Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma

Abstract

Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score ≥ 2 (membranous staining in ≥ 1% of cells) was considered positive. Results Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1-positive tumors. Demographic and staging variables were equally distributed among PD-L1-positive and -negative patients. An association between higher MEL score and higher response rate and longer PFS (hazard ratio, 0.76; 95% CI, 0.71 to 0.82) and OS (hazard ratio, 0.76; 95% CI, 0.69 to 0.83) was observed ( P < .001 for each). Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1-negative tumors may also achieve durable responses.

Fig 1.

Photomicrographs showing immunohistochemical staining of programmed death-ligand 1 (PD-L1; 22C3 antibody) in melanoma (MEL) samples. MEL score ≥ 2 is considered PD-L1 positive. PD-L1 staining is evidenced by the presence of the brown chromogen, whereas blue is hematoxylin counterstain.

Fig 2.

Efficacy according to melanoma (MEL) score for programmed death-ligand 1 (PD-L1) expression. (A) Objective response rate (ORR) and associated 95% CIs. (B) Kapan-Meier estimates of progression-free survival (PFS) and associated 95% CIs at 9 months. (C) Kaplan-Meier estimates of overall survival (OS) and associated 95% CIs at 12 months. Response was assessed per RECIST, version 1.1, by independent central review. MEL score ≥ 2 is considered PD-L1 positive.

Fig 3.

Box plots of observed percentage change from baseline in tumor size at week 12 by melanoma (MEL) score. The analysis population was patients with evaluable programmed death-ligand 1 (PD-L1) expression who had tumor size data at week 12 (n = 292). MEL score, 0 (0% staining); MEL score, 1 (> 0% to < 1% staining); MEL score, 2 (≥ 1% to < 10% staining); MEL score, 3 (≥ 10% to < 33% staining); MEL score, 4 (≥ 33% to < 66% staining); and MEL score, 5 (≥ 66% to 100% staining). MEL score ≥ 2 is considered PD-L1 positive. Outer boundaries of boxes represent the 1st and 3rd quartiles, and lines in between represent the median.

Fig 4.

Efficacy by PD-L1 positivity. (A) Kaplan-Meier estimate of progression-free survival (PFS) assessed per RECIST, version 1.1, by independent central review. (B) Kaplan-Meier estimate of overall survival (OS). Melanoma score ≥ 2 is considered PD-L1 positive. NR, not reached; PD-L1, programmed death-ligand 1.

Fig A1.

CONSORT diagram. BICR, blinded independent central review; MEL, melanoma; PD-L1, programmed death-ligand 1.