Immunotherapy Combo Regimens on Horizon in Lymphoma

Anas Younes, MD

Nivolumab (Opdivo) may be the only checkpoint inhibitor that is approved by the FDA as a treatment of patients with Hodgkin lymphoma, but other immunotherapies—alone and in combination with other novel agents—are emerging in other indications.

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, explained Anas Younes, MD, chief of the Lymphoma Service at Memorial Sloan Kettering (MSK) Cancer Center.

Younes reviewed a number of these combination trials during his presentation at the 34th Annual Chemotherapy Foundation Symposium™, held November 9-11, 2016 in New York City.

“We now have multiple agents for Hodgkin lymphoma (HL), and some of them are highly active as single agents, for example, brentuximab yields a roughly 75% response rate and a 34% complete response rate, and nivolumab has an approximately 70% response rate.”

“There’s a lot of excitement about combining them, because they can be easily combined without overlapping toxicity,” Younes continued. 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 and nivolumab in the pre-transplant 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 CR 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, which has a CR 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 explained, which though not sufficient for FDA approval at the time, did 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 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-cell lymphoma. 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.

Finally, there is understandable interest in combining checkpoint inhibitors with chemotherapy, and these agents are being combined with frontline CHOP in diffuse large, B-cell lymphoma, with bendamustine-based regimens for follicular lymphoma, and with ABVD in HL. Younes said that all of these trials are either starting to enroll patients or about to begin enrollment.

With many studies underway exploring the potential of immune checkpoint-based combinations in lymphoma, a number of questions will need to be addressed, Younes noted. The optimal duration of immune checkpoint inhibitors, for example, remains unknown. “For now, we say that it is good to give it until progression,” said Younes, while also monitoring patients for CR.

“Clinical trials with maintenance immune checkpoint inhibitor therapy also should evaluate the effect on minimal residual disease (MRD),” he concluded. He added that by giving these agents in the adjuvant setting after chemotherapy, the approach has the potential to eradicate MRD, and most trials in this setting now include assessment of MRD.