Anas Younes, MD
Nivolumab (Opdivo) may be the only checkpoint inhibitor that the FDA has approved thus far for a hematologic malignancy, but research is moving forward rapidly across the spectrum of blood cancers with ongoing clinical trials for immunotherapy agents alone and in combination with other novel therapies.
Key researchers in the field provided updates on the evolving landscape for several cancer types during the 34th Annual CFS™ Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® that Physicians’ Education Resource (PER®) hosted November 9-11, 2016, in New York City.
In May, the FDA approved nivolumab as a treatment for patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation and posttransplantation brentuximab vedotin (Adcetris).
The approval was based on an objective response rate of 65% (95% CI, 55-75; n = 62) in a combined analysis of 95 patients with relapsed or refractory cHL who received nivolumab either in the phase II CheckMate-205 trial or the phase I CheckMate-039 trial.1
Evidence continues to build for single-agent PD-1 inhibitors nivolumab and pembrolizumab (Keytruda) in relapse HL settings, said Anas Younes, MD, chief of the Lymphoma Service at Memorial Sloan Kettering (MSK) Cancer Center, during his presentation (Table)
. Younes was the key investigator on the pivotal nivolumab trial. Now, studies testing immune checkpoint inhibitors in combination with other drugs for the treatment of both Hodgkin and non-Hodgkin lymphoma are beginning to garner attention among researchers, noted Younes.
“We now have multiple agents for Hodgkin lymphoma [HL], and some of them are highly active as single agents; for example, brentuximab vedotin yields a roughly 75% response rate and a 34% complete response rate, and nivolumab has an approximately 70% response rate,” Younes said.
“There’s a lot of excitement about combining them, because they can be easily combined without overlapping toxicity,” he added. Agents currently being explored in combination with checkpoint inhibitors include brentuximab vedotin, HDAC inhibitors, ibrutinib, and traditional chemotherapy. Preliminary results from a phase I/II study of brentuximab vedotin and nivolumab in the pretransplant setting in patients with relapsed or refractory HL are among those to be shared at the upcoming annual meeting of the American Society of Hematology (ASH) to be held December 3-6, 2016, in San Diego, said Younes, an investigator on the trial.
The combination is currently demonstrating a complete response rate of 50%, but Younes stressed that because these findings are from an ongoing trial, “we’ll have to wait until it finishes.” As a benchmark, he compared this response rate with single-agent brentuximab vedotin, which has a complete response rate of about 30%.
Another potential combination involves HDAC inhibitors. Younes explained that the rationale for investigating these agents with checkpoint inhibition is that they can upregulate tumor-associated antigens and downregulate PD-1.
An earlier study of the oral pan-DAC inhibitor panobinostat, currently approved for the treatment of multiple myeloma, showed an overall response rate of 24% as a single agent, Younes said. Although that was though not sufficient for FDA approval at the time, those findings demonstrate downregulation of PD-1 on the T cells of patients with relapsed HL.
Against that backdrop, a phase I/II trial of the HDAC inhibitor entinostat in combination with pembrolizumab (Keytruda) is currently in development at MSK, Younes said, “and we’ll see if this strategy improves the efficacy.”
Ibrutinib (Imbruvica), a BTK inhibitor approved in mantle cell lymphoma and chronic lymphocytic leukemia, also is being explored in combination with checkpoint inhibition. Antitumor responses and synergy between BTK and PD-1 antibodies have been observed in B-cell lymphoma samples in preclinical research, and Younes said multiple companies are now moving forward with studies of this combination.
One recently completed international trial, PCI32765-LYM-1002, combined nivolumab and ibrutinib in patients with relapsed chronic lymphocytic leukemia, follicular lymphoma, and diffuse large B-cell lymphoma (DLBCL). Analysis of the results will take another few months, but Younes hopes they will be ready in time for the 2017 ASCO Annual Meeting in June.