The FDA has granted accelerated approval to Opdivo (nivolumab) for the treatment of patients with
classical Hodgkin lymphoma (cHL) who have relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin (Adcetris).
The approval was based on two single arm, multicenter trials of nivolumab in adults with relapsed or refractory cHL. The trials enrolled patients regardless of PD-L1 expression status on Reed-
Sternberg cells. The primary efficacy endpoint was objective response rate (ORR) as determined by an independent radiographic review committee. Additional outcome measures included duration of
Efficacy was evaluated in 95 patients previously treated with autologous HSCT and post-transplantation brentuximab vedotin. Patients had a median of five prior systemic regimens (range: 3,
15) and received a median of 17 doses of nivolumab (range: 3, 48). Single-agent nivolumab produced a 65 percent ORR (95% CI: 55%, 75%), with 58 percent partial remission and 7 percent complete remission. The median time-to-response was 2.1 months (range: 0.7 to 5.7 months). The estimated median DOR was 8.7 months.
Safety was evaluated in 263 patients with relapsed or refractory cHL. Ninety-eight percent of patients had received autologous HSCT. Patients received a median of 10 doses of nivolumab (range:
1, 48) at the approved dose-schedule. The most common (reported in at least 20%) adverse reactions of any grade were fatigue, upper respiratory tract infection, cough, pyrexia, and diarrhea. Additional common adverse reactions (reported in at least 10%) included rash, pruritus, musculoskeletal pain, nausea, vomiting, abdominal pain, headache, peripheral neuropathy, arthralgia, dyspnea, infusion-related reactions, and hypothyroidism or thyroiditis.
Other immune-mediated adverse reactions, occurring in 1-5 percent of patients included rash, pneumonitis, hepatitis, hyperthyroidism, and colitis. Serious adverse reactions were reported in 21 percent of patients. The most common SAEs, reported in 1-3 percent of patients were pneumonia, pleural effusion, pneumonitis, pyrexia, infusion-related reaction, and rash.
A new "Warning and Precaution" was issued for complications of allogeneic HSCT after nivolumab. Transplant related deaths have occurred, and health care professionals should follow patients closely for early evidence of transplant-related complications, such as hyper-acute
graft-versus-host disease (GVHD), severe acute GVHD, steroid-requiring febrile syndrome, hepatic veno- occlusive disease, and other immune-mediated adverse reactions. The FDA has required the
manufacturer to further study the safety of allogeneic HSCT after nivolumab.
The recommended dose schedule of nivolumab is 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity. Continued approval for the cHL indication may be contingent upon verification of clinical benefit through a randomized phase III trial.