Urelumab Safe and Active as Monotherapy and in Combination with Nivolumab in Several Types of Cancer

Walter Alexander

January 2017, Vol 7, No 1 - Immunotherapy


The investigational CD137 agonist urelumab, given as monotherapy and in combination with the anti–PD-1 monoclonal antibody nivolumab, demonstrated safety and, in some patients with hematologic and solid tumor malignancies, promising antitumor activity, according to results of 2 early-phase studies presented at the 2016 Society for Immunotherapy of Cancer annual meeting.

Urelumab is a fully human immunoglobulin G4 monoclonal antibody that binds to and activates CD137-expressing cytotoxic T-cells.

Because urelumab and nivolumab enhance immune-cell activity through distinctly different mechanisms, their activity in patients with advanced cancers may be synergistic.

Erminia Massarelli, MD, PhD, MS, Associate Clinical Professor, Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, discussed the 2 studies.

Urelumab in 2 Clinical Trials

The monotherapy study evaluated urelumab in patients with advanced malignancies or advanced non-Hodgkin lymphoma (NHL). The combination study evaluated urelumab plus nivolumab in patients with advanced solid tumors or B-cell lymphoma and in patients with diffuse large B-cell lymphoma, melanoma, non–small-cell lung cancer (NSCLC), or squamous-cell carcinoma of the head and neck (cohort expansion).

The mean patient age was approximately 65 years. In the combination study, 28% of patients received no previous treatment and 70% received between 1 and ≥3 previous lines of therapy. In the monotherapy study, all the patients had been previously treated.

An analysis of the changes in interferon gamma–induced periph­eral cytokine expression (CXCL9/CXCL10) after treatment showed larger increases with urelumab plus nivolumab than with urelumab monotherapy. Also, in a small sample of melanoma tumors, increased CD8-positive T-cells and CXCL9 gene expression were observed.

In the monotherapy trial of 123 patients, drug-induced liver injury in 1 patient led to the discontinuation of urelumab. No treatment-related deaths were reported, and only 3 of 70 patients in the trial withdrew as a result of treatment-related adverse events.

Response Rates

The monotherapy overall response rate (ORR) was 10% (5% with a complete response and 5% with partial remission), with all responses in B-cell NHL. The confirmed disease control rates for B-cell NHL, colo­rectal cancer, squamous-cell head and neck cancer, and other solid tumors were 28%, 18%, 20%, and 39%, respectively.

Among 128 patients receiving combination therapy with flat-dose urelumab and nivolumab, adverse events led to treatment discontinuation in 10% of patients (any grade, 5%; grade 3/4, 5%). Fatigue was the most frequently reported adverse event. “This indicates that these 2 agents can be safely administered together,” Dr Massarelli said.

The ORR (confirmed and unconfirmed) was 50% among 46 patients with melanoma who were anti–PD-1/PD-L1 naïve, and the disease control rate (confirmed and unconfirmed) was 70%. The disease control rates were 21% for patients with diffuse large B-cell lymphoma, 21% for NSCLC (anti–PD-1/PD-L1) progressors, 35% for patients with NSCLC who were anti–PD-1/PD-L1 naïve, 23% for patients with head and neck cancer, and 33% for those with other solid tumors.

Patients with Melanoma

“It is of particular interest that in melanoma patients receiving the urelumab plus nivolumab combination who were anti–PD-1/PD-L1 naïve, PD-L1 status [≥1% or <1%] had no effect on overall response rate, with rates of 50% [≥1%] and 47% [<1%], respectively,” Dr Massarelli pointed out.

Clinical Implications

She concluded that in the urelu­mab monotherapy trial, the 0.1-mg/kg and 8-mg doses demonstrated manageable safety profiles and peripheral pharmacodynamic activity, with antitumor effects observed especially among some patients with lymphoma.

Among patients receiving the combination of urelumab and nivolumab, safety was manageable at all evaluated doses, and promising antitumor activity was observed in melanoma.

According to Dr Massarelli, urelumab is being evaluated in other ongoing clinical trials in combination with nivolumab and with other immuno-oncology or targeted agents.