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.

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BACKGROUND Antibodies inhibiting the programmed death receptor 1 (PD-1) have shown significant activity in the treatment of advanced cutaneous melanoma. The efficacy and safety of PD-1 blockade in patients with uveal melanoma has not been well characterized. METHODS 58 stage IV uveal melanoma patients received PD-1 or PD-L1 antibodies between 2009 and 2015 at nine academic centers. Patients who were evaluable for response were eligible for analysis. Imaging was performed every 12-weeks and at the investigators’ discretion. Safety and clinical efficacy outcomes including best overall response (BOR), progression-free survival (PFS), overall survival (OS) were determined retrospectively. RESULTS Of 56 eligible patients, 48 (86%) had received prior therapy and 35 (63%) had been treated with ipilimumab. Three patients had an objective response to ipilimumab and 8 patients had stable disease as the best response. 38 (68%) received pembrolizumab, 16 (29%) received nivolumab, and 2 (4%) received atezolizumab. Objective tumor responses were observed in two patients for an overall response rate of 3.6% (95% CI 1.8-22.5%). Stable disease (≥ 6 months) was observed in 5 (9%) patients. The median PFS was 2.6 months (95% CI 2.4-2.8 months) and the median OS was 7.6 months (95% CI 0.7-14.6 months). There was no association between prior treatment with ipilimumab or liver directed therapy and PFS or OS. Treatment was well tolerated and only 1 patient discontinued treatment due to toxicity. CONCLUSIONS PD-1 and PD-L1 antibodies rarely confer durable remissions in patients with metastatic uveal melanoma. Clinical trial enrollment should be prioritized in this population.

Parathyroid cancer patients typically have a long survival, which often includes multiple reoperations for recurrence and thus a high rate of surgical complications. Patients in whom there is a high index of suspicion for parathyroid cancer should be referred to a dedicated endocrine surgery center for their initial operation.