On February 6, Innate Pharma announced that the randomized, placebo-controlled, Phase II EffiKIR trial (NCT01687387) evaluating lirilumab as a single-agent maintenance treatment in elderly patients with acute myeloid leukemia (AML) missed its primary efficacy endpoint of leukemia-free survival. The initial signs toward lack of efficacy in this trial came in March 2015, when the Data and Safety Monitoring Board recommended stopping treatment in one of the arms as it was unable to beat placebo.

The two experimental arms of the trial tested lirilumab 0.1mg/kg every three months and 1mg/kg monthly, respectively, against placebo control. It was assumed then that the arm administering lower and infrequent dosing of lirilumab would struggle. However, in unblinding the study, the company revealed the failing arm to be the one administering the 1mg/kg/month regimen, thereby unwittingly casting doubts over the possibility of success for the other treatment arm that was administering a less potent regimen.

Lirilumab is licensed to Bristol-Myers Squibb (BMS) and has an extensive clinical development program spanning solid tumors and hemato-oncologic indications. It functions in a similar manner to BMS’ checkpoint inhibitors, Yervoy (ipilimumab) and Opdivo (nivolumab), but instead of affecting T-lymphocytes as they do, it activates natural killer (NK) cells by binding to KIR receptors. Although these cells are known to be capable of cytotoxic abilities on viral-infected and tumor cells, the role of NK cells in eliminating tumors is not well-established in the clinic. NK cells represent a minor fraction of the human lymphocyte population, indicating a need for the development of clinical protocols to sufficiently activate and increase the number of these cells in cancer patients to help elicit a tumor response.

Innate Pharma’s positioning of lirilumab in the maintenance setting in the EffiKIR trial may have played against the chances of the drug, as in this state the patient is in complete remission, with normal blood counts and undetectable leukemia in the bone marrow. Despite lirilumab-mediated activation of NK cells, lack of active disease in these patients might have prevented the formation of an effective and durable tumor response.

Combining lirilumab with other therapies may turn out to be a more effective strategy, as has already been seen with Opdivo and Merck & Co.’s Keytruda (pembrolizumab), which demonstrated synergistic activity when combined with Yervoy and chemotherapy. The EffiKIR study stands out in this respect, as it is the only clinical study in lirilumab’s clinical program that is evaluating the agent as a monotherapy. Although it fell short on its own in AML, when given in combination with Opdivo, lirilumab had a promising start in squamous cell carcinoma of the head and neck. Fortunately, lirilumab has an extensive clinical development program, with the rest of the trials pairing the candidate with strong players like Opdivo, BMS’ Empliciti (elotuzumab) and Roche’s Rituxan (rituximab). GlobalData expects that the combination trials of lirilumab are more likely to achieve the success it has failed to meet in the EffiKIR trial.

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