The investigational immunotherapy NKTR-214, designed to increase tumor-killing T-cells and natural killer (NK) cells in the tumor microenvironment, may be a promising approach for a variety of solid tumors, according to data from a Phase 1 trial recently presented at the Society for Immunotherapy of Cancer 2016 Annual Meeting in Maryland.
The findings, revealed in the oral presentation, “New Cancer Immunotherapy Agents in Development,” show that NKTR-214 induces a strong activation of the immune system and promising anti-tumor efficacy, with a favorable safety and tolerability profile.
NKTR-214 is a CD122 agonist designed to stimulate a patient’s own immune system to fight cancer. By binding CD122, which is a subunit of the IL-2 receptor, the agent induces the rapid proliferation of T-cells and NK cells and their mobilization into the tumor microenvironment. In addition, the drug enhances PD-1 expression in these immune cells, posing it as a promising therapy to be used in combination with immune checkpoint inhibitors.
“We are extremely pleased with the single-agent activity of NKTR-214 and the potential of NKTR-214 to transform the immuno-oncology landscape,” Howard W. Robin, president & CEO of Nektar Therapeutics, said in a news release. “As the first I-O agent to demonstrate that it can increase tumor-infiltrating lymphocytes (TILs) and increase PD-1 expression on immune cells in humans, NKTR-214 complements not only existing checkpoint inhibitors, such as nivolumab, but also other I-O mechanisms in development.”
Interim results from a first-in-human, dose-escalating Phase 1/2 study of NKTR-214 as a monotherapy in patients with locally advanced or metastatic solid tumors, including renal cell carcinoma, melanoma, bladder, colorectal, and other solid tumors, have shown promising results.
The open-label study (NCT02869295) enrolled 20 patients who were placed in one of four cohorts, each treated with a different outpatient dose of NKTR-214 once every three weeks. Doses ranged from 0.003 mg/kg to 0.012 mg/kg.
Among the 18 patients evaluable for anti-tumor activity, 12 (67%) had stable disease at the initial eight-week scan, and seven (39%) had reductions in tumor size, as assessed by RECIST 1.1.
One patient with metastatic melanoma who had been previously treated with Yervoy (ipilimumab) and a BRAF inhibitor had stable disease following 13 cycles of NKTR-214 (0.003 mg/kg dose). In addition, among the five patients with metastatic renal cell carcinoma whose disease had progressed following treatment with a kinase inhibitor, NKTR-214 (0.006 mg/kg) induced one unconfirmed partial response and two tumor reductions of 6% and 10%.
Based on the positive data of the 0.006 mg/kg dosing regimen, an extra cohort of patients was added to the study in September, testing the o.006 mg/kg dose in an every two-week schedule. To date, five patients have been enrolled in this cohort, all of whom are still receiving NKTR-214.
Safety profiles from the 25 evaluable patients have shown favorable results. The most common Grade 1-2 adverse events were fatigue, rash, cough, reduced appetite, fever and hypotension. No immune-related side effects, deaths, or Grade 4 adverse events were reported in the study.
Only one patient experienced dose-limiting toxicity in the 0.012 mg/kg cohort, but he continued on treatment at a 0.006 mg/kg dose. In addition, the three patients that experienced Grade 3 hypotention rapidly recovered following fluid administration.
“NKTR-214 resulted in robust activation of the immune system and encouraging anti-tumor activity, including a partial response observed in a patient who continues to be treated with NKTR-214,” said Dr. Ivan Gergel, senior vice president, Drug Development, and chief medical officer of Nektar. “NKTR-214 was also well tolerated in patients when administered as an every two-week or every three-week outpatient therapy. We are very encouraged by the clinical profile emerging for NKTR-214 and the totality of the data from this ongoing single-agent trial of NKTR-214.”
Based on NKTR-214’s ability to activate the immune system, Nektar has entered into a clinical collaboration with Bristol-Myers Squibb to assess the safety and efficacy of combining NKTR-214 with the immune checkpoint inhibitor Opdivo (nivolumab) in several Phase 1/2 clinical trials. These will enroll up to 260 patients with melanoma, kidney cancer, non-small cell lung cancer, triple-negative breast cancer, and bladder cancer. The initial dose-escalating trial of Opdivo in combination with NKTR-214 is underway.