Though the standard of care for patients with relapsed/refractory classic Hodgkin lymphoma (cHL) induces high rates of response, duration of response is estimated to be only 6 months. Failure of these therapies (which include salvage chemotherapy, autologous hematopoietic cell transplantation (AHCT), and brentuximab vedotin [BV]) leave few subsequent treatment options.
The U.S. Food and Drug Administration approved pembrolizumab in March 2017 for adults and children with relapsed/refractory cHL, based on results from the multicenter, single-arm, phase II KEYNOTE-087 trial. Patients treated with the PD-1 inhibitor had an overall response rate of 69 percent, with the benefit persisting across subgroups of patients with varying degrees of prior therapies and transplant status, according to an analysis published in the Journal of Clinical Oncology by Robert Chen, MD, from the City of Hope National Medical Center in Duarte, California, and colleagues.
The researchers evaluated the clinical activity of pembrolizumab in 210 patients (median age = 35 years; range = 18-76 years) enrolled in KEYNOTE-087 who "represented the spectrum of relapsed/refractory disease" and had disease progression after:
- AHCT and subsequent BV (cohort 1; n=69)
- salvage chemotherapy and BV (cohort 2; n=81)
- AHCT, not including BV after transplantation (cohort 3; n=60)
All patients had relapsed or refractory cHL after a median of four lines of therapy (range = 1-12 therapies), an Eastern Cooperative Oncology Group performance status score of 0-1, and adequate organ function. Patients were excluded from the trial if they had received immunosuppressive therapy within 7 days of the study; a monoclonal antibody within 4 weeks of the study; chemotherapy, targeted small-molecule therapy, or radiation therapy within 2 weeks of the study; or allogeneic HCT within 5 years of the study.
Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 2 years or until disease progression, intolerable toxicity, or investigator decision.
At data cutoff (September 25, 2016), 120 patients were still receiving pembrolizumab, with a median treatment exposure of 8.3 months (range = 0.03-14.99 months).
After a median of 13 treatment cycles (range = 1-21), the objective response rate (ORR; primary endpoint) was 69 percent (95% CI 62.3-75.2), which included a complete remission rate of 22.4 percent (95% CI 16.9-28.6) and a partial remission rate of 46.7 percent:
- 73.9% in cohort 1 (95% CI 61.9-83.7)
- 64.2% in cohort 2 (95% CI 52.8-74.6)
- 70.0% in cohort 3 (95% CI 56.8-81.2)
In an analysis of the 73 patients who were refractory to firstline therapy, the ORR was 79.5 percent (95% CI 68.4-88.0). The ORR in patients who had not previously received BV (n=35) was also high, at 71.4 percent (95% CI 53.7-85.4).
The median duration of response was not reached at data cutoff, and most patients (n=31; 75.6%) had a sustained response at ≥6 months. At 6 months, rates of overall survival (OS) and progression-free survival (PFS) were 99.5 and 72.4 percent, respectively. Fourteen patients went on to receive HCT (10 allogeneic HCT and 4 AHCT).
The most common treatment-related adverse events (AEs) were hypothyroidism (12.4%) and pyrexia (10.5%), and the most common grade 3/4 AEs were neutropenia (2.4%), dyspnea (1%), and diarrhea (1%). Sixty patients (28.6%) reported immune-mediated AEs and infusion-related reactions (IRRs).
Nine patients (4.3%) discontinued treatment because of AEs (including myocarditis, myelitis, myositis, pneumonitis, IRRs, and cytokine release syndrome), and 26 patients (12.4%) experienced AEs that resulted in dose interruptions. Two patients died during follow-up, but the deaths were deemed unrelated to pembrolizumab.
"The existing data suggest 200 mg every 3 weeks as the optimal dose for pembrolizumab," the researchers wrote. "This fixed dose is associated with a low rate of discontinuation as a result of AEs and an acceptable safety profile, which differs from the safety profile of current cytotoxic therapies for cHL and BV."
The study is limited by its short duration of follow-up, which "precluded the accurate estimation of OS and PFS," and response duration, the authors noted. A phase III study comparing pembrolizumab and BV in relapsed/refractory HL is also ongoing.
The study was designed by representatives of Merck, which sponsored the study and is the manufacturer of pembrolizumab.
Drs. Chen, Zinzani, and Fanale report financial relationships with Merck.
Reference
Chen R, Zinzani PL, Fanale MA, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol. 2017 April 25. [Epub ahead of print]
