Prognostic role of gamma-glutamyl transferase in metastatic melanoma patients treated with immune checkpoint inhibitors

Abstract

Background: Hepatic immune-related adverse events (irAE) including elevated liver function tests (transaminases) occur in 1.4-22.3% of melanoma patients receiving immune checkpoint inhibitors (ICPI) and constitute a potentially serious toxicity that is challenging to treat. In contrast to the liver transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST), only little is known about the frequency and impact of gamma-glutamyl transferase (GGT) elevations.

Methods: GGT determined prior to and during therapy of metastatic melanoma patients treated with ICPI were retrospectively assessed in two independent cohorts (PD-1: n = 218, Ipi + Nivo: n = 148). Overall survival (OS) and best objective response were analyzed according to baseline and immune-related GGT (irGGT) elevations during treatment.

Results: In multivariate analysis, OS was reduced in patients with elevated baseline GGT (PD-1 group: hazard ratio [HR] 1.76, p = .0073; Ipi + Nivo group: HR 1.77, p = .032). Immune-related GGT elevation was recorded in 17% (PD-1 group) and 38.5% (Ipi + Nivo group). Of these patients, the majority (81 and 68%, respectively) had normal ALT and AST and showed no clinical signs of hepatotoxicity. Patients who experienced irGGT elevation had superior response (PD-1 group: odds ratio [OR] 3.57, p = .00072; Ipi + Nivo group: OR 1.74, p = .12) and OS (PD-1 group: HR 0.37, p = .0016; Ipi + Nivo group: HR 0.33, p = .00050).

Conclusions: The frequency of hepatic irAE is currently underestimated. The addition of the sensitive enzyme GGT to the laboratory panel before and during therapy with ICPI allows to detect two to three times more patients developing hepatic or hepatobiliary toxicity than known so far. Immune-related GGT elevations correlate with response and favorable survival. Precis for use in the Table of Contents The frequency of hepatotoxicity under immune checkpoint blockade is currently underestimated. We suggest the addition of gamma-glutamyl transferase to the laboratory panel in checkpoint inhibitor patients for the detection of hepatobiliary toxicity.

Keywords: Gamma-glutamyl transferase; Hepatotoxicity; Immune checkpoint inhibitors; Immune-related adverse events; Melanoma; PD-1.

Fig. 1

Overall survival expressed by Kaplan–Meier estimator according to baseline levels of gamma-glutamyl transferase (GGT) in a patients receiving PD-1 antibodies, and in b patients receiving combined therapy with ipilimumab plus nivolumab. GGT gamma-glutamyl transferase; HR hazard ratio; P p value

Fig. 2

Overall survival expressed by Kaplan–Meier estimator according to occurrence of immune-related elevations of gamma-glutamyl transferase (irGGT elevation) in a patients receiving PD-1 antibodies, and in b patients receiving combined therapy with ipilimumab plus nivolumab. Three-month landmark analysis of overall survival c in the PD-1 group and d in the Ipi + Nivo group excluding patients who died or were lost to follow-up within the first three months after start of therapy. HR hazard ratio; irGGT elevation immune-related gamma-glutamyl transferase elevation; P p value

Fig. 3

Associations of immune related gamma-glutamyl transferase elevations with a and b best objective response, c and d occurrence of hepatitis considering cases with clinical signs of hepatitis or elevations of transaminases alone, and e and f elevations of alkaline phosphatase (ALP). Statistical differences were calculated utilizing two-sided Fisher’s exact test. ALP alkaline phosphatase; CR complete response; irGGT immune-related gamma-glutamyl transferase elevation; OR odds ratio (given together with 95% confidence interval); P p value, PD progressive disease; PR partial response; SD stable disease