In a phase Ib study published in Blood, treatment with AFM13, a CD30/CD16A bispecific tetravalent innate immune cell engager, was safe and produced promising response rates when combined with pembrolizumab in patients with heavily treated Hodgkin lymphoma.
“While treatment with immune checkpoint blockade using PD-1 blocking antibodies has proven highly effective in Hodgkin lymphoma, there is still room for improvement using immunological therapy in this disease,” said study coauthor Stephen Ansell, MD, PhD, from Mayo Clinic in Rochester, Minnesota.
The first-in-class bispecific antibody AFM13 binds to CD30 found on tumor cells as well as to CD16A on natural killer cells and macrophages, Dr. Ansell explained. “Thus, the combination of AFM13 with pembrolizumab may be more effective than either agent alone in producing responses in this patient population.”
In this open-label phase I trial, investigators enrolled patients with CD30+ classical Hodgkin lymphoma that had relapsed after or was refractory to standard therapy such as brentuximab vedotin. Thirty patients were enrolled at 14 sites in the U.S. and 4 sites in Spain from June 2016 to March 2019.
The study was conducted in two parts to determine the estimated maximum tolerated dose (MTD)/maximum administered dose (MAD) of the AFM13 and pembrolizumab combination. First, patients received fixed doses of pembrolizumab 200 mg every 3 weeks with escalating doses of AFM13; the second part of the study extended the assessment of the MTD/MAD of AFM13 when combined with pembrolizumab.
Dosing of pembrolizumab and AFM13 started in week 1 and week 2, respectively. Patients were assigned to receive AFM13 in one of three dosing cohorts:
- cohort 1: 0.1 mg/kg 3 times per week for up to 2 weeks, 0.5 mg/kg/week for up to 6 weeks, and 0.5 mg/kg every 3 weeks for up to 16 weeks
- cohort 2: 0.5 mg/kg 3 times per week for up to 2 weeks, 1.5 mg/kg/week for up to 6 weeks, and 1.5 mg/kg every 3 weeks for up to 16 weeks
- cohort 3: 3.0 mg/kg 3 times per week for up to 2 weeks, 7.0 mg/kg/week for up to 6 weeks, and 7.0 mg/kg every 3 weeks for up to 16 weeks
There were no AFM13 dose modifications in cohorts 1 or 2, whereas 7 patients in cohort 3 and the second part of the study required at least one AFM13 dose modification. Across all cohorts, approximately 90% of patients experienced AFM13 dose interruptions.
“In this heavily pretreated patient population, the combination of AFM13 and pembrolizumab [had] safety profiles similar to the known profiles of each agent alone,” the authors reported. Six patients had an adverse event that resulted in any study-drug discontinuation, including infusion-related reaction (n=5), acute myocardial infarction (n=1), myocardial ischemia (n=1), gastritis (n=1), and hypotension (n=1). No dose-limiting toxicity–related discontinuations of AFM13 were reported.
At the highest treatment dose (AFM13 7 mg/kg plus pembrolizumab 200 mg), the treatment combination led to an overall response rate (ORR) of 88%, with an ORR of 83% in the entire study population. A complete metabolic response was observed in 11 patients (37%), and a partial metabolic response was reported in 14 patients (47%). Progressive disease was reported in 10% of the study population (n=3).
A total of 21 of 25 patients who responded to treatment also achieved best response at the first tumor assessment, whereas the remaining 4 patients reached best objective response at around 26 weeks or later, the authors noted.
“This proof-of-concept study holds promise as a novel immunotherapy combination worthy of further investigation,” the researchers concluded. However, the study was limited by its lack of a placebo group, Dr. Ansell said, noting that an additional randomized study is needed to determine whether the AFM13 and pembrolizumab combination is more effective than either agent alone. In addition, “whether the benefit [associated with the combination therapy] is durable will require longer follow-up.”
The authors report no relevant conflicts of interest.
Bartlett NL, Herrera AF, Domingo-Domenech E, et al. A phase 1b study of AFM13 in combination with pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2020 July 30. [Epub ahead of print]