Interim [18F]FDG PET/CT can predict response to anti-PD-1 treatment in metastatic melanoma

Annette Kopp-Schneider,Dimitrios Papamichail,Christos Sachpekidis,Antonia Dimitrakopoulou-Strauss,Uwe Haberkorn,Jessica C. Hassel,Leyun Pan

doi:10.1007/s00259-020-05137-7

Abstract

PurposeIn an attempt to identify biomarkers that can reliably predict long-term outcomes to immunotherapy in metastatic melanoma, we investigated the prognostic role of [18F]FDG PET/CT, performed at baseline and early during the course of anti-PD-1 treatment.MethodsTwenty-five patients with stage IV melanoma, scheduled for treatment with PD-1 inhibitors, were enrolled in the study (pembrolizumab, n = 8 patients; nivolumab, n = 4 patients; nivolumab/ipilimumab, 13 patients). [18F]FDG PET/CT was performed before the start of treatment (baseline PET/CT) and after the initial two cycles of PD-1 blockade administration (interim PET/CT). Seventeen patients underwent also a third PET/CT scan after administration of four cycles of treatment. Evaluation of patients’ response by means of PET/CT was performed after application of the European Organization for Research and Treatment of Cancer (EORTC) 1999 criteria and the PET Response Evaluation Criteria for IMmunoTherapy (PERCIMT). Response to treatment was classified into 4 categories: complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD). Patients were further grouped into two groups: those demonstrating metabolic benefit (MB), including patients with SMD, PMR, and CMR, and those demonstrating no MB (no-MB), including patients with PMD. Moreover, patterns of [18F]FDG uptake suggestive of radiologic immune-related adverse events (irAEs) were documented. Progression-free survival (PFS) was measured from the date of interim PET/CT until disease progression or death from any cause.ResultsMedian follow-up from interim PET/CT was 24.2 months (19.3–41.7 months). According to the EORTC criteria, 14 patients showed MB (1 CMR, 6 PMR, and 7 SMD), while 11 patients showed no-MB (PMD). Respectively, the application of the PERCIMT criteria revealed that 19 patients had MB (1 CMR, 6 PMR, and 12 SMD), and 6 of them had no-MB (PMD). With regard to PFS, no significant difference was observed between patients with MB and no-MB on interim PET/CT according to the EORTC criteria (p = 0.088). In contrary, according to the PERCIMT criteria, patients demonstrating MB had a significantly longer PFS than those showing no-MB (p = 0.045). The emergence of radiologic irAEs (n = 11 patients) was not associated with a significant survival benefit. Regarding the sub-cohort undergoing also a third PET/CT, 14/17 patients (82%) showed concordant responses and 3/17 (18%) had a mismatch of response assessment between interim and late PET/CT.ConclusionPET/CT-based response of metastatic melanoma to PD-1 blockade after application of the recently proposed PERCIMT criteria is significantly correlated with PFS. This highlights the potential ability of [18F]FDG PET/CT for early stratification of response to anti-PD-1 agents, a finding with possible significant clinical and financial implications. Further studies including larger numbers of patients are necessary to validate these results.

Highlights

Metastatic melanoma is a highly aggressive tumor, largely refractory to existing therapies, and associated with a very poor prognosis [1]
This immunomodulatory approach activates the immune system against tumors through the binding of the cytotoxic T lymphocyte–associated protein 4 (CTLA-4) and/or the programmed cell death protein 1 (PD-1), both of which are expressed by T cells [3, 4]
The monoclonal antibody ipilimumab, which acts by blocking CTLA-4, is considered a landmark agent in this context, being the first immunotherapeutic drug demonstrating a clear benefit in survival of patients with advanced melanoma, which led to its approval by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2011 [5]

Summary

Introduction

Metastatic melanoma is a highly aggressive tumor, largely refractory to existing therapies, and associated with a very poor prognosis [1]. The main form of immunotherapy applied in this new era of melanoma management involves immune checkpoint blockade. This immunomodulatory approach activates the immune system against tumors through the binding of the cytotoxic T lymphocyte–associated protein 4 (CTLA-4) and/or the programmed cell death protein 1 (PD-1), both of which are expressed by T cells [3, 4]. The monoclonal antibody ipilimumab, which acts by blocking CTLA-4, is considered a landmark agent in this context, being the first immunotherapeutic drug demonstrating a clear benefit in survival of patients with advanced melanoma, which led to its approval by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2011 [5]. The antiPD-1 monoclonal antibodies have shown superiority over ipilimumab, leading to their application both as single agents and in combination with ipilimumab, which is nowadays seldom used as monotherapy [9,10,11,12,13]

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