.
The study is the first phase 3 trial of a PD-L1 inhibitor drug and has shown longer survival than trials of PD-1 inhibitors.
The authors note that the trial was “open label”, meaning that patients and doctors knew whether or not they were being given immunotherapy. In addition, after the study treatment finished some (17%) of those given chemotherapy on the trial were prescribed another immunotherapy drug (mostly nivolumab) by their own doctor. This could have increased survival in the chemotherapy group, meaning that the difference between two groups may be greater than shown in this study.
Writing in a linked comment, Professor Elisabeth Quoix, Hôpitaux Universitaires de Strasbourg, France, said: "After decades of disappointments with non-specific vaccines or more recently tumour associated antigen specific vaccines, immunotherapy with antibodies that target the PD-L1 and PD-1 pathway have emerged as a major therapeutic breakthrough. This treatment improves the prognosis of patients with non-small-cell lung cancer that cannot benefit from targeted therapies… The time in which chemotherapy will no more be the mainstay of treatment of metastatic non-small-cell lung cancer is perhaps not so far away. Nevertheless… Several points need to be clarified, such as the optimum therapeutic schedule and the optimum duration of treatment, to limit treatment costs. Additionally combinations of different immunotherapies might be of interest."
Summary
Background: Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer.
Methods: We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227.
Findings: Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95% CI 11·8–15·7] vs 9·6 months [8·6–11·2]; hazard ratio [HR] 0·73 [95% CI 0·62–0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95% CI 12·6–18·0] with atezolizumab vs 10·3 months [8·8–12·0] with docetaxel; HR 0·74 [95% CI 0·58–0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95% CI 0·59–0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95% CI 0·54–0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60–0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group.
Interpretation: To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile.
Authors
Achim Rittmeyer, Fabrice Barlesi, Daniel Waterkamp, Keunchil Park, Fortunato Ciardiello, Joachim von Pawel, Shirish M Gadgeel, Toyoaki Hida, Dariusz M Kowalski, Manuel Cobo Dols, Diego L Cortinovis, Joseph Leach, Jonathan Polikoff, Carlos Barrios, Fairooz Kabbinavar, Osvaldo Arén Frontera, Filippo De Marinis, Hande Turna, Jong-Seok Lee, Marcus Ballinger, Marcin Kowanetz, Pei He, Daniel S Chen, Alan Sandler, David R Gandara
[link url="https://www.sciencedaily.com/releases/2016/12/161213074345.htm"]The Lancet material[/link]
[link url="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32517-X/abstract"]The Lancet article summary[/link]