Robert Chen, MD
Craig H. Moskowitz, MD
AS REPORTED in the Journal of Clinical Oncology by Robert Chen, MD, of City of Hope National Medical Center, and colleagues, 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/ refractory classical Hodgkin lymphoma.1 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 (PD-L1) and PD-L2.
Craig H. Moskowitz, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
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 transplant and subsequent brentuximab vedotin (Adcetris; n = 69), salvage chemotherapy and brentuximab vedotin (ineligible for autologous transplant due to chemoresistant disease; n = 81), and autologous transplant but 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, 54% were male, 99% had an Eastern Cooperative Oncology Group performance status of 0 or 1, median number of lines of prior systemic therapy was 4, 100% had refractory disease or relapsed after ≥ 3 lines of therapy, 36% had undergone prior radiotherapy, 9% had bulky lymphadenopathy, 32% had B symptoms at baseline, and 83% had received 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 complete response in 47 (22.4%, 95% CI = 16.9%–28.6%). Response rates were 73.9% in patients with progression after stem cell transplant and subsequent brentuximab vedotin, 64.2% in those with progression after salvage chemotherapy and brentuximab vedotin, and 70.0% in those with progression after transplant without subsequent brentuximab vedotin.
“Pembrolizumab was associated with high response rates and an acceptable safety profile in patients with [relapsed/refractory classic Hodgkin lymphoma], offering a new treatment paradigm for this disease.”— Robert Chen, MD, and colleagues
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Response rates were 71.4% in 28 patients with < 3 prior lines of therapy and 68.7% in 182 with ≥ 3 prior lines of therapy; 79.5% in 73 who were refractory to first-line therapy; 64.2% in 81 refractory to front-line therapy, salvage therapy, and brentuximab vedotin; 56.5% in 23 refractory to all previous lines of therapy; and 71.4% in 35 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 with disease refractory to ≥ 1 previous line.
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).2
At 6 months, the progression-free survival rate was 72.4%, and the overall survival rate 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 a 9-month progression-free survival of 63.4% and a 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 9 patients (4.3%), due to myocarditis, myelitis, myositis, pneumonitis, infusion-related reactions, and cytokine-release syndrome, and treatment interruption in 12% of the patients. 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 classic 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.” ■
DISCLOSURE: The study was supported by Merck. For full disclosures of the study authors, visit ascopubs.org.
1. 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. April 25, 2017 (early release online).
2. Keytruda (pembrolizumab) injection prescribing information, Merck Sharp & Dohme Corp, March 2017. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s015lbl.pdf. Accessed June 20, 2017.