High Response Rates Seen With Immunotherapy in Early Study of Hodgkin Lymphoma

Keytruda (pembrolizumab) is associated with an exceptional overall response rate in patients with relapsed/refractory Hodgkin lymphoma, according to data from a phase 2 study.

Data from the KEYNOTE-087 study showed overall response rates of about 70 to 80 percent in three separate groups of relapsed/refractory Hodgkin lymphoma patients, including patients who relapsed after treatment with Adcetris (brentuximab vedotin), patients who failed to respond to Adcetris, patients who relapsed or progressed after autologous stem cell transplant (ASCT), and those ineligible for ASCT, said Robert W. Chen. Chen presented these data during the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO), a gathering of 30,000 oncology professionals in Chicago.

In the study, 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 Adcetris post ASCT. Cohort 2 included patients who were unable to achieve a complete response or partial response (PR) to salvage chemotherapy and did not receive ASCT, but relapsed after treatment with or failed to respond to Adcetris. Finally, cohort 3 included patients who failed to achieve a response to or progressed after ASCT and did not receive Adcetris post ASCT.

Study participants were treated with Keytruda, 200 mg intravenously every three 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 three cohorts. The percentage of patients receiving greater than three prior lines of therapy was 73 percent in cohort 1, 60 percent in cohort 2 and 37 percent in cohort 3. The median number of lines of systemic therapy was five, four and three in each cohort, respectively. By design, all patients in cohorts 1 and 2 had prior Adcetris failure, as did 40 percent in cohort 3.

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

“About 90 percent 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 nine treatment cycles, the most common adverse events in the combined cohorts were pyrexia (13 percent), diarrhea (10 percent), and neutropenia, fatigue and cough (8 percent each). In addition, 7 percent of patients experienced hypothyroidism, 6 percent suffered from dry skin and 6 percent had nausea. There were eight grade 3/4 treatment-related adverse events in four patients. One patient with an infusion-related reaction and one with pneumonitis discontinued Keytruda.

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

“[Adcetris] was approved five years ago for R/R Hodgkin lymphoma, but since then there has been no other therapy,” said Chen.

Because the PD-1 ligands PD-L1 and PD-L2 are often overexpressed in relapsed/refractory Hodgkin lymphoma, treatment with Keytruda, 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 1b study, KEYNOTE-013, Keytruda demonstrated an overall response rate of 65 percent in patients with heavily pretreated classical Hodgkin lymphoma.

A phase 3 trial comparing Keytruda with Adcetris is being conducted in Adcetris-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 complete response with anti-PD-1 agents is not clear, said Nancy Bartlett, 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 Keytruda 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.