EMA Recommends Approval of Pembrolizumab for Hodgkin Lymphoma

Roger Dansey, MD

Roger Dansey, MD

Pembrolizumab (Keytruda) has been recommended for approval by the EMA’s Committee for Medicinal Products for Human Use (CHMP) for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) who have progressed following autologous stem cell transplant (ASCT) and brentuximab vedotin, or who are transplant-ineligible and have failed brentuximab vedotin.

The recommendation is based on results from the phase II KEYNOTE-087¹and phase Ib KEYNOTE-013²trials. In KEYNOTE-087, at a median follow-up of 9.4 months, the overall response rate (ORR) with the PD-1 inhibitor pembrolizumab was 69% (95% CI, 62-75). The ORR included complete responses (CRs) in 22% of patients and partial responses (PRs) in 47% of patients. The median duration of response was 11.1 months (range, 0+ to 11.1) among the 145 responding patients.

The positive opinion will now be reviewed by the European Commission and a final approval decision for use in the European Union is expected in about 2 months. In the United States, pembrolizumab was approved by the FDA earlier this month for the treatment of adult and pediatric patients with cHL who are refractory or have relapsed after 3 or more lines of therapy.

“This CHMP positive recommendation brings us one step closer to offering appropriate patients in the European Union with classical Hodgkin lymphoma a new treatment option to help fight this hematologic cancer,” Roger Dansey, MD, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories, the manufacturer of pembrolizumab, said in a statement.

The KEYNOTE-087 trial included 210 adult patients with relapsed/refractory cHL. The median age was 35 (range, 18-76) and 9% of patients were older than 65. Fifty-four percent of patients were male and 88% were white. The ECOG performance status was 0 for 49% of patients and 1 for 51% of patients.

The median number of prior therapies was 4 (range, 1-12) and 58% of patients were refractory to their last prior therapy, including 35% with primary refractory disease and 14% with cHL that was chemorefractory to all prior regimens. Prior treatment included autologous hematopoietic stem cell transplantation (61%), brentuximab vedotin (83%), and radiation therapy (36%).

Pembrolizumab was administered at 200 mg every 3 weeks until disease progression, unacceptable toxicity, or up to 2 years in patients who did not progress. Patients were assessed every 12 weeks to determine the status of their disease.

The most common adverse events were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%). Adverse events occurring in at least 10% of patients included dyspnea, arthralgia, vomiting, nausea, pruritus, hypothyroidism, upper respiratory tract infections, headache, peripheral neuropathy, hyperbilirubinemia and increased creatinine.

Serious adverse reactions occurred in 16% of patients. The most frequent serious adverse events included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Adverse events requiring corticosteroid therapy occurred in 15% of patients.

Adverse reactions led to discontinuations and treatment interruptions in 5% and 26% of patients, respectively. There were 2 patient deaths that were both unrelated to disease: 1 patient died of septic shock and 1 patient died of GVHD after subsequent allogeneic hematopoietic stem cell transplantation.

In the KEYNOTE-013 study, patients received pembrolizumab at 10 mg/kg every 2 weeks for up to 2 years. Sixty-eight percent of patients had received ≥4 prior lines of therapy and 71% had failed prior ASCT. All patients had progressed on prior brentuximab vedotin.

The ORR of 64.5% included 5 CRs (16.1%) and 15 PRs (48.4%). Additionally, 23% of patients experienced stable disease with pembrolizumab. After a median of 9.7 months of follow-up, median duration of response was not yet reached (range, 0-13.4+ months), with most responses (n = 14) ongoing at the time of the analysis. At the data cutoff, 45% of patients remained on therapy.

The most common treatment-related all-grade AEs were hypothyroidism (16%), diarrhea (13%), nausea (13%), and pneumonitis (10%). Five patients had grade 3 AEs; however, no grade 4 events or treatment-related deaths occurred. Altogether, 2 patients (6%) discontinued therapy due to AEs.

References:

1. Chen RW, Zinzani PL, Fanale MA, et al. Pembrolizumab for relapsed/refractory classical Hodgkin lymphoma (R/R cHL): phase 2 KEYNOTE-087 study.J Clin Oncol34, 2016 (suppl; abstr 7555).
2. Armand P, Shipp MA, Ribrag V, et al. PD-1 Blockade with Pembrolizumab in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Safety, Efficacy, and Biomarker Assessment. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 680. (suppl; abstr 7555).