Concomitant combination of nivolumab plus doxorubicin, vinblastine, and dacarbazine (AVD) resulted in high response rates and progression-free survival (PFS) among patients with previously untreated early-stage, unfavorable classical Hodgkin lymphoma (cHL), according to results of a phase 2 study published in JAMA Oncology.
“The investigator-initiated NIVAHL phase 2 randomized clinical trial is the first trial, to our knowledge, evaluating a first-line treatment of early-stage unfavorable cHL based on anti–PD-L1,” the authors wrote.
Although first-line standard-of-care multiagent chemotherapy, such as eBEACOPP, induces high cure rates, it is associated with short- and long-term toxicities. Less intense regimens, such as bleomycin with AVD (ABVD), also induce high response rates, but shorter PFS. The aim of this trial was to determine if the addition of nivolumab to AVD would be effective and tolerable in early-stage cHL. Bleomycin was omitted to limit incidence of pneumonitis.
The investigator-initiated, multicenter, open-label phase 2 trial randomly assigned 109 patients with early-stage, unfavorable cHL to 2 parallel groups: 4 cycles of nivolumab plus AVD given concomitantly, or 4 doses of nivolumab followed by 2 cycles of nivolumab-AVD and 2 cycles of AVD. All patients received 30 Gy of involved-site radiation consolidation. The primary endpoint was complete remission (CR). The key secondary endpoint was treatment-related morbidity, defined as any grade 3-4 organ-related adverse event (AE) or grade 4 anemia, thrombocytopenia, or infection.
At baseline, the median age was 27 and 60% of patients were female. The majority of patients were Ann Arbor stage IIA or IIB and German Hodgkin Study Group risk factors included large mediastinal mass, extranodal involvement, involvement of 3 or more nodal areas, and elevated erythrocyte sedimentation rate. The most common histologic subtype was nodular sclerosis (64%), followed by classic disease without subtyping (21%), mixed cellularity (12%), and lymphocyte-rich (3%).
“We observed early and sustained responses in both treatment groups and an unexpectedly high interim CR rate, even after 4 doses of nivolumab alone,” the authors wrote.
First interim restaging occurred after 2 cycles of concomitant nivolumab-AVD or 4 doses of nivolumab in the sequential group, in which 100% and 96% of patients, respectively, experienced an objective response. CR was achieved by 87% of patients in the nivolumab-AVD group and 51% of patients in the sequential nivolumab group.
Of the 101 evaluable patients for the primary endpoint, 90% (95% CI, 79%-97%) and 94% (95% CI, 84%-99%) of patients in the concomitant or sequential groups achieved, respectively, achieved CR at the end of treatment. The sequential group met prespecified benchmark for 80% efficacy in the 95% confidence intervals. The objective response rates were 100% in the concomitant arm and 98% in the sequential arm.
After a median follow-up of 14 months, the 12-month PFS was 100% in the concomitant arm and 98% in the sequential arm. The 12-month overall survival was 100% in both arms.
Grade 3 to grade 4 treatment-related AEs occurred in 76% and 80% of patients in the concomitant and sequential arms, respectively. The key secondary endpoint of grade 3 to grade 4 organ-related AEs occurred in 24% of patients in the concomitant arm and 30% of patients in the sequential arm. In the concomitant and sequential arms, grade 3-4 anemia was reported in 4% and 2% of patients, respectively, thrombocytopenia in 0% and 2%, respectively, and infection in 5% and 2%, respectively.
The authors concluded that these data indicate that “anti–PD-1–based first-line treatment of early-stage cHL warrants further evaluation within future trials, comparing a fully concomitant treatment with standard of care or an individualized approach with sequential anti–PD-1 treatment guided, eg, by interim PET.”
Bröckelmann PJ, Goergen H, Keller U, et al. Efficacy of nivolumab and AVD in early-stage unfavorable classic Hodgkin lymphoma. The randomized phase 2 German Hodgkin Study Group NIVAHL Trial [published online April 30, 2020]. JAMA Oncol. doi: 10.1001/jamaoncol.2020.0750