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

Abstract

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 MethodsSix 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. ResultsOf 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. ConclusionPD-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.

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“…Although PD-L1 expression in tumor cells correlates with the response to PD-1/PD-L1 blockage therapy (Taube et al 2014, Daud et al 2016, the clinical benefit is not limited to patients whose tumors are positive for PD-L1 , suggesting that the expression of PD-L1 24:12 in tumor cells cannot be fully translated to the clinic as an isolated criterion (biomarker) for the indication of PD-1/ PD-L1 blockage. It is possible that other characteristics of the immune microenvironment may also be important in predicting the effect of PD-L1 blockage.…”

Melanoma Treatment with Intratumoral Electroporation of Tavokinogene Telseplasmid (pIL-12, Tavokinogene Telseplasmid)

“…A third Investigators were requested to maintain one untreated lesion for the duration of the trial to enable the assessment of systemic antitumor immune responses. PD-L1 expression and expression of an IFN-γ gene signature, which has been associated with increased PD-L1 expression, have been identified as positive predictor of response to PD-1 and PD-L1 antibody therapy [11,63,64]. IT-Tavo-EP has been shown to increase IFN-γ gene expression potentially priming less inflamed tumors to respond to PD-1 and PD-L1 antibodies.…”

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“…Despite the different IHC PD-L1 assays seeming to lack sufficient sensitivity, they have to some extent been able to predict the response to treatment with the different immune checkpoint inhibitors. This is particularly true for patients with high expression levels of PD-L1 in NSCLC, urothelial carcinoma and melanoma (23)(24)(25).…”