Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC

Abstract

We explored the association between liver metastases, tumor CD8⁺ T-cell count, and response in patients with melanoma or lung cancer treated with the anti-PD-1 antibody, pembrolizumab. The melanoma discovery cohort was drawn from the phase I Keynote 001 trial, whereas the melanoma validation cohort was drawn from Keynote 002, 006, and EAP trials and the non-small cell lung cancer (NSCLC) cohort from Keynote 001. Liver metastasis was associated with reduced response and shortened progression-free survival [PFS; objective response rate (ORR), 30.6%; median PFS, 5.1 months] compared with patients without liver metastasis (ORR, 56.3%; median PFS, 20.1 months) P ≤ 0.0001, and confirmed in the validation cohort (P = 0.0006). The presence of liver metastasis significantly increased the likelihood of progression (OR, 1.852; P < 0.0001). In a subset of biopsied patients (n = 62), liver metastasis was associated with reduced CD8⁺ T-cell density at the invasive tumor margin (liver metastasis⁺ group, n = 547 ± 164.8; liver metastasis^- group, n = 1,441 ± 250.7; P < 0.016). A reduced response rate and shortened PFS was also observed in NSCLC patients with liver metastasis [median PFS, 1.8 months; 95% confidence interval (CI), 1.4-2.0], compared with those without liver metastasis (n = 119, median PFS, 4.0 months; 95% CI, 2.1-5.1), P = 0.0094. Thus, liver metastatic patients with melanoma or NSCLC that had been treated with pembrolizumab were associated with reduced responses and PFS, and liver metastases were associated with reduced marginal CD8⁺ T-cell infiltration, providing a potential mechanism for this outcome. Cancer Immunol Res; 5(5); 417-24. ©2017 AACR.

Figure 1

Multivariable analysis of pretreatment prognostic factors. ORs were calculated for PFS in each subgroup. The statistical significance and the CIs are depicted on the right columns. The dotted vertical line designates the PFS for the entire cohort.

Figure 2

PFS and response rate in patients with melanoma treated with pembrolizumab. A and B, The discovery cohort (n = 223). A, Kaplan–Meier PFS curve; patients with liver metastasis are shown in gray, whereas those without liver metastasis are shown in black. B, Waterfall plots for patients without and with liver metastasis.

Figure 3

PFS and response rate in the validation cohort (n = 113) patients with melanoma treated with pembrolizumab. A, Kaplan–Meier PFS curve with liver metastasis (gray) and those without liver metastasis (black). B, Waterfall plot for patients in the validation cohort. PFS was calculated from the time of randomization. Log-rank analysis was used to calculate the differences between these groups.

Figure 4

IHC analysis of CD8, PD-1, and PD-L1 in samples obtained from patients before pembrolizumab, according to response and metastatic pattern. A, CD8⁺ T-cell density by response category (responder group n = 25, nonresponder group n = 35; P < 0.0001). B, CD8⁺ T-cell density by liver metastasis status (liver metastasis⁺ group n = 22, mean count 547 ± 164.8; liver metastases⁻ group n = 40, mean count 1,441 ± 250.7; P < 0.016). C and D, PD-1 and PD-L1, respectively, expression by liver metastasis. NS, not significant. E, Examples of CD8, PD-1, and PD-L1 expression in samples obtained from distant tumors in terms of metastatic location and response. Magnification, ×20. Serial cut tissue sections (2 μm) were stained for S100, CD8, PD-1, and PD-L1. **, <0.016; ****, <0.0001.

Figure 5

PFS and response rate in patients with NSCLC treated with pembrolizumab. A, Kaplan–Meier PFS curve; patients with liver metastasis are shown in gray, whereas those without liver metastasis are shown in black. B, Waterfall plots for patients without and with liver metastasis.