A combination of Opdivo (nivolumab) and standard Vidaza (azacitidine) chemotherapy reduced the tumor burden in one-third of acute myeloid leukemia (AML) patients and doubled survival rates over patients treated with Vidaza alone, according to a Phase 2 trial.
The combination, which was tested in patients with relapsed or refractory disease, was particularly effective in those with a higher amount of T-cells in their bone marrow before treatment, which may function as a biomarker for selecting patients more likely to benefit.
The study, “Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Non-randomized, Open-label, Phase 2 Study,” was published in Cancer Discovery.
“Over the last decade, six PD-1, PD-L1 and CTLA-4 antibodies have been approved for over 25 indications in 10 tumor types in the U.S. and Europe,” Naval Daver, MD, associate professor of leukemia at the University of Texas MD Anderson Cancer Center, said in a press release. “However, single agent PD-1 antibodies have shown little effect in patients with relapsed AML.”
Vidaza is a chemotherapy agent approved in Europe and commonly used in the U.S. for older patients with untreated AML. It works by preventing modifications in the DNA — DNA methylation — that are often used by cancer cells to avoid death and proliferate.
But while Vidaza promotes anti-tumor signaling, the agent seems to increase the production of immune checkpoint molecules, which dampen immune surveillance and limit the effectiveness of the treatment.
Researchers at MD Anderson thus developed a Phase 2 trial (NCT02397720) to determine if blocking these immune checkpoint molecules with Opdivo was safe for relapsed or refractory AML patients and improved their responses.
The trial included 70 patients, at a median age of 70, who had received at least one prior therapy for their condition. Treatment consisted of Vidaza, given under the skin (subcutaneous) or into the blood (intravenous), plus Opdivo, given every two weeks as an infusion.
Overall, 33% of patients saw a reduction in their tumor burden after receiving the treatment, including 22% with complete responses. An additional 9% had their disease stabilized for more than six months. In contrast, the response rate for similar patients receiving Vidaza alone at MD Anderson was 20%.
Patients who had never received Vidaza or other hypomethylating agent benefited the most from the combination, with more than half (52%) experiencing a reduction in tumor burden, compared with 22% of historical controls.
After a median follow-up of 21.4 months, 81% of the patients had died. The median overall survival was 6.3 months, but reached 10.6 months among patients receiving the combination as a second-line treatment. This was double the 5.3 months seen among similar patients treated with Vidaza alone at the cancer center.
Researchers also found that high levels of total T-cells had a “high sensitivity and specificity rate for predicting response, indicating it might serve as a reliable biomarker for selecting patients for this combination therapy,” according to Daver.
Patients whose bone marrow was composed of 13.2% or more T-cells had a response rate of 56%, compared with 22% of those with lower T-cell levels.
“We believe that implementation of clinical and immune biomarkers to select patients are likely to yield further improved outcomes with these types of therapies in AML,” Daver said.
The treatment was well-tolerated, with only 11% of patients experiencing severe to life-threatening adverse events. The most common adverse reactions were penumonitis, kidney inflammation, and skin rash, and most patients responded to steroids. However, two patients with pneumonia and overreactive immune cells did not respond to steroids and died.
An ongoing Phase 3 trial (NCT03092674) studying this combination in AML patients who have not received prior treatments is currently suspended pending a safety review, according to the trial’s web page. The trial is also testing the combination of Opdivo with other therapies, including midostaurin, decitabine, and cytarabine. No other information regarding the suspension is currently available.