Baseline Biomarkers for Outcome of Melanoma Patients Treated with Pembrolizumab

Abstract

Purpose: Biomarkers for outcome after immune-checkpoint blockade are strongly needed as these may influence individual treatment selection or sequence. We aimed to identify baseline factors associated with overall survival (OS) after pembrolizumab treatment in melanoma patients.

Experimental design: Serum lactate dehydrogenase (LDH), routine blood count parameters, and clinical characteristics were investigated in 616 patients. Endpoints were OS and best overall response following pembrolizumab treatment. Kaplan-Meier analysis and Cox regression were applied for survival analysis.

Results: Relative eosinophil count (REC) ≥1.5%, relative lymphocyte count (RLC) ≥17.5%, ≤2.5-fold elevation of LDH, and the absence of metastasis other than soft-tissue/lung were associated with favorable OS in the discovery (n = 177) and the confirmation (n = 182) cohort and had independent positive impact (all P < 0.001). Their independent role was subsequently confirmed in the validation cohort (n = 257; all P < 0.01). The number of favorable factors was strongly associated with prognosis. One-year OS probabilities of 83.9% versus 14.7% and response rates of 58.3% versus 3.3% were observed in patients with four of four compared to those with none of four favorable baseline factors present, respectively.

Conclusions: High REC and RLC, low LDH, and absence of metastasis other than soft-tissue/lung are independent baseline characteristics associated with favorable OS of patients with melanoma treated with pembrolizumab. Presence of four favorable factors in combination identifies a subgroup with excellent prognosis. In contrast, patients with no favorable factors present have a poor prognosis, despite pembrolizumab, and additional treatment advances are still needed. A potential predictive impact needs to be further investigated. Clin Cancer Res; 22(22); 5487-96. ©2016 AACR.

Figure 1. Overall survival according to confirmed baseline factors independently associated with outcome following pembrolizumab

Kaplan-Meier curves of overall survival considering patients of all three cohorts of patients treated with pembrolizumab (n=616) according to the pattern of distant metastasis (A), LDH-ratio (the measured LDH serum concentration divided by the upper limit of normal) (B), relative lymphocyte count (C) and relative eosinophil count (D). Censoring is indicated by vertical lines; P-values were calculated by log rank statistics.

Figure 2. Overall survival and proportion of patients with objective response following pembrolizumab according to the count of favorable baseline factors

LDH, pattern of distant metastases, relative lymphocyte count and relative eosinophil count) had independent prognostic impact in the combined discovery and confirmation cohort, as well as in the validation cohort. Kaplan Meier curves for OS are presented for all patients according the count of favorable pre-treatment values considering those four factors. Among 512 patients with complete data, the median survival was 16.9, 10.8, 4.2, 1.4 months for patients with 0, 1, 2, or 3 favorable factor(s), respectively. Median survival was not reached for 13.7% of patients who had favorable values in all four factors. Censoring is indicated by vertical lines (A). The proportion of patients with objective response (PR or CR as best overall response according to RECIST V1.1) in 389 of 512 patients with available data is presented according to the number of favorable baseline factors. The differences between the categories were all statistically significant (p<0.05) in pairwise comparisons using Chi-Square/Fisher´s exact tests except the difference between patients with 0 and 1 favorable factor (p=0.674; B).

Figure 3. Overall survival and proportion of patients with objective response following pembrolizumab according to the relative lymphocyte and eosinophil counts

LDH, pattern of distant metastases, relative lymphocyte count and relative eosinophil count had independent prognostic impact in 512 patients with available data in all four baseline factors. Here, the analysis is limited to the impact of relative lymphocyte and eosinophil counts. The pattern of visceral metastasis and LDH are not considered here, as these are well-established prognostic markers. Kaplan Meier curves for OS are presented according the count of favorable pre-treatment values. Censoring is indicated by vertical lines. The differences in OS between categories were significant in all pairwise comparisons (all log rank p<0.001; A). The proportion of patients with objective response (PR or CR as best overall response according to RECIST V1.1) in 389 of 512 patients with available response data is presented according to the number of favorable baseline factors. An objective response was observed in 42.5%, 23.6%, and 12.5% of patients with 2, 1, or 0 favorable baseline values. The differences between the categories were all statistically significant (p=0.042 for 0 vs.1 favorable factor; p<0.001 for 1 vs 2 favorable factors) using Chi-Square/Fishers’s exact tests (B).