Pembrolizumab Shows Antitumour Activity in Patients with Advanced NSCLC

KEYNOTE-001 study results

KEYNOTE-001 investigators published the study results on 19 April 2015 in The New England Journal of Medicine. They wrote that pembrolizumab had an acceptable side-effect profile and showed antitumour activity in patients with advanced non–small cell lung cancer (NSCLC). PD-L1 expression in at least 50% of tumour cells correlated with improved efficacy of pembrolizumab.

Pembrolizumab, a highly selective, humanised antibody against PD-1, can disrupt the engagement of PD-1 with its ligands and impede inhibitory signals in T cells, with resultant tumour recognition by cytotoxic T cells. Developing reliable, validated biomarkers that identify patients with an increased probability of response to anti–PD-1 and anti–PD-L1 antibodies remains a challenge. Because the PD-1 pathway may be a key mechanism of immune escape in a subgroup of patients with NSCLC, PD-L1 expression in tumour or inflammatory cells is a candidate biomarker. However, PD-L1 expression has not been formally validated as a biomarker in contemporaneously collected tumour tissue. In this study, the investigators assessed the efficacy and safety of PD-1 inhibition with pembrolizumab in patients with advanced NSCLC. They also sought to define and validate an expression level of the PD-L1 that is associated with the likelihood of clinical benefit.

The study researchers assigned 495 patients receiving pembrolizumab at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks to either a training group of 182 patients or a validation group of 313 patients.

PD-L1 expression was assessed in tumour samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1. Response was assessed every 9 weeks by central review.

Common side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule.

Among all the patients, the objective response rate was 19.4%, and the median duration of response was 12.5 months. The median duration of progression-free survival (PFS) was 3.7 months, and the median duration of overall survival (OS) was 12.0 months.

PD-L1 expression in at least 50% of tumour cells was selected as the cut-off from the training group. Among patients with a proportion score of at least 50% in the validation group, the response rate was 45.2%. Among all the patients with a proportion score of at least 50%, median PFS was 6.3 months; median OS was not reached.

PD-L1 expression

The authors discussed that analysis of PD-L1 expression permitted the identification of patients with an enhanced likelihood of a response to pembrolizumab. A proportion score of at least 50% was associated with a higher response rate and longer PFS and OS than was a proportion score of less than 50% in both previously untreated patients and previously treated patients, which indicates that this is a subgroup of patients in whom the PD-L1 pathway can be successfully targeted.

Furthermore, the magnitude of benefit that was observed in previously treated patients clearly exceeds that anticipated with standard therapy, with median OS not reached among patients with a proportion score of at least 50%, regardless of previous treatment, at the time of data cut-off. This finding suggests that a proportion score of at least 50% may represent a new biomarker for the treatment of NSCLC, although interpretation in the context of other immune checkpoint inhibitors and their respective biomarkers may require cross-compound comparisons. The study design, which does not include a non-pembrolizumab comparator, prevents the assessment of the prognostic implications of PD-L1 expression.

Current or former smoking status was associated with an increased response to treatment, an association that was also observed by other investigators and is hypothesized to be based on a higher mutational burden in these patients. However, when assessed according to PD-L1 subgroup, the response rate was similar according to smoking status. This finding, along with the much higher response rate among patients with a proportion score of at least 50%, as compared with that of current or former smokers, suggests that although smoking history may provide insight into a patient profile associated with a greater benefit for pembrolizumab, PD-L1 expression is a better predictor of response.

Evaluation according to the quartile of proportion score suggests a positive correlation between the response rate and PD-L1 expression, although the analysis was limited by the small sample size in some groups and large confidence intervals for response. These data in combination with responses among patients with a proportion score of less than 1% suggest that tumour PD-L1 expression is not associated with the ideal test characteristics of approved genetically based biomarkers. The investigators did not seek to identify a PD-L1 cut-off that would capture all patients with a possible response but rather one that would identify patients with a greater likelihood of response.

Determination of whether archival samples can be substituted for those collected contemporaneously, the true prevalence of the proportion-score subgroups, and the degree of clinical benefit in patients with NSCLC with a proportion score of less than 50% are being assessed in ongoing randomised trials enrolling both previously treated and previously untreated patients.

The authors concluded that they have shown the efficacy and safety of pembrolizumab for previously treated and previously untreated patients with NSCLC. Prospective testing of PD-L1 expression is feasible and retrospectively identified patients with an enhanced likelihood of having a clinical benefit from treatment with pembrolizumab.

The study was supported by Merck Sharp & Dohme, a subsidiary of Merck.


Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer. NEJM 2015; Online First 19 April. DOI: 10.1056/NEJMoa1501824