Immunotherapy Potentiates the Effect of Chemotherapy in Metastatic Melanoma-A Retrospective Study.

Reut Hadash-Bengad,Michal Lotem,Nadia Caplan,Alexander Yakobson,Emma Hajaj,Galit Eisenberg,Marina Orevi,Sharon Merims,Jonatan E Cohen,Stephen Frank,Shiri Klein,Tamar Peretz

doi:10.3389/fonc.2020.00070

Abstract

Melanoma survival increased with targeted- and immunotherapy agents, yet most patients ultimately progress and require salvage therapy. In our experience, some progressive disease patients on immune-checkpoint inhibitors (ICIs) demonstrate deep and sustained responses to chemotherapy. We hypothesized that ICIs improve the response to subsequent chemotherapy in metastatic melanoma. We conducted a retrospective study to compare the efficacy of chemotherapy given with prior immunotherapy, to its efficacy given without it. We measured progression free survival (PFS), overall survival, and response rate. Immune-monitoring was performed on sequential peripheral blood mononuclear cell samples taken from a chemotherapy-responsive patient. The chemotherapy post-immunotherapy group (CpI) included 11 patients, the chemotherapy without prior immunotherapy (CNPI) group included 24 patients. Median PFS was 5.2 months in the CpI vs. 2.5 months in the CNPI groups; HR 0.37 [95% Confidence interval (CI) 0.144–0.983], P = 0.046. Immune-monitoring showed an increased proportion of CD8+ cells, with elevated PD-1 and CD69 expression, while on chemotherapy, as compared with all-time points on ICIs, suggesting immune-activation. Immunotherapy potentiates the effect of chemotherapy in metastatic melanoma possibly through activation of CD8+ T cells.

Highlights

Metastatic melanoma has evolved in recent years from an almost universally lethal disease to one with effective treatments and potential of a cure
Based on our observations and data pertaining to chemotherapy modulation of the tumor-microenvironment, we hypothesized that previous treatment with immune checkpoint inhibitors increases the efficacy of chemotherapy when given at a later stage of the disease, in patients with metastatic melanoma. In this single-center retrospective study, we aimed to evaluate the efficacy of chemotherapy administered in the setting of metastatic melanoma after previous treatment with immunecheckpoint inhibitors, compared to chemotherapy administered to similar patients who had not received prior immunecheckpoint inhibitors
Two patients are described as having significant responses to chemotherapy-as-salvage after progressing on immune-checkpoint inhibitors (ICIs), drawing our attention to this phenomenon

Summary

Introduction

Metastatic melanoma has evolved in recent years from an almost universally lethal disease to one with effective treatments and potential of a cure. The two major therapeutic advances were the development of targeted therapy toward the BRAF mutation-driven, constitutively-activated MAPK pathway using inhibitors of BRAF and MEK, and immunotherapy which used immune checkpoint inhibitors (i.e., anti-CTLA4 and anti-PD1 monoclonal antibodies). Median overall survival has increased from ∼9 months in the chemotherapy era [1], to almost 24 months with a combination of the BRAF and MEK inhibitors dabrafenib and trametinib [2], and 37.5 months with the anti-PD-1 nivolumab [3]. Immunotherapy Potentiates Chemotherapy in Melanoma fraction of long term survivors, with early reports of 41% 5-year survival rates with first line anti-PD1 [4] and a 5-year survival rate of 52% with combination checkpoint inhibition [5]. A large fraction of patients will demonstrate primary- or develop acquired resistance to these therapies [6]. Some of the progressing patients will still be fit for further lines of therapy and may be offered chemotherapy

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