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.

Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

Figures

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

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.