Finding Biomarkers

A lot of research has also explored using these 2 types of immunotherapy in combination. Currently, the only FDA-approved combination for melanoma is ipilimumab plus nivolumab for patients with unresectable or metastatic melanoma.

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The combination was approved based on phase 2 data from CheckMate-069 that showed that it shrank tumors in 60% of patients with melanoma lacking the BRAF V600 mutation compared with 11% of patients treated with ipilimumab alone.1

Dr Daud recently conducted a study designed to begin to find a novel predictive biomarker to identify which patients are most likely to respond to single-agent or combination checkpoint inhibitor therapy.

For the study, Dr Daud and colleagues used metastatic melanoma samples taken from 102 patients treated with anti-PD-1 monotherapy or anti-PD-1 in combination with CTLA-4 therapy and had objective responses.2

Patients with lower levels of T cells — called partially exhausted cytotoxic lymphocytes (peCTL) —  within their tumor benefited most from combination therapy, they found . The levels of peCTL were significantly higher in patients who responded to treatment compared with those who did not (P < .0001).

Patients with higher levels of peCTL had similar rates of response whether they were treated with anti-PD-1 therapy alone or in combination. In contrast, patients with low peCTL had a significantly higher overall response rate when treated with combination therapy compared with anti-PD-1 monotherapy (35% vs 5.6%; P = .045).

“The combination therapy appears to be giving an additional kick to the pre-existing T cells in the tumor microenvironment,” Dr Daud said. “Based on our data and clinical trial and biomarker data from the last 2 years, it appears that in combination, ipilimumab is not recruiting new T cells but pushing existing ones to work harder. We have shown that the peCTLs have high level expression of not only PD-1 but also CTLA-4 providing a mechanism for this to happen.”