Strategies Combining Nivolumab Show Promise for Classic Hodgkin Lymphoma

In a study of 2 experimental, nivolumab (Opdivo)-based, first-line treatment strategies in patients with early-stage unfavorable classic Hodgkin lymphoma, published in JAMA Oncology, researchers found that both strategies combining nivolumab and doxorubicin (Adriamycin), vinblastine (Velban), and dacarbazine (AVD) were feasible, highly effective, and resulted in excellent 12-month progression-free survival (PFS), they wrote.

“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. “Anti-PD-1-based first-line treatment of early-stage (classic Hodgkin lymphoma) 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, e.g., by interim PET.”

Patients were randomized 1:1 to either concomitant treatment with 4 cycles of nivolumab and AVD (N-AVD) or sequential treatment with 4 doses of nivolumab, 2 cycles of N-AVD, and 2 cycles of AVD at standard doses, followed by 30-Gy involved-site radiotherapy. The primary endpoint was complete remission (CR) rate after study treatment, aiming at excluding a CR rate of 80% or lower via a 2-sided 95% CI for each treatment group. 

In this open-label, multicenter, randomized phase II clinical trial, open between April 2017 and October 2018, eligibility was defined by age 18 to 60 years, classic Hodgkin lymphoma confirmed by expert pathology review, early-stage unfavorable disease by German Hodgkin Study Group criteria (stage I to II with risk factors), and absence of serous concomitant disease or organ dysfunction. Moreover, the trial took place at 35 trial centers across Germany, ranging from academic centers to private offices. 

Overall, 109 patients were included in the study. At interim staging after 2 cycles of N-AVD or 4 doses of nivolumab monotherapy, 100% and 96%, respectively, of response-eligible patients achieved an objective response, with CR in 47 (87%) and 26 (51%) patients, respectively. 

Further, of 101 patients eligible for primary endpoint analysis, 46 of 51 (90%; 95% CI, 79%-97%) patients receiving concomitant therapy and 47 of 50 (94%; 95% CI, 84%-99%) patients receiving sequential therapy achieved CR after study treatment. With a median follow-up of 13 months, 12-month PFS was 100% for patients receiving concomitant treatment and 98% (95% CI, 95%-100%) for patients receiving sequential therapy. 

“Follow-up within the present trial is still limited, but the 12-month PFS of 100% for the concomitant group and 98% for the sequential group is outstanding,” the authors wrote. “Taking into account the discussed pitfalls concerning PET after anti-PD-1 therapy and the favorable clinical course of the 7 patients formally failing to achieve a CR, we conclude very good efficacy of both treatment strategies despite marginally missing the primary end point in the concomitant therapy group.”

Notably, incidence of treatment-related adverse events (AEs) with nivolumab alone in the study was similar to previously reported data in patients with relapsed classic Hodgkin lymphoma. However, researchers did observe relevant immune-related organ-related AEs earlier than previously reported, possibly due to preserved immunocompetence in treatment naïve patients. Additionally, most serious AEs were attributed to the combination of N-AVD, and fewer than 10% were caused by either AVD or nivolumab alone. 

Notably though, the researchers did not observe any measurable differences regarding occurrences of AEs or efficacy after establishing the antiphlogistic prophylaxis during the trial conduct. 

“Because all patients in the sequential treatment group received further chemotherapy and radiotherapy, we cannot estimate the long-term efficacy of anti-PD-1 therapy alone in first-line treatment of patients with cHL,” the authors wrote. “However, a PET-guided approach might allow for a chemotherapy-free and radiotherapy-free fixed-duration anti-PD-1 treatment in selected patients with early-stage cHL who have early and sustained negative and disease activity seen on results of PET scan. This should be evaluated in a phase II trial, ideally also including patients with comorbidities or of older age who are in need of innovative treatment.”

Reference:

Bröckelmann PJ, Goergen H, Keller U, et al. Efficacy of Nivolumab and AVD in Early-Stage Unfavorable Classic Hodgkin Lymphoma. JAMA Oncology. doi:10.1001/jamaoncol.2020.0750.