Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial

Abstract

Background: Pembrolizumab improved survival as first- and second-line therapy compared with chemotherapy in patients with highly programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer (NSCLC). We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy.

Patients and methods: In the open-label phase 1b KEYNOTE-001 trial, treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 (≥1% staining, assessed using a prototype assay) were randomly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 (Q3W) or 2 (Q2W) weeks. Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received ≥1 pembrolizumab dose. Using pre-treatment tumor tissue, a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score (TPS).

Results: Between 1 March 2013 and 18 September 2015, 101 patients received pembrolizumab 2 mg/kg Q3W (n = 6), 10 mg/kg Q3W (n = 49), or 10 mg/kg Q2W (n = 46). Of these, 27 (26.7%) had TPS ≥50%, 52 (51.5%) had TPS 1%-49%, and 12 (11.9%) had TPS <1%. The objective response rate (ORR) was 27% (27/101, 95% CI 18-37) and median overall survival was 22.1 months (95% CI 17.1-27.2). In patients with PD-L1 TPS ≥50%, ORR, 12-month PFS, and 12-month OS were higher [14/27 (51.9%; 95% CI 32%-71%), 54%, and 85%, respectively] than the overall population [27/101 (26.7%; 95% CI 18.4%-36.5%), 35%, 71%]. Pembrolizumab was well tolerated, with only 12 (11.9%) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths.

Conclusions: Pembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS ≥50%.

Clinical trial name and number: KEYNOTE-001 (ClinicalTrials.gov, NCT01295827).

Keywords: anti-PD-1; immunotherapy; non-small cell lung cancer; pembrolizumab.

Figure 1.

Efficacy of pembrolizumab. (A) Maximum percentage change from baseline in the sum of the longest diameters of target lesions per RECIST v1.1 by independent central review in patients with measurable disease at baseline. (B) Kaplan–Meier estimate of duration of response per RECIST v1.1 by independent central review in responding patients.*RECIST v1.1, Response Evaluation Criteria in Solid Tumors (version 1.1); TPS, tumor proportion score. *TPS <1% data is not shown as there was only one patient with duration of response; as of the cut-off date, duration of response has been 17.5 months in this patient.

Figure 2.

Kaplan–Meier estimates of PFS per RECIST v1.1 by independent central review (A) and OS (B) by PD-L1 expression level. OS, overall survival; PFS, progression-free survival; RECIST v1.1, Response Evaluation Criteria in Solid Tumours (version 1.1); TPS, tumor proportion score.