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.

Partially exhausted tumor-infiltrating lymphocytes predict response to combination immunotherapy

“…while the presence of liver metastasis has been reported to inversely correlate with response to checkpoint inhibitors in melanoma, non-small cell lung cancer, and recently also in bladder cancer (13,22). While no correlation with disease stage was observed ( Figure 2, A and B), the presence of liver metastasis was associated with reduced percentages of tumor-infiltrating peCTLs ( Figure 2, C and D).…”

“…While age was not correlated, sex significantly correlated with the percentage of peCTLs, with males having a larger proportion of these cells compared with females (males, 25.95% vs. females 17.5%, P = 0.041, Mann-Whitney test) ( Given prior data regarding the reduced response to anti-PD-1 therapy in patients with elevated LDH and liver metastasis (11,22), we examined these and other disease characteristics, including American Joint Committee on Cancer (AJCC) stage (stage III vs. IV). Disease stage is known to be correlated with survival (23), + T cell population, with age on the x axis (n = 93).…”

“…Further studies in other tumor types and animal models may reveal additional information about the mechanism of liver metastasis-induced tolerance (31). The effect of female sex on reduced response rate to PD-1 has been recently reported (22,32). Additional data are needed to determine the validity and generalizability of this observation.…”

“…Although the association of elevated LDH with reduced response rate to anti-PD-1 therapy is well documented (4,14), the lack of association with reduced peCTLs suggests that other immune cells such as NK cells (27) or tumor macrophages (28) may be involved in mediating the effects of LDH on immunotherapy. The effects of liver metastasis have been recently shown to reduce ORR and progression-free survival (PFS) to anti-PD-1 antibodies in melanoma and non-small cell lung cancer (22), and also in urothelial cancer (13) in immunotherapy-treated patients, and remains an area of active investigation. Preclinical data suggest that activated CD8 + T cells can be selectively deleted in the liver (29) and that liver tolerance (30) is operational in allotransplantation.…”

Immunological aspect of the liver and metastatic uveal melanoma

“…The result may be correlated with low expression of PD-L1 in metastatic UM, compared to that of non-hepatic metastatic CM [63] . It is of note that a poor response to anti-PD-1 antibody therapy has also been reported in CM patients with hepatic metastasis [64] . This further supports the hypothesis that the liver immune microenvironment itself hampers T-cell immune response against cancer cells.…”