Can New Combo Fill ‘Unmet Need’ in R/R Hodgkin Lymphoma?

Acimtamig, a first-in-class CD3src/CD16A bispecific innate cell engager (ICE), combined with an off-the-shelf cord-blood-derived natural killer cell product (AlloNK), shows safety and efficacy in the treatment of patients with relapsed or refractory (R/R) classical Hodgkin lymphoma, who otherwise have poor prognoses.

“Acimtamig in combination with AlloNK shows promising efficacy, with a well-managed safety profile, with the potential to address an unmet need in patients with R/R Hodgkin lymphoma who have exhausted standard-of-care treatment options,” said first author Joseph Maakaron, MD, of the Division of Hematology, Oncology and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, in presenting the findings at the American Society of Clinical Oncology (ASCO) 2src25 annual meeting in Chicago. 

Patients with classical Hodgkin lymphoma who relapse after standard-of-care treatments, including chemotherapy, brentuximab vedotin, and checkpoint inhibitors, have few remaining treatment options.

Acimtamig has previously shown some efficacy as monotherapy in the treatment of Hodgkin lymphoma, and when it was further combined with an allogenic cord blood-derived natural killer cell product, encouraging objective response rates were observed in a proof-of-concept study. 

To test the approach in a more rigorous multicenter trial, Maakaron and colleagues conducted the current open-label phase 2 LuminICE-2src3 trial, enrolling 24 patients with R/R Hodgkin lymphoma.

For the study, the patients were treated in one of four cohorts investigating two doses of acimtamig (2srcsrc mg or 3srcsrc mg weekly flat dosing for 6 weeks) in combination with two dose levels of AlloNK after standard lymphodepletion of up to three cycles and followed by a randomized part using the Simon two-stage design. 

While the patients had a median age of 42.5 years, the range was wide, ranging from age 23 to 8src years, and 16 (67%) were men.

About two thirds of patients (66.7%) had extranodal disease, and they had all been heavily pre-treated with brentuximab vedotin and programmed cell death protein 1 inhibitors, with a median of 4.5 prior lines of treatment, including previous stem cell transplant and CAR T cell therapy among 14 (58%) patients.

“The patients had essentially exhausted all standard-of-care therapy options,” Maakaron emphasized.

As of the latest cut-off, the study achieved its primary endpoint of an objective response rate, with a rate of 88% among the patients, with 14 (58%) achieving complete responses. 

Across all four dose cohorts, clinically meaningful deep responses were seen, with 1src ongoing responses. A progression-free survival estimate of 61% was observed at 6 months.

More robust maximum peaks were observed after the third infusion, which was presumed to be due to a steady state that had been achieved at that time, he added.

The safety profile was consistent with previous reports, with the therapy combination being well tolerated. The most common treatment-related side effects were mild to moderate infusion-related reactions, occurring in 5src% of patients.

There were no cases of graft vs host disease or immune effector cell-associated neurotoxicity syndrome, and cytokine release syndrome (CRS) was reported in six patients shortly after infusion. 

All treatment-emergent adverse events including infusion-related reactions and CRS events were controlled with standard-of-care interventions and quickly resolved.

There were no fatal treatment-emergent adverse events.

“Acimtamig with AlloNK may provide a safe, effective, and durable new therapeutic option for patients with R/R Hodgkin lymphoma, with a progression-free survival estimate of 61% at 6 months,” Maakaron said.

“These early results support the co-administration approach of acimtamig with an off-the-shelf, commercially scalable, allogenic, cryopreserved natural killer cell product in a multicenter setting,” he said.

Study Shows Best Response Rates to Date

Commenting on the findings at the meeting, Sarah C. Rutherford, MD, associate professor of clinical medicine at Weill Cornell Medicine in New York City, said the need for better treatment options for those who have relapsed after standard therapies is pressing. 

“This is really an unmet need in the field,” she underscored. 

“Novel treatments in R/R classic Hodgkin lymphoma after brentuximab vedotin, checkpoint inhibitors, and autologous transplant are limited, and most don’t really work that well.”

“We tend to use single-agent chemotherapies, repeat checkpoint inhibitors, and radiation, but these patients really suffer because of that, and clinical trial options have been lacking.”

Rutherford noted that, with the innovative combination, safety and tolerability were important concerns.

“I was really struck by the tolerability of this regimen, with only five patients having grade 3 and one [having] grade 4 treatment-emergent adverse events.”

Furthermore, the response rates were impressive, she noted.

“These are the best response rates observed to date in the post-brentuximab vedotin and checkpoint inhibitor setting, and the toxicities appear manageable,” she said.

“I think it’s going to be unlikely to be as widely adopted as checkpoint inhibitors because of the nature of the cellular therapy approach, but I do think this is a very promising agent,” Rutherford said.

“I think it’s the current best available trial option, and in the future, some version of this could become a third-line thera