Development of a Metastatic Uveal Melanoma Prognostic Score (MUMPS) for Use in Patients Receiving Immune Checkpoint Inhibitors

Abstract

Metastatic uveal melanoma (mUM) is a rare disease. There are limited data on prognostic clinical factors for overall survival (OS) in patients with mUM treated with immune checkpoint inhibitors (ICI). Retrospective and non-randomized prospective studies have reported response rates of 0–17% for anti-PD1/L1 ± anti-CTLA4 ICI in mUM, indicating a potential benefit only in a subset of patients. This study evaluates the characteristics associated with ICI benefit in patients with mUM. We performed a single-center retrospective cohort study of patients with mUM who received anti-PD1/L1 ± anti-CTLA4 ICI between 2014–2019. Clinical and genomic characteristics were collected from a chart review. Treatment response and clinical progression were determined by physician assessment. Multivariable Cox regression models and Kaplan–Meier log-rank tests were used to assess differences in clinical progression-free survival (cPFS) and OS between groups and identify clinical variables associated with ICI outcomes. We identified 71 mUM patients who received 75 lines of ICI therapy. Of these, 54 received anti-PD1/L1 alone, and 21 received anti-PD1/L1 + anti-CTLA4. Patient characteristics were: 53% female, 48% were 65 or older, 72% received one or fewer lines of prior therapy. Within our cohort, 53% of patients had developed metastatic disease <2 years after their initial diagnosis. Bone metastases were present in 12% of patients. The median cPFS was 2.7 months, and the median OS was 10.0 months. In multivariable analyses for both cPFS and OS, the following variables were associated with a good prognosis: ≥2 years from the initial diagnosis to metastatic disease (n = 25), LDH < 1.5 × ULN (n = 45), and absence of bone metastases (n = 66). We developed a Metastatic Uveal Melanoma Prognostic Score (MUMPS). Patients were divided into 3 MUMPS groups based on the number of the above-mentioned prognostic variables: Poor prognosis (0–1), Intermediate prognosis (2) and Good prognosis (3). Good prognosis patients experienced longer cPFS (6.0 months) and OS (34.5 months) than patients with intermediate (2.3 months cPFS, 9.4 months OS) and poor prognosis disease (1.8 months cPFS, 3.9 months OS); p < 0.0001. We developed MUMPS—a prognostic score based on retrospective data that is comprised of 3 readily available clinical variables (time to metastatic diagnosis, presence of bone metastases, and LDH). This MUMPS score has a potential prognostic value. Further validation in independent datasets is warranted to determine the role of this MUMPS score in selecting ICI treatment management for mUM.

Combination of Immune Checkpoint Inhibitors and Liver-Specific Therapies in Liver-Metastatic Uveal Melanoma: Can We Thus Overcome Its High Resistance?

“…A prognostic score for patients with MUM, including the variables time to metastatic diagnosis, presence of bone metastases, and LDH, was recently developed [ 41 , 42 , 43 ]. Based on the results of our analysis, the parameters age (cut-off: ≥55 years), as well as LDH, S100, and NLR (cut-off: 3.5), should be considered in case of prognosis assessment.…”

The Future of Checkpoint Inhibitors in Uveal Melanoma: A Narrative Review

“…Additionally, the demographic characteristics of patients differed between those receiving monotherapy and those with combination therapy. Among patients receiving single-agent anti-PD-1/L1, 54% were 65 years or older, whereas this proportion in those receiving anti-PD-1 + anti-CTLA-4 was 33%, which may reflect a drug selection bias by oncologists in this center [ 44 ]. Overall, the conclusions of these retrospective studies on the effect of dual-agent ICIs are somewhat controversial, and none are sufficiently convincing due to their small samples.…”

“…Thus, for patients with MUM who lack options, ICIs are worthy of consideration. Although there has not been a definite biomarker of prognostication for ICIs in MUM, several studies agreed that the lactate dehydrogenase (LDH) level is associated with ICI treatment response [ 34 , 37 , 44 ]. The low LDH values potentially indicate the benefit of treatment of ICIs in MUM [ 49 ].…”

Prognostic Biomarkers in Uveal Melanoma: The Status Quo, Recent Advances and Future Directions

“…Mounting evidence points towards a unique biological behaviour in UM, with infiltration by immune cells strongly linked with a tumour growth stimulatory effect, instead of a tumour suppressing effect, which is normally present in other types of neoplasias [ 272 , 311 , 329 ]. In addition, unlike in cutaneous melanoma, immune checkpoint inhibition has not yielded meaningful results for the majority of UM patients [ 123 , 330 , 331 ]. Together, these results highlight the presence of a strongly immunosuppressive microenvironment in primary UM, and our knowledge on this distinctive phenomenon remains in its infancy [ 329 , 332 , 333 ].…”

“…Interestingly, an association between BAP1 loss and the infiltration of the tumoural microenvironment by lymphocytes and macrophages, with concomitant overexpression of genes involved in immunosuppression has been established [ 332 ]. Classically and well-established checkpoint inhibitor molecules such as CTLA4 and PD-1 seem to be relevant only for limited subsets of UM patients [ 123 , 330 , 331 ]. On the other hand, a recent study involving single cell RNA sequencing demonstrated that an emerging checkpoint inhibitor molecule, lymphocyte-activation gene-3 (LAG3), is expressed at high levels in most of T-CD8+ cytotoxic UM TILs [ 334 ].…”