Nivolumab might be a new treatment option for a patient population with a high unmet need [patients with classical Hodgkin lymphoma after failure of both ASCT and brentuximab vedotin]. Ongoing follow-up will help to assess the durability of response.— Anas Younes, MD, and colleagues
In a phase II trial reported in The Lancet Oncology by Anas Younes, MD, of Memorial Sloan Kettering Cancer Center, and colleagues, treatment with the anti–PD-1 (programmed cell death protein 1) immune checkpoint inhibitor nivolumab (Opdivo) produced response in two-thirds of patients with classical Hodgkin lymphoma after failure of both autologous stem cell transplantation (ASCT) and brentuximab vedotin (Adcetris).1 Malignant cells in classical Hodgkin lymphoma feature alterations at 9p24.1, which result in overexpression of PD-1 ligand (PD-L1) and evasion of immune surveillance.
In this ongoing single-arm study, 80 adults with recurrent disease who had failed to respond to ASCT and had either relapsed after or failed to respond to brentuximab vedotin were enrolled between August 2014 and February 2015 from 34 sites in Europe and North America. Nivolumab treatment consisted of a 3-mg/kg infusion over 60 minutes every 2 weeks until disease progression, death, unacceptable toxicity, or withdrawal from the study. The primary endpoint was objective response at a prespecified minimum follow-up of 6 months, as assessed by an independent radiologic review committee.
Patients had a median age of 37 years (9% ≥ 60 years); 64% were male; Eastern Cooperative Oncology Group performance status was 0 for 53% and 1 for 48%; disease stage was I in 1%, II in 14%, III in 18%, and IV in 68%; 23% had B symptoms at baseline; the median number of prior lines of treatments was four, with 49% receiving at least five lines; 74% received prior radiation therapy, and 93% had one and 8% had two prior ASCTs; 100% had brentuximab vedotin treatment after ASCT, 54% had no response to previous brentuximab vedotin, and 11% had at least one line of brentuximab vedotin; and time from completion of most recent regimen to nivolumab treatment was < 3 months for 55%, 3 to 6 months for 23%, and > 6 months for 23%.
Nivolumab treatment produced an objective response in 66% of patients with classical Hodgkin lymphoma after failure of both ASCT and brentuximab vedotin on independent review.
Estimated median duration of response was 7.8 months, although most responders continued to have a response at the time of analysis.
Responses and Survival
Median follow-up was 8.9 months (interquartile range = 7.8–9.9 months). Objective response by independent radiologic review committee was observed in 53 patients (66.3%, 95% confidence interval [CI] = 54.8%–76.4%), including complete remission in 9%. Median time to response was 2.1 months, with 31 of 53 responses (58%) observed at the first scan at 9 weeks. The independent radiologic review committee estimated median duration of response was 7.8 months (95% CI = 6.6 months to not reached) on the current analysis; as of the cutoff for the current analysis, 33 responders (62%) had continued response, with 20 having response of ≥ 4 months. Post-hoc analysis among 43 patients with no response to the most recent brentuximab vedotin treatment showed an independent radiologic review committee response in 31 patients (72%). On investigator assessment, objective response was achieved in 58 patients (72.5%), with complete remission in 28%. Estimated median duration of response was 9.1 months, although 37 of 58 responders still on treatment were censored prior to the median.
Independent radiologic review committee 6-month progression-free survival was 76.9% (95% CI = 64.9%–85.3%), and overall survival was 98.7% (95% CI = 91.0%–99.8%). At 12 months, 24 events (23 progressions and 1 death) had been reported, with median progression-free survival of 10.0 months (95% CI = 8.41 months to not reached).
The most common drug-related adverse events of any grade were fatigue (25%), infusion-related reaction (20%), and rash (16%). The most common drug-related grade 3 or 4 adverse events were neutropenia (5%) and increased lipase (5%). Serious adverse events were reported in 25% of patients, with the most common being pyrexia (4%). Pneumonitis occurred in two patients (3%). Infusion was interrupted due to hypersensitivity reaction in 6% of patients. Cycle delay occurred in 60% of patients, with 55% of delays being due to adverse events. Treatment was discontinued due to adverse events in 5% of patients. Three patients died during the study, with none of the deaths considered related to study treatment.
The investigators concluded: “Nivolumab resulted in frequent responses with an acceptable safety profile in patients with classical Hodgkin’s lymphoma who progressed after autologous stem-cell transplantation and brentuximab vedotin. Therefore, nivolumab might be a new treatment option for a patient population with a high unmet need. Ongoing follow-up will help to assess the durability of response.” ■
Disclosure: The study was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit www.thelancet.com.
1. Younes A, Santoro A, Shipp M, et al: Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: A multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. July 20, 2016 (early release online).