Clinical Models to Define Response and Survival With Anti–PD-1 Antibodies Alone or Combined With Ipilimumab in Metastatic Melanoma

Abstract

PURPOSE Currently, there are no robust biomarkers that predict immunotherapy outcomes in metastatic melanoma. We sought to build multivariable predictive models for response and survival to anti-programmed cell death protein 1 (anti–PD-1) monotherapy or in combination with anticytotoxic T-cell lymphocyte-4 (ipilimumab [IPI]; anti–PD-1 ± IPI) by including routine clinical data available at the point of treatment initiation. METHODS One thousand six hundred forty-four patients with metastatic melanoma treated with anti–PD-1 ± IPI at 16 centers from Australia, the United States, and Europe were included. Demographics, disease characteristics, and baseline blood parameters were analyzed. The end points of this study were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The final predictive models for ORR, PFS, and OS were determined through penalized regression methodology (least absolute shrinkage and selection operator method) to select the most significant predictors for all three outcomes (discovery cohort, N = 633). Each model was validated internally and externally in two independent cohorts (validation-1 [N = 419] and validation-2 [N = 592]) and nomograms were created. RESULTS The final model for predicting ORR (area under the curve [AUC] = 0.71) in immunotherapy-treated patients included the following clinical parameters: Eastern Cooperative Oncology Group Performance Status, presence/absence of liver and lung metastases, serum lactate dehydrogenase, blood neutrophil-lymphocyte ratio, therapy (monotherapy/combination), and line of treatment. The final predictive models for PFS (AUC = 0.68) and OS (AUC = 0.77) included the same variables as those in the ORR model (except for presence/absence of lung metastases), and included presence/absence of brain metastases and blood hemoglobin. Nomogram calculators were developed from the clinical models to predict outcomes for patients with metastatic melanoma treated with anti–PD-1 ± IPI. CONCLUSION Newly developed combinations of routinely collected baseline clinical factors predict the response and survival outcomes of patients with metastatic melanoma treated with immunotherapy and may serve as valuable tools for clinical decision making.

Clinical Factors Associated with Long-Term Survival in Metastatic Melanoma Treated with Anti-PD1 Alone or in Combination with Ipilimumab

“…Interestingly, ECOG performance status < 2 and DNLR ≤ 3 were found not found to be significant in the multivariable analysis. This is in contrast to the findings of Silva et al who recently produced a multivariable prediction model for response to immune checkpoint inhibitors which included NLR as a continuous variable and ECOG performance status with a cutoff of ≥1 [ 7 ]. Unaccounted co-variability between ECOG performance status and other factors within our multivariable analysis may explain the lack of an independent association with survival in our analyses.…”

“…Additionally, anemia and elevated creatinine were not found to be associated with short term survival on multivariable analysis. Anemia has been previously described as associated with shorter survival but the biology underlying this finding is unknown [ 7 , 27 ].…”

“…Factors associated with long-term survival in melanoma treated with ICI remain not well understood. Recently, models to predict response and median overall survival for MM treated with ICI have been constructed using clinical parameters including Eastern Cooperative Oncology Group (ECOG) performance status, presence of liver and lung metastases, serum lactate dehydrogenase (LDH) level, blood neutrophil-lymphocyte ratio (NLR), type of therapy, and line of treatment [ 7 ]. One study found that the presence of liver or bone metastases was independently associated with reduced likelihood of survival at 5 years, whereas ECOG performance status of 0 was independently associated with an increased likelihood of 5-year survival in nivolumab-treated patients [ 8 ].…”

Current State of Adjuvant Therapy for Melanoma: Less Is More, or More Is Better?

“…10 The presence of liver and brain metastasis is linked to poor prognosis for patients with advanced melanoma who are treated with anti-PD1 agents, either as monotherapy or combined with ipilimumab. 25 Although combination checkpoint inhibition has demonstrated excellent efficacy for asymptomatic patients with brain metastases from melanoma, the intracranial response rate and prognosis for those with symptoms or who require steroids are far from satisfactory, with substantial compromise of quality of life. 26,27 The use of adjuvant therapy may potentially prevent the development of these devastating complications of distant metastatic disease by curing patients at the first available opportunity.…”

Causes, consequences and clinical significance of aneuploidy across melanoma subtypes

“…As new studies make evident that distinct metastatic sites– e.g. lung versus liver - and mutational profiles mechanistically implicated in aneuploidy ( 26 , 27 , 29 ) – BRAF V600E versus V600K, as well as 9p21 loss, where CDKN2A/B reside - are associated with differences in ICI treatment response in melanoma ( 99 , 119 , 120 ), future efforts on the understanding of the tumor-immune interaction need to account for organ-specific immune cell composition and mutational background of the tumors at high resolution, as evidenced by a recent study based on single-cell sequencing in uveal melanoma ( 121 ). In non-cutaneous and acral melanoma, while the lower mutational load may play a role in the poorer response to ICI therapies, the association with aneuploidy load remains to be assessed.…”