Lung cancer is the leading cause of cancer deaths worldwide.1 Most patients present with stage IV disease, which has a median overall survival of 8–10 months and a 5-year relative survival of about 4%.2, 3, 4 First-line treatment for patients with non-small-cell lung cancer (NSCLC) without any actionable mutation is generally based on platinum-doublet chemotherapy. Until recently, eligible patients with progressive disease following first-line therapy typically received chemotherapy with docetaxel or pemetrexed, which has been associated with a 1-year survival of about 30%.5 In eligible subsets of patients with specific tumour biomarkers, such as EGFR mutations or ALK or protein kinase ROS1 rearrangements, targeted therapy with tyrosine kinase inhibitors has shown clinical efficacy, but resistance eventually develops.6, 7
Research in context
Evidence before this study
Because the field of immunotherapy with anti-PD-L1 or anti-PD-1 immune checkpoint inhibitors has expanded rapidly in recent years, we did a 5-year systematic search of the English language literature using both PubMed and selected annual congresses (American Society of Clinical Oncology, European Society for Medical Oncology, European Cancer Congress, and World Conference on Lung Cancer). Search dates were between Jan 1, 2011, and Aug 22, 2016, and terms included “PD-1” and “PD-L1,” in addition to relevant generic and investigational drug names of immune checkpoint inhibitors (“nivolumab”, “BMS-936558”, “pembrolizumab”, “lambrolizumab”, “MK-3475”, “atezolizumab”, “MPDL3280A”, “durvalumab”, “MEDI4736”, “avelumab”, and “MSB0010718A”). Most clinical studies were published after 2013. Additional search terms were used to identify literature about patients with advanced non-small-cell lung cancer (NSCLC). Recent evidence from phase 2 and phase 3 trials indicates that anti-PD-L1 and anti-PD-1 antibodies have efficacy and are well tolerated in patients with squamous and non-squamous histological subtypes of NSCLC. Tumour PD-L1 expression might have predictive value for efficacy of anti-PD-1 antibodies in non-squamous NSCLC. Avelumab is a human anti-PD-L1 IgG1 antibody that is approved in the USA for the treatment of metastatic Merkel cell carcinoma and has shown promising antitumour activity and a manageable safety profile in several other tumour types. Unlike other anti-PD-L1 or anti-PD-1 antibodies approved or in advanced clinical development, avelumab has been shown to mediate antibody-dependent cellular cytotoxicity in vitro. Based on safety, pharmacokinetic, target occupancy, and preliminary efficacy data obtained during a dose-escalation study of avelumab, the dose of 10 mg/kg given as a 1-h intravenous infusion every 2 weeks was selected for phase 1 dose expansion in various tumours.
Added value of this study
We report the safety and antitumour activity of avelumab monotherapy in a large phase 1 cohort of patients with progressive or platinum-resistant metastatic or recurrent NSCLC. Eligible patients in this cohort were not preselected based on NSCLC histology, PD-L1 expression status, or EGFR or ALK status. Clinical activity was recorded independent of PD-L1 expression, or squamous versus non-squamous histology. This is the largest cohort of patients studied in a phase 1 trial of avelumab and further characterises its clinical attributes.
Implications of all the available evidence
Avelumab had a manageable safety profile and promising clinical activity in a population of patients with progressive, platinum-treated, metastatic, or recurrent NSCLC. Responses occurred irrespective of PD-L1 expression status and in squamous and non-squamous tumours. These findings support the therapeutic benefit of anti-PD-L1 antibodies in patients with previously treated NSCLC. These results with avelumab have provided the rationale for an ongoing phase 3 trial in the second-line NSCLC population and underscore the potential benefits of immunotherapy for patients with this difficult-to-treat disease.
NSCLC tumours can evade immune activity through several mechanisms, including the expression of molecules (immune checkpoints) that inhibit T-cell activation. In particular, PD-L1 expression is often upregulated in immunogenic tumours, including NSCLC,8, 9 and binding of PD-L1 to its receptor on T cells, PD-1, inhibits tumour immunity by suppressing T-cell activation,8, 10, 11 enabling tumours to escape T-cell surveillance. PD-L1–PD-1 axis blockade might stimulate a patient's antitumour immune response by promoting T-cell reactivity against tumour neoantigens.12 Patients with recurrent or metatstatic NSCLC have few therapeutic options. However, recently, PD-L1–PD-1-targeted immune checkpoint inhibitors have been shown to increase overall survival versus docetaxel in patients with previously treated advanced NSCLC, leading to regulatory approval of three anti-PD-L1–PD-1 therapies (atezolizumab, nivolumab, and pembrolizumab) in this setting.13, 14, 15, 16 These agents might therefore be able to address a major unmet need. Correlative and translational studies in NSCLC and other tumour types suggest that the clinical benefits of immune checkpoint inhibition might be affected by tumour histology, mutational load, molecular drivers of disease, and expression of PD-L1 by tumours, although responses have been achieved independently of these factors.9, 17, 18 However, patient selection and stratification based on such factors are important characteristics to consider in clinical study design and prespecified subgroup analyses.
Avelumab (MSB0010718C) is a human anti-PD-L1 IgG1 antibody that has been approved in the USA for the treatment of metastatic Merkel cell carcinoma. Avelumab inhibits PD-L1–PD-1 interactions but leaves the PD-L2–PD-1 pathway intact. By contrast with other PD-L1–PD-1 drugs assessed in clinical trials so far, avelumab binding to the surface of tumour cells via PD-L1 has the potential to induce natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC) of tumour cells, as shown by preclinical models, which might contribute to its clinical activity.19, 20 A large, multicohort, phase 1 dose-escalation and dose-expansion trial is being done21 to assess the safety and activity of avelumab in patients with a range of advanced solid tumours. In the phase 1a dose-escalation part of the study, avelumab was safely given by intravenous infusion every 2 weeks, had a predictable pharmacokinetic profile at doses up to 20 mg/kg, and showed preliminary evidence of antitumour activity, including durable responses and stable disease.21, 22 The 10 mg/kg dose, which has a half-life of about 4 days, was selected for further study in dose-expansion cohorts in a range of tumour types. Here, we present phase 1b results from this study in a cohort of patients with advanced NSCLC whose disease has progressed after platinum-based chemotherapy and are unselected for PD-L1 expression.