Long-term survival and immunological parameters in metastatic melanoma patients who responded to ipilimumab 10 mg/kg within an expanded access programme

Abstract

Background: Ipilimumab can result in durable clinical responses among patients with advanced melanoma. However, no predictive marker of clinical activity has yet been identified. We provide preliminary data describing the correlation between immunological parameters and response/survival among patients with advanced melanoma who received ipilimumab 10 mg/kg in an expanded access programme.

Methods: Patients received ipilimumab 10 mg/kg every 3 weeks (Q3W) for four doses (induction) and Q12W from week 24 (W24) as maintenance therapy. Tumor assessments were conducted Q12W. Expression of inducible T cell costimulator (ICOS) on CD4(+) and CD8(+) T cells was assessed at baseline, W7, W12 and W24, and the ratio between absolute neutrophils (N) and lymphocytes (L) determined at baseline, W4, W7 and W10.

Results: Median overall survival among 27 patients was 9.6 months (95 % CI 3.2-16.1), with 3- and 4-year survival rates of 20.4 %. Five patients survived >4 years. Patients with an increase in the number of circulating ICOS(+) T cells at W7 were more likely to experience disease control and have improved survival. An N/L ratio below the median at W7 and W10 was also associated with better survival compared with an N/L ratio above the median.

Conclusions: Ipilimumab can induce long-term survival benefits in heavily pretreated patients with metastatic melanoma. Changes in the number of circulating ICOS(+) T cells or N/L ratio during ipilimumab treatment may represent early markers of response. However, given the limited sample size, further investigation is required.

Fig. 1

Kaplan–Meier analysis of OS for 27 patients with metastatic melanoma treated with ipilimumab 10 mg/kg. SE standard error

Fig. 2

Tumor response patterns among five patients with long-term survival (>4 years) following treatment with ipilimumab 10 mg/kg. Patient A had a PR at W48 then developed new subcutaneous lesions at W96. These lesions had resolved by W108 when the patient reached a CR that lasted until W192, at which point a further subcutaneous lesion was identified. Patient B had durable SD until W60 when new subcutaneous lesions were detected. The patient was retreated with ipilimumab 10 mg/kg and subsequently achieved a CR, ongoing at W204. Patient C had PD at W12, with the appearance of subcutaneous and soft tissue lesions. By W24, the patient’s disease had stabilized, culminating in a PR at W120, ongoing at W216. Patient D had PD at W12 after developing new liver lesions. Shrinkage of existing lesions resulted in a pathologic CR of cutaneous lesions at W56 and of liver lesions at W102 [13]. Patient D subsequently developed new cutaneous lesions and was retreated with ipilimumab 3 mg/kg within the amended EAP from W156, achieving an eventual CR at W180, ongoing at W216 in the absence of further treatment. Patient E had a PR in lung lesions at W12 [13] with a continued slow, steady shrinkage of tumor load until W120, after which there were no further changes

Fig. 3

Changes in ICOS⁺ circulating T cells counts and clinical outcome with ipilimumab treatment. a Increase in absolute CD4⁺ICOS⁺ or CD8⁺ICOS⁺ circulating T cells from baseline at W7, W12 and W24. Each symbol represents 1 patient. b Absolute counts of CD4⁺ICOS⁺ or CD8⁺ICOS⁺ circulating T cells in peripheral blood samples from responders (R patients who achieved disease control) or non-responders (NR patients with PD). c Kaplan–Meier analysis of OS according to increases from baseline in circulating CD4⁺ICOS⁺ and CD8⁺ICOS⁺ T cell counts at W7

Fig. 4

Correlation between N/L ratio at W7 and W10 and patient survival