High Response Rates Achieved with Pembrolizumab in Refractory Hodgkin Lymphoma

Robert W. Chen, MD

Pembrolizumab (Keytruda) is associated with an exceptional overall response rate (ORR) in patients with relapsed/refractory Hodgkin lymphoma.

Data from the phase 2 KEYNOTE-087 study showed ORRs of about 70-80% in 3 separate cohorts of relapsed/refractory Hodgkin lymphoma patients, including patients who relapsed after treatment with brentuximab vedotin, patients who failed to respond to brentuximab, patients who relapsed or progressed after autologous stem cell transplant (ASCT), and those ineligible for ASCT, said Robert W. Chen, MD, at the 2016 ASCO Annual Meeting.

KEYNOTE-087 was a multicenter, single-arm, nonrandomized study of pembrolizumab in 3 cohorts of patients with relapsed/refractory NHL. Cohort 1 included patients who failed to achieve a response to, or progressed after ASCT, and relapsed after treatment with or failed to respond to brentuximab post ASCT. Cohort 2 included patients who were unable to achieve a complete response (CR) or partial response (PR) to salvage chemotherapy and did not receive ASCT, but relapsed after treatment with or failed to respond to brentuximab. Finally, cohort 3 included patients who failed to achieve a response to or progressed after ASCT and did not receive brentuximab post ASCT.

Study participants were treated with pembrolizumab, 200 mg intravenously every 3 weeks on day 1 of each 21-day treatment cycle for up to 24 months. A flat dose was chosen because of the flat exposure-response relationship for efficacy and safety in the 2 mg/kg to 10 mg/kg dosage range across prior clinical studies.

A prespecified interim analysis, based on investigator-assessed response, was performed after 30 patients reached first response assessment in all 3 cohorts. The percentage of patients receiving greater than 3 prior lines of therapy was 73% in cohort 1, 60% in cohort 2, and 37% in cohort 3. The median number of lines of system therapy was 5, 4, and 3 in each cohort, respectively. By design, all patients in cohorts 1 and 2 had prior brentuximab failure, as did 40% in cohort 3.

The best ORRs by investigator review were 73% in cohort 1, 83% in cohort 2, and 73% in cohort 3. The ORR was 78% in the 37 patients with primary refractory disease. A CR as best response was observed in 27%, 30%, and 30% in cohorts 1, 2, and 3, respectively, and was 35% in patients with primary refractory disease. Most responses occurred at the first assessment at 12 weeks.

“About 90% of patients in each cohort had a reduction in tumor size from baseline,” said Chen, assistant professor of medicine, City of Hope National Medical Center. Fifty-three patients remained on treatment at the time of the interim analysis.

With a median of 9 treatment cycles, the most common adverse events in the combined cohorts were pyrexia (13%), diarrhea (10%), and neutropenia, fatigue, and cough (8% each). In addition, 7% of patients experienced hypothyroidism, 6% suffered from dry skin, and 6% had nausea. There were 8 grade 3/4 treatment-related adverse events in 4 patients. One patient with an infusion-related reaction and one with pneumonitis discontinued pembrolizumab.

The prognosis is poor for patients with Hodgkin lymphoma who relapse after ASCT or progress after brentuximab treatment, said Chen.

Because the PD-1 ligands PD-L1 and PD-L2 are often overexpressed in relapsed/refractory Hodgkin lymphoma, treatment with pembrolizumab, a humanized monoclonal antibody against PD-1 that prevents binding to PD-L1 and PCD-L2, is anticipated to offer antitumor activity in this patient population. In a prior phase Ib study, KEYNOTE-013, pembrolizumab demonstrated an ORR of 65% in patients with heavily pretreated classical Hodgkin lymphoma.

A phase III trial comparing pembrolizumab with brentuximab is being conducted in brentuximab-naïve chemorefractory patients and in those in whom ASCT has failed, said Chen.

The appropriate duration of treatment for patients with relapsed/refractory Hodgkin lymphoma who achieve CR with anti-PD-1 agents is not clear, said Nancy Bartlett, MD, Professor, Division of Oncology, Department of Medicine, Washington University.

“To be able to supply an answer, the retreatment response rate must be known, and if the retreatment response rate is high, we could consider intermittent treatment like we do with rituximab in low-grade lymphoma,” she said.

The other possibility would be to consider a less frequent maintenance schedule.

The ability to incorporate pembrolizumab and other anti-PD-1 agents such as nivolumab into earlier lines of therapy, especially in high-risk patients, is an intriguing possibility, she added. These high-risk patients could include older patients, those with a positive interim positron emission tomography scan, and those with amplification of 9p24.1. In a series of newly diagnosed patients with Hodgkin lymphoma, amplification of 9p24.1 was associated with shorter PFS and advanced stage, she said.

In addition, she added that rational immunotherapy combinations in post-transplant failures has “exciting potential.”

Chen RW, Zinzani PL, Fanale MA. Pembrolizumab for relapsed/refractory classical Hodgkin lymphoma (R/R cHL): phase 2 KEYNOTE-087 study. Presented at: ASCO 2016; June 3-7, 2016; Chicago. Abstract 7555.

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