On October 9, 2016 Bristol-Myers Squibb Company (NYSE:BMY) and Innate Pharma SA (Euronext Paris: FR0010331421 – IPH) reported safety data for two Phase I studies conducted by Bristol-Myers Squibb, testing lirilumab in combination with nivolumab or ipilimumab, respectively, in patients with advanced refractory solid tumors (Press release, Bristol-Myers Squibb, OCT 9, 2016, View Source [SID:SID1234515665]). Lirilumab is a first-in-class antibody directed against the inhibitory killer-cell immunoglobulin-like receptors (KIRs) expressed predominantly on natural killer (NK) cells and some T cells. It was licensed by Innate to Bristol-Myers Squibb and is being studied for its potential to complement nivolumab or ipilimumab, which act on different cell types and via different mechanisms of action.

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The safety profile of the combination of lirilumab and nivolumab therapy was similar to that of nivolumab monotherapy, with the exception of an increased frequency of low grade infusion-related reactions in patients treated with the lirilumab combinations. These reactions were clinically managed and similar to those seen with lirilumab alone. In the limited population (22 patients) studied for the combination of lirilumab and ipilimumab, there did not appear to be additional safety concerns compared to ipilimumab monotherapy.

Based on these data, further evaluation of lirilumab in combination with nivolumab is warranted. Efficacy data from the lirilumab and nivolumab combination study will be reported separately.

"We are very pleased by these safety results. They add to an existing body of data that support our scientific platform targeting NK receptors and the rationale for the development of lirilumab, our anti-KIR antibody licensed to Bristol-Myers Squibb, in various combinations," said Pierre Dodion, Chief Medical Officer of Innate Pharma. "We are now looking forward to the efficacy data that will be presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 2016 conference."

"These studies are part of Bristol-Myers Squibb’s ongoing efforts to explore innovative and complementary combinations of immunotherapies with the ultimate goal of achieving quality long-term survival for patients living with different types of cancer," said Timothy Reilly, Vice President & Head of Oncology Early Assets Development at Bristol-Myers Squibb. "The preliminary safety data of this novel anti-KIR antibody, lirilumab, in combination with nivolumab or ipilimumab, provide support for this approach. Through ongoing collaborations and extensive translational research programs, Bristol-Myers Squibb is working to develop and understand the next generation of transformational Immuno-Oncology combinations with the potential to impact the standard of care in oncology for patients with unmet needs."

The results were presented by Dr. Neil H. Segal, Memorial Sloan-Kettering Cancer Center, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 congress (October 7 – 11, 2016) in Copenhagen, Denmark, in a poster entitled "Safety of the natural killer (NK) cell-targeted anti-KIR Antibody, lirilumab (liri), in combination with nivolumab (nivo) or ipilimumab (ipi) in two phase I studies in advanced refractory solid tumors" (poster number 1086P).

About the Phase I trial of lirilumab in combination with nivolumab (anti-PD-1) in solid tumors (CA223-001):

CA223-001 is a Phase I dose escalation and cohort expansion study of lirilumab in combination with nivolumab in patients with advanced solid tumors. In this trial, patients received lirilumab (0.1, 0.3, 1.0, or 3.0 mg/kg) once every 4 weeks and nivolumab (3 mg/kg) once every 2 weeks, in 8-week treatment cycles for a maximum of 12 cycles.

The purpose of this Phase I open label study is to determine the safety of the combination of lirilumab and nivolumab and to explore the preliminary anti-tumor activity of the combination in patients with a range of advanced solid tumors.

In the escalation and expansion phases, 159 patients were treated. No dose-limiting toxicities (DLTs) were reported with lirilumab and nivolumab treatment. The overall rate of treatment-related adverse events (TRAEs) was reported as 71.7 percent (114/159) and the rate of Grade 1-2 TRAEs was 56.6 percent (90/159), with the most common being fatigue (20.8 percent), pruritus (18.9 percent), and infusion-related reaction (17.6 percent). The rate of Grade 3-4 TRAEs was 15.1 percent (24/159). Discontinuations due to TRAEs occurred in 7.5 percent (12/159), with only treatment related pneumonitis (3/159; Grade 2) and diarrhea (2/159; Grade 2) occurring in more than one patient.

About the Phase I trial of lirilumab in combination with ipilimumab (anti-CTLA4) in solid tumors (CA223-002):

CA223-002 was a Phase I dose escalation and cohort expansion study of lirilumab in combination with ipilimumab in patients with advanced solid tumors. In this trial, patients received lirilumab (0.1, 0.3, 1.0, or 3.0 mg/kg) + ipilimumab (3 mg/kg) once every 3 weeks for 4 doses (induction phase) and then every 12 weeks for 4 doses (maintenance phase).

The purpose of this Phase I open label study was to determine the safety of the combination of lirilumab and ipilimumab and to provide preliminary information on the anti-tumor activity of the combination.

The study enrolled 22 patients. The overall rate of treatment-related adverse events (TRAEs) was reported as 68.2 percent (15/22) and the rate of Grade 1-2 TRAEs was 59.1 percent (13/22), with fatigue (27.3 percent) and diarrhea (22.7 percent) being the most common. The rate of Grade 3-4 TRAEs was 9.1 percent (2/22) and included erythematous rash and pruritus (1/22) and hypopituitarism (1/22). This study is complete and the combination of lirilumab with ipilimumab is no longer being evaluated.

Poster details:

Category: Immunotherapy of cancer
Poster: 1086P
Date: Sunday, October 9, 2016
Presentation Time: 1:00 – 2:00 p.m.
Location: Bella Center, Hall E, Copenhagen
Presenter: Dr. Neil H. Segal, Memorial Sloan-Kettering Cancer Center

About lirilumab (IPH2102/BMS-986015):

Lirilumab is a fully human monoclonal antibody that is designed to act as a checkpoint inhibitor by blocking the interaction between KIR2DL-1,-2,-3 inhibitory receptors and their ligands. Blocking these receptors facilitates activation of NK cells and, potentially some subsets of T cells, ultimately leading to destruction of tumor cells.

Lirilumab is licensed to Bristol-Myers Squibb Company. As part of the agreement with Innate Pharma, Bristol-Myers Squibb holds exclusive worldwide rights to develop, manufacture and commercialize lirilumab and related compounds blocking KIR receptors, for all indications. Under the agreement, Innate Pharma conducts the development of lirilumab through Phase II in acute myeloid leukemia ("AML").

Innate is currently testing lirilumab in a randomized, double-blind, placebo-controlled Phase II trial as maintenance treatment in elderly patients with AML in first complete remission ("EffiKIR" trial). In addition, lirilumab is also being evaluated by Bristol-Myers Squibb in clinical trials in combination with other agents in a variety of tumor types.