Resistance to anti-PD1 therapies in patients with advanced melanoma: systematic literature review and application of the Society for Immunotherapy of Cancer Immunotherapy Resistance Taskforce anti-PD1 resistance definitions

Abstract

Nearly half of advanced melanoma patients do not achieve a clinical response with anti-programmed cell death 1 protein (PD1) therapy (i.e. primary resistance) or initially achieve a clinical response but eventually progress during or following further treatment (i.e. secondary resistance). A consensus definition for tumor resistance to anti-PD1 monotherapy was published by Society for Immunotherapy of Cancer Immunotherapy Resistance Taskforce (SITC) in 2020. A systematic literature review (SLR) of clinical trials and observational studies was conducted to characterize the proportions of advanced melanoma patients who have progressed on anti-PD1 therapies. The SLR included 55 unique studies and the SITC definition of primary resistance was applied to 37 studies that specified disease progression by best overall response. Median and range of patients with primary resistance in studies that specified first-line and second-line or higher anti-PD1 monotherapy was 35.50% (21.19–39.13%; n = 4 studies) and 41.54% (30.00–56.41%, n = 3 studies); median and range of patients with primary resistance in studies that specified first-line and second-line or higher combination therapy was 30.23% (15.79–33.33%; n = 6 studies), and 70.00% (61.10–73.33%; n = 3 studies). Primary resistance to anti-PD1 monotherapies and when in combination with ipilimumab are higher in patients receiving second-line or higher therapies, in patients with acral, mucosal, and uveal melanoma, and in patients with active brain metastases. The percentage of patients with primary resistance was generally consistent across clinical trials, with variability in resistance noted for observational studies. Limitations include applying the SITC definitions to combination therapies, where consensus definitions are not yet available. Future studies should highly consider utilizing the SITC definitions to harmonize how resistance is classified and facilitate meaningful context for clinical activity.

Immune Checkpoint Inhibitors: A Narrative Review on PD-1/PD-L1 Blockade Mechanism, Efficacy, and Safety Profile in Treating Malignancy

“…The presence of the KIR3DS1 allele has correlated with decreased PFS in patients with NSCLC. Although not completely understood, assays have shown that this resistance may be due to natural killer (NK) cell dysfunction resulting in their inability to properly express PD-1 [ 48 ]. Further analysis involving randomized trials will be needed to confirm whether this genetic variant is a predictive marker for a patient's response to PD-1 inhibitor treatment.…”

Melanom

“…In addition, PD-1-based immune checkpoint inhibitors are much less effective in uveal melanoma than in other types of melanoma (response rate for PD-1 antibody monotherapy 7%-12%; response rate for a combination of ipilimumab and nivolumab 10%-18%). 22,23 A positive treatment study in metastasized uveal melanoma was first published in 2021. 24 In this international, randomized study, the novel compound tebentafusp was compared with an established medication of the investigator's choice (pembrolizumab, ipilimumab, or dacarbazin).…”

“…Due to the fact that BRAF mutations are not present in uveal melanomas, BRAF‐targeted therapies cannot be utilized for this condition. In addition, PD‐1‐based immune checkpoint inhibitors are much less effective in uveal melanoma than in other types of melanoma (response rate for PD‐1 antibody monotherapy 7%–12%; response rate for a combination of ipilimumab and nivolumab 10%–18%) 22,23 . A positive treatment study in metastasized uveal melanoma was first published in 2021 24 .…”

Melanom

“…Des Weiteren sind PD-1-basierte Immuncheckpoint-Inhibitionstherapien beim Uvea-Melanom weitaus weniger wirksam als bei anderen Melanomtypen (Ansprechrate einer PD-1-Monotherapie 7%-12%; Ansprechrate der Kombination aus Ipilimumab und Nivolumab 10%-18%). 22,23 Im Jahr 2021 wurde erstmals über eine positive Therapiestudie für das metastasierte Uvea-Melanom berichtet. 24 In dieser internationalen randomisierten Phase-III-Studie wurde das neue Medikament Tebentafusp im Vergleich zu investigators choice (Pembrolizumab, Ipilimumab, oder Dacarbazin) eingesetzt.…”

“…Aufgrund der fehlenden BRAF ‐Mutation kommen BRAF‐zielgerichtete Therapieansätze für das Uvea‐Melanom nicht in Betracht. Des Weiteren sind PD‐1‐basierte Immuncheckpoint‐Inhibitionstherapien beim Uvea‐Melanom weitaus weniger wirksam als bei anderen Melanomtypen (Ansprechrate einer PD‐1‐Monotherapie 7%–12%; Ansprechrate der Kombination aus Ipilimumab und Nivolumab 10%–18%) 22,23 . Im Jahr 2021 wurde erstmals über eine positive Therapiestudie für das metastasierte Uvea‐Melanom berichtet 24 .…”