Approval was based on data from 210 adult cHL patients enrolled in a multicenter, non-randomized, open-label clinical trial. Patients had refractory or relapsed disease after autologous stem cell transplantation (ASCT; 129 patients) and/or brentuximab vedotin (175 patients), and received a median of four prior systemic therapies (range: 1, 12). With a median follow-up of 9.4 months (range: 1-15), the overall response rate was 69% (95% CI: 62, 75). This included partial responses in 47% of patients and complete responses in 22%. The estimated median response duration was 11.1 months (range 0+ to 11.1). Efficacy in pediatric patients was extrapolated from results observed in adults.
Safety was evaluated in 210 adults with cHL. In adults, the most common (at least 20%) adverse reactions were fatigue, pyrexia, cough, musculoskeletal pain, diarrhea, rash and hypertransaminasemia. Additional common adverse reactions (at least 10%) included dyspnea, arthralgia, vomiting, nausea, pruritus, hypothyroidism, upper respiratory tract infections, headache, peripheral neuropathy, hyperbilirubinemia and increased creatinine. Other immune-mediated adverse reactions occurring in 0.5%-9% of patients included infusion reactions, hyperthyroidism, pneumonitis, uveitis, myositis, myelitis and myocarditis. Fifteen percent had an adverse reaction requiring systemic corticosteroid therapy. Pembrolizumab was discontinued due to adverse reactions in 5% of patients, and treatment was interrupted due to adverse reactions in 26%.
Safety was also evaluated in 40 children with advanced melanoma, PD-L1 positive solid tumors, or lymphoma. The safety profile in the pediatric patients was similar to that observed in adults. Adverse reactions occurring at a higher rate (difference of 15% or greater) in children than adults included fatigue, vomiting, abdominal pain, hypertransaminasemia and hyponatremia. Pembrolizumab exposure in these pediatric patients at a dose of 2 mg/kg every 3 weeks was comparable to that seen in adults. FDA has required the sponsor to evaluate pembrolizumab’s long-term safety in pre-pubertal patients, and those who have not completed pubertal development.
A new “Warning and Precaution” was added for complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT) after pembrolizumab. Transplant-related deaths have occurred, and health care professionals should follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host-disease (GVHD), severe (grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions. FDA has required the sponsor to further study the safety of allogeneic HSCT after pembrolizumab therapy.
The recommended dose and schedule of pembrolizumab for cHL is 200 mg every 3 weeks for adults and 2 mg/kg (up to 200 mg) every 3 weeks for pediatric patients.
Full prescribing information for pembrolizumab is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s015lbl.pdf
FDA granted pembrolizumab Orphan Drug Designation for the treatment of HL, and Breakthrough Therapy Designation for the current indication. This application also received priority review status and accelerated approval. Further studies are required to confirm clinical benefit of pembrolizumab for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).