The role of immunotherapy is emerging as an effective, and in some cases, dramatic treatment in the non-small cell lung cancer (NSCLC) landscape. The programmed cell death 1 (PD-1) inhibitor pembrolizumab (Keytruda) is approved for the treatment of previously treated patients with metastatic NSCLC and was originally approved to treat patients with advanced melanoma in 2014.
PD-1 is a negative costimulatory receptor expressed primarily on the surface of activated T cells.1
Binding of PD-1 to one of its ligands, PD-L1, can inhibit T cell cytotoxic responses. Tumors have been hypothesized to utilize this pathway to escape immune surveillance.2
Lung cancer is the leading cause of cancer deaths in the United States with NSCLC being responsible for approximately 85% of all cases. According to the National Cancer Institute, in 2015 an estimated 158,040 deaths will result from 221,200 diagnosed lung cancers.3
Despite several available targeted therapies, most patients do not have mutations for which FDA-approved treatments exist.
The large international phase I KEYNOTE-001 trial recently led to accelerated approval for pembrolizumab in NSCLC.4
This study evaluated the efficacy and safety of pembrolizumab in patients with advanced NSCLC. Of the 495 patients reported, 394 had experienced disease progression after undergoing platinum-based chemotherapy. The remaining 101 patients had not been previously treated. Patients received pembrolizumab at a dose of either 2 mg/kg or 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks.
The anti–PD-L1 antibody clone 22C3 was utilized in an immunohistochemical assay to determine each patient’s PD-L1 expression. Two groups were created, a training group made up of 182 patients and a validation group made up of the remaining 313. During the course of the study, computed tomography or magnetic resonance imaging was performed every 9 weeks and the resultant images were assessed with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In the training group, patients with staining for PD-L1 in at least half of their cells were more likely to clinically respond to pembrolizumab. There were no clear differences between patients with staining in a minority of their cells versus no PD-L1 staining in this training set.
The objective response rate was 19.4%—18.0% in the 394 previously treated patients, and 24.8% in the 101 untreated patients. The best overall response was stable disease in 21.8% of patients. In contrast to current or former smokers who had a response rate of 22.5%, patients who had never smoked cigarettes had a response rate of 10.3%. The response rate for patients with PD-L1 expression in at least half of their cells was 45.2%.
Analysis of median progression-free survival and overall survival in patients with PD-L1 staining in at least half of their cells was 6.1 months for previously treated patients and 12.5 months for previously untreated patients. The median duration of response exceeded a year among those who responded, without clear differences based on PD-L1 expression.
Pembrolizumab showed modest toxicity with fatigue, pruritus, and anorexia being the most common treatment-related adverse events. Serious adverse events were reported in 9.5% of cases, a proportion that is lower than that anticipated with chemotherapy. More specifically, the most common inflammatory or immune-mediated adverse events were hypothyroidism, infusion- related reactions, and pneumonitis.
No significant differences were observed in efficacy or toxicity among patients receiving 10 mg/kg either every 2 or 3 weeks. There were an insufficient number of patients treated with the 2 mg/kg to draw meaningful conclusions.
The KEYNOTE-010 trial compares pembrolizumab to docetaxel in patients with NSCLC whose tumors express PD-L1 and have progressed after systemic platinum-based treatments. This study will be able to answer the relative efficacy of the 2 mg/kg dose and the 10 mg/kg dose.
In the KEYNOTE-001 study, PD-L1 expression was assessed based on tissue collected contemporaneously to treatment instead of archived tissue. As some patients on KEYNOTE-010 underwent new biopsies while others submitted archival biopsies, the role of a new biopsy to assess likelihood of benefit can also be assessed in this phase II/III study.