The FDA has approved pembrolizumab (Keytruda, Merck) for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after two or more prior lines of therapy. The indication is approved under the FDA’s accelerated approval regulations based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. pembrolizumab is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy. With this indication, pembrolizumab becomes the first anti-PD-1 therapy to be approved for the treatment of PMBCL, a type of non-Hodgkin’s lymphoma. This is the second indication for pembrolizumab for the treatment of a hematologic malignancy.
The approval was based on data from KEYNOTE-170, a multicenter, open-label, single-arm trial evaluating pembrolizumab in 53 patients with relapsed or refractory PMBCL. Patients were not eligible for the trial if they had active noninfectious pneumonitis, allogeneic HSCT within the past five years (or greater than five years but with symptoms of graft versus host disease), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy. Patients received pembrolizumab 200 mg every three weeks until unacceptable toxicity or documented disease progression, or for up to 24 months for patients who did not progress. Disease assessments were performed every 12 weeks and assessed by blinded independent central review according to the 2007 revised International Working Group criteria. Efficacy was based on overall response rate (ORR) and duration of response (DOR).
Among the 53 patients accrued in KEYNOTE-170, the baseline characteristics were: median age of 33 years (range, 20–61 years); 43% were male; 92% were white; 43% had an ECOG performance status (PS) of 0, and 57% had an ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of PMBCL was three (range, 2–8). Thirty-six percent had primary refractory disease, 49% had relapsed disease refractory to the last prior therapy, and 15% had untreated relapse. Twenty-six percent of patients had undergone prior autologous HSCT, and 32% of patients had prior radiation therapy. All patients had received rituximab (Rituxan, Genentech) as part of a prior line of therapy.
In KEYNOTE-170, the ORR was 45%, with a complete response rate (CRR) of 11% and a partial response rate of 34%. Median DOR, based on 24 patients who responded, was not reached (range, 1.1+ to 19.2+ months). For the 24 responders, the median time to first objective response (complete or partial response) was 2.8 months (range, 2.1–8.5 months). Median follow-up time was 9.7 months.
Among the 53 patients with PMBCL treated in KEYNOTE-170, pembrolizumab was discontinued due to adverse reactions in 8% of patients, and treatment was interrupted due to adverse reactions in 15%. Twenty-five percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 26% of patients, and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (occurring in 20% or greater of patients) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).
There is limited experience with pembrolizumab in pediatric patients. Efficacy for pediatric patients with PMBCL was extrapolated from the results in the adult PMBCL population. In a study of 40 pediatric patients with advanced melanoma, lymphoma, or PD-L1-positive advanced, relapsed, or refractory solid tumors, patients were administered pembrolizumab 2 mg/kg every three weeks. Patients received pembrolizumab for a median of three doses (range, 1–17 doses), with 34 patients (85%) receiving pembrolizumab for two doses or more. The safety profile in these pediatric patients was similar to that seen in adults treated with pembrolizumab. Toxicities that occurred at a higher rate (15% or greater difference) in pediatric patients when compared with adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).
Source: Merck; June 13, 2018.