IL-8 levels indicate tumour response early in anti-PD-1 therapy

“Measuring IL-8 serum levels may become a useful complementary tool for the clinical management of patients treated with checkpoint inhibitors.” Dr Miguel Sanmamed, Postdoctoral Fellow, Yale University, New Haven, US

Anti-PD-1 has recently been approved for metastatic melanoma, metastatic NSCLC, metastatic renal cell carcinoma and metastatic bladder carcinoma. Dr Sanmamed and his colleagues at Navarra University (Spain) and Yale University have been working with samples from metastatic melanoma, metastatic NSCLC patients treated with both anti-PD-1 monoclonal antibodies (nivolumab and pembrolizumab) and anti-CTLA-4 monoclonal antibodies (ipilimumab).

A single predictive biomarker has not been identified that can be used to select and/or exclude patients for anti PD-1 therapy. The challenge is to find reliable biomarkers to predict which patients will demonstrate a good response to anti-PD-1 treatment. “Right now we use PD-L1 expression by immunohistochemistry in tumour biopsies as the best predictor of response, but we have seen responses in PD-L1 negative patients and non-responses in PD-L1 positive patients that illustrate the limitations of this biomarker and the room for improvement,” explained Dr Sanmamed.

Serum IL-8 levels have been found to provide a good surrogate of tumour burden. “We found that by monitoring this interleukin in the blood that the levels go down when tumours respond and rise when they progress.”

Prior to this study, the researchers first studied serum IL-8 levels in a small group of cancer patients before and after surgery and found that serum IL-8 levels significantly dropped at day 5-7 after surgery. Similarly, other metastatic melanoma patients treated with BRAF inhibitors, showed that at the moment of tumor reduction, serum IL-8 significantly decreased over pretreatment levels.

In the current study, Dr Sanmamed measured IL-8 levels in serum samples at different time points and investigated whether serum IL-8 levels reflect or predict response. In total, 44 patients with metastatic melanoma and 19 with metastatic NSCLC were treated with anti-PD-1 monoclonal antibody therapy as a single-agent, or in combination with anti-CTLA-4 monoclonal antibody. Blood samples were taken sequentially at baseline, 2-4 weeks after starting treatment, at time of best response and at disease progression. Serum IL-8 levels in the samples were determined, and blood samples were compared to radiographic tumour response records.

Three patient groups were studied: initially, a group of 29 metastatic melanoma patients treated with a single-agent anti-PD-1. Afterwards, results were extended in two independent cohorts: a cohort of 19 metastatic NSCLC patients treated with nivolumab or pembrolizumab, and a second cohort of 15 metastatic melanoma patients treated with nivolumab plus ipilimumab.

Reporting the results, Dr Sanmamed said that, in responders, serum IL-8 levels significantly decreased over baseline levels at the moment of best response, but in non-responders, serum levels significantly increased at the moment of progressive disease. “Furthermore, we found that in responders that subsequently progressed on anti-PD-1 therapy, IL-8 significantly increased over best response levels.”

Results in the other two cohorts confirmed the association of serum IL-8 levels and clinical response. “We found a significant decrease in IL-8 levels at the moment of tumor reduction and significant increase at the moment of tumor growth,” he continued.

Together, the data indicate an association between serum IL-8 levels and tumor burden changes during treatment with checkpoint inhibitors. However, the researchers were unable to study the significance of serum changes at the moment of progressive disease in melanoma patients treated with the combination, due to the limited sample size.

The researchers also found that serum IL-8 levels decreased 2-3 weeks after commencement of therapy, correlating with response. “This is a beautiful correlation between early changes in serum IL-8 levels and response that allows us to predict clinical outcomes of the patients. Likewise, we found a correlation between serum IL-8 level early change and overall survival, so when it decreased then the overall survival was longer.”

Also, serum IL-8 levels may be useful to distinguish pseudoprogression versus true progression in patients treated with anti-PD-1.

“Measuring IL-8 serum levels may become a useful complementary tool for the clinical management of patients treated with checkpoint inhibitors,” concluded Dr Sanmamed.

Based on Sanmamed M, Perez-Gracia J et al. Changes in serum IL8 levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small cell lung cancer patients (1055O). Presented on Friday 7 October 2016.

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