As reported in the Journal of Clinical Oncology by Chen et al, the phase II KEYNOTE-087 trial has shown that the programmed cell death protein 1 (PD-1)–inhibitor pembrolizumab (Keytruda) is highly active in patients with relapsed or refractory classical Hodgkin lymphoma. Findings in the study supported the March 2017 accelerated approval of pembrolizumab for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma or those who have relapsed after at least three prior lines of therapy. Hodgkin Reed-Sternberg cells contain chromosomal alterations that induce overexpression of programmed cell death ligand 1 and 2 (PD-L1/L2).
In the trial, 210 patients enrolled from 51 sites worldwide between June 2015 and March 2016 received pembrolizumab at 200 mg once every 3 weeks. Patients were categorized on the basis of lymphoma progression after autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (Adcetris; n = 69), salvage chemotherapy and brentuximab vedotin (ineligible for ASCT due to chemoresistant disease; n = 81), and ASCT without subsequent brentuximab vedotin (n = 60). Response was assessed every 12 weeks. The primary endpoints were objective response rate on central review and safety.
Among all patents, median age was 35 years (range = 18–76 years; 9% ≥ 65 years), 54% were male, 99% had an Eastern Cooperative Oncology Group performance status of 0 or 1, the median number of lines of prior systemic therapy was 4 (range = 1–12; 87% ≥ 3 lines), 100% had refractory disease or relapsed after ≥ 3 lines of therapy, 36% had prior radiotherapy, 9% had bulky lymphadenopathy, 32% had B symptoms at baseline, and 83% had prior brentuximab vedotin treatment.
At the time of analysis, patients had received a median of 13 treatment cycles. Among all patients, objective response was observed in 145 patients (69.0%, 95% confidence interval [CI] = 62.3%–75.2%), with a complete response in 47 (22.4%, 95% CI = 16.9%–28.6%). Response rates were 73.9% in patients with disease progression after ASCT and subsequent brentuximab vedotin, 64.2% in those with disease progression after salvage chemotherapy and brentuximab vedotin, and 70.0% in those with disease progression after ASCT without subsequent brentuximab vedotin.
The response rates were 71.4% in 28 patients with < 3 prior lines of therapy and 68.7% in 182 patients with ≥ 3 prior lines of therapy; 79.5% in 73 patients whose disease was refractory to first-line therapy; 64.2% in 81 patients whose disease was refractory to front-line therapy, salvage therapy, and brentuximab vedotin; 56.5% in 23 patients whose disease was refractory to all previous lines of therapy; and 71.4% in 35 patients who had not previously received brentuximab vedotin. Response rates were 67.8% in 146 patients with relapse after ≥ 3 lines of therapy and 71.2% in 170 patients whose disease was refractory to ≥ 1 previous line.
The median duration of response was not reached among all patients or in any of the three cohorts. Product labeling indicates an estimated median duration of response of 11.1 months (range = 0+ to 11.1 months) after a median follow-up of 9.4 months (range = 1–15 months). At 6 months, progression-free survival was 72.4% and overall survival was 99.5%. An ad hoc analysis performed with 46% of patients still receiving pembrolizumab at a data cutoff in December 2016 showed that median overall survival was not reached, with 9-month progression-free survival of 63.4% and 9-month overall survival of 97.5%.
With a median of 13 treatment cycles, the most common adverse events of any grade were pyrexia (24%), cough (21%), and fatigue (20%), with the most common grade 3 or 4 events being anemia (3.8%) and neutropenia (2.9%). The most common treatment-related adverse events were hypothyroidism (12%) and pyrexia (11%), with the most common grade 3 or 4 events being neutropenia (2.4%), dyspnea (1.0%), and diarrhea (1.0%). Immune-mediated adverse events or infusion-related reactions occurred in 29% of patients, with hypothyroidism (14%) being the most common immune-mediated event. Treatment-related adverse events resulted in discontinuation of pembrolizumab in nine patients (4.3%; due to myocarditis, myelitis, myositis, pneumonitis, infusion-related reactions, cytokine-release syndrome) and treatment interruption in 12%. Death occurred in two patients during follow-up, due to septic shock and acute graft-vs-host disease, with neither death considered to be related to treatment.
The investigators concluded: “Pembrolizumab was associated with high response rates and an acceptable safety profile in patients with [relapsed/refractory classical Hodgkin lymphoma], offering a new treatment paradigm for this disease.” They noted: “[P]embrolizumab showed excellent results in both relapsed and refractory patients and was well tolerated at a fixed dose, consistent with prior pembrolizumab clinical experience in oncology patients. A randomized phase III study to compare pembrolizumab with [brentuximab vedotin] in patients with [relapsed/refractory disease] has been initiated.”
The study was supported by Merck.
Craig H. Moskowitz, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.
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