Wirksamkeit von systemischen Therapien mit Immuncheckpointinhibitoren bei Patienten mit metastasiertem malignem Melanom in Abhängigkeit von der Höhe der Serum-Laktatdehydrogenase zu Beginn der Therapie

Abstract

In der vorliegenden Arbeit werden die Ergebnisse einer retrospektiven, monozentrischen Untersuchung vorgestellt, in der die Wirksamkeit einer Erstlinientherapie mit Checkpointinhibitoren bei Patienten mit metastasiertem Melanom in Abhängigkeit der Höhe der Serum-LDH zu Therapiebeginn untersucht wurde. Primär wurde die Wirksamkeit einer Therapie in Bezug auf progressionsfreies, Gesamtüberleben und Therapieansprechen zwischen Patienten mit normwertiger und erhöhter Baseline-LDH verglichen.

51 Patienten (m=29; w=22) im inoperablen Stadium III (n=8) bzw. IV (n=43) nach AJCC 2017 waren mit Nivolumab (n=14), Pembrolizumab (n=28) bzw. Ipilimumab in Kombination mit Nivolumab (n=9) behandelt worden. Der mittlere Beobachtungszeitraum aller 51 Patienten lag bei 12,1 Monaten. Patienten mit mukosalen und uvealen Primärmelanomen wurden aus der Untersuchung ausgeschlossen. Bei 15/51 (29.4%) der Patienten lagen Hirnmetastasen vor. Das mediane Alter zum Zeitpunkt der Diagnose einer fortgeschrittenen Melanomerkrankung betrug 69 Jahre (38-87 Jahre). Eine BRAF-Mutation wiesen 8/51 (15.7%) der Patienten auf. Die Serum-LDH zum Zeitpunkt des Therapiebeginns lag im Median bei 277 U/l (166-1364 U/l) und war bei 24/51 (47.1%) Patienten erhöht. Die disease control rate (DCR) für das gesamte Kollektiv betrug 41.18% (CR 13.7%, n=7; PR 17.6%, n=9; SD 9.8%, n=5). Es zeigten sich keine signifikanten Zusammenhänge zwischen der Höhe der Serum-LDH zu Therapiebeginn und dem Ansprechen auf die Therapie. Hingegen zeigte sich eine normwertige Baseline-LDH im Vergleich zu einer erhöhten mit einem signifikant längeren progressionsfreien (PFS) und Gesamtüberleben (OS) assoziiert. So hatten Patienten mit normwertiger Baseline-LDH ein mittleres PFS von 105 Tagen und ein mittleres OS von 14.1 Monaten verglichen mit 55 Tagen und 9.8 Monaten bei jenen mit zu Therapiebeginn erhöhter Serum-LDH. Patienten mit Hirnmetastasen hatten kein signifikant verkürztes Gesamtüberleben (mittleres OS 12.9 Monate; medianes OS 12.0 Monate; 0.0-26.0 Monate). Kein Patient mit einer Baseline-LDH von >561 U/l zeigte ein Ansprechen. Für einen Teil der Patienten zeigte sich in der quantitativen Testung ein signifikanter inverser Zusammenhang zwischen Serum-LDH und Dauer der Therapie.

Summa summarum konnte die Baseline-LDH im Rahmen von Checkpointinhibitortherapien in der Firstline-Situation im hier untersuchten Kollektiv als unabhängiger prädiktiver Parameter hinsichtlich des Überlebens (PFS wie OS) identifiziert werden, bei nicht vorhandener prädiktiver Aussagekraft in Bezug auf das Therapieansprechen kommt der prätherapeutisch gemessenen Serum-LDH jedoch keine therapieentscheidende Bedeutung zu, die eine gerechtfertigte Patientenstratifizierung erlauben würde.

The presented paper discusses the subject of the effectiveness of systemic therapy with immune checkpoint inhibitors in patients with metastatic malignant melanoma depending on the level of serum lactate dehydrogenase (serum LDH) at the beginning of therapy based on a retrospective data collection. It contains a descriptive summary of the results and sums up qualitative and quantitative relationships. The examined patient cohort got outpatient treatment at the Department of Dermatology, Venereology and Allergology of the Saarland University Hospital, receiving systemic first-line therapy with immune checkpoint inhibitors as part of the specialist dermatological treatment of advanced melanoma as of 1st of May 2016. Any systemic second-line therapies were presented by means of descriptive statistics. Advances in the understanding of interactions between tumor and immune system and the mechanisms of T cell regulation led to the development of immune checkpoint inhibitors, followed by the approval of the CTLA-4 inhibitor ipilimumab in 2011 and the PD-1 inhibitors nivolumab and pembrolizumab in 2014 by the US-American Food and Drug Administration (FDA). This revolutionised the systemic treatment of metastatic melanoma and significantly improved prognosis for subgroups of patients (Gellrich et al., 2020; Roesch & Berking, 2017). In the presented work, it was considered whether the analysis of the laboratory parameter serum LDH, which is routinely determined in everyday clinical practice before starting system therapy in patients with advanced melanoma, results in a statistical connection with other patient characteristics. This study investigated the relationships between serum LDH measured before therapy and parameters that can describe the effectiveness of a therapy. Relationships that relate to treatment response and survival patterns in order to gain insight into possible strategies for patient stratification were evaluated. In total, this collective included 51 patients with inoperable metastatic cutaneous melanoma in tumor stage III or IV according to AJCC 2017 without systemic pretreatment, with or without evidence of a BRAF mutation. The active substances used in the first line were nivolumab, pembrolizumab or the combination of ipilimumab with nivolumab. The observation period of all 51 patients was 12.1 months on average. The main aim of this examination was to investigate the effectiveness of first-line immune checkpoint inhibitor therapy in terms of progression-free survival, overall survival, and therapy response in patients with normal and elevated baseline LDH. The progression-free survival and overall survival were compared between the two groups using a log rank test. A normal serum LDH compared to an elevated one was associated with a significantly longer progression-free survival as well as with a significantly longer overall survival. Patients with a baseline LDH of normal values had a mean progression-free survival of 105 days and a mean overall survival of 14.1 months compared to 55 days and 9.8 months in those with elevated serum LDH at the start of therapy. The importance of an elevated serum LDH as an independent prognostic parameter (Balch et al., 2001, 2009; Gershenwald, Scoyler, et al., 2017) was therefore confirmed in our collective. For the 51 examined firstline immune checkpoint inhibitor therapies, a disease control rate of 41.18% was shown with a complete remission rate of 13.73%. In addition, 15.69% of the patients remained in complete remission due to the first-line therapy over a median observation period of 20.0 months. Furthermore, no patient with a serum LDH >561 u/L responded to first-line therapy with immune checkpoint-inhibiting antibodies. The incidence of therapy-related side effects that had led to the discontinuation of therapy was 13.73%. No significant correlation between baseline LDH and therapy response could be determined. For some of the patients, however, there was a connection between serum LDH and duration of therapy. When examining the relationships between serum LDH and other baseline characteristics, a significant difference in serum LDH status was shown depending on the number of organ locations involved (<3 versus ≥3). In summary, it can be said for the collective examined here that the serum LDH measured before the start of therapy does not represent an independent predictive parameter for the effectiveness of a therapy in terms of a response to systemic first-line therapy with immune checkpoint inhibitors. All evaluations in this direction did not show any statistically significant results. In view of this conclusion, serum LDH is considered an influential factor for survival prognosis in the context of therapy with immune checkpoint inhibitors. If the predictive value for therapy response is not available, the level of serum LDH at the time of starting therapy cannot be used to provide diagnostic or therapeutic guidance for a doctor in clinical practice dealing with patients with metastatic malignant melanoma.