FDA Approves Pembrolizumab for Relapsed or Refractory Classical Hodgkin Lymphoma in Adult and Pediatric Patients
The U.S. Food and Drug Administration (FDA) has approved pembrolizumab (Keytruda), an anti–PD-1 (programmed cell death protein 1) therapy, for the treatment of adult and pediatric patients who have refractory classical Hodgkin lymphoma or have relapsed after three or more prior lines of therapy. Under the FDA’s accelerated approval regulations, this indication is approved 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 the confirmatory trials. In refractory or relapsed classical Hodgkin lymphoma, pembrolizumab is approved for use in adult patients at a fixed dose of 200 mg and in pediatric patients at a dose of 2 mg/kg (up to a maximum of 200 mg). Pembrolizumab is administered intravenously every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
“The results from KEYNOTE-087 showed that most patients with relapsed or refractory classical Hodgkin lymphoma responded to treatment with pembrolizumab, and 22% experienced complete remission,” said Roger M. Perlmutter, MD, PhD, President, Merck Research Laboratories. “Today’s approval—the first for pembrolizumab in a hematologic malignancy—reinforces the hope that immunotherapy will prove useful in a wide variety of cancers.”
“For the patients with classical Hodgkin lymphoma who are not cured with existing treatments, there are limited options, and treating their disease becomes more challenging,” said Craig Moskowitz, MD, Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center. “This approval is an important step forward in treating these patients, who are generally young and have a particularly poor prognosis, and gives us the opportunity to help patients in their fight against this devastating disease.”
KEYNOTE-087 Data Supporting the Approval
The accelerated FDA approval was based on data in 210 patients with relapsed or refractory classical Hodgkin lymphoma enrolled in the multicenter, nonrandomized, open-label KEYNOTE-087 study. Patients with active, noninfectious pneumonitis; an allogeneic hematopoietic stem cell transplantation within the past 5 years (or greater than 5 years but with symptoms of graft-vs-host disease; active autoimmune disease; a medical condition that required immunosuppression; or an active infection requiring systemic therapy were ineligible for the trial.
Patients received pembrolizumab at a dose of 200 mg every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients who did not progress. The major efficacy outcome measures (overall response rate [ORR], complete remission rate [CRR], and duration of response) were assessed by blinded independent central review according to the 2007 revised International Working Group (IWG) criteria.
Overall, 58% of patients were refractory to the last prior therapy, including 35% with primary refractory disease and 14% whose disease was chemorefractory to all prior regimens. Additionally, 61% of patients had undergone prior autologous stem cell transplant, 17% had no prior brentuximab (Adcetris) use, and 36% had prior radiation therapy.
Of 210 patients in the trial, the overall response rate with pembrolizumab (200 mg every 3 weeks) was demonstrated to be 69% (95% confidence interval [CI] = 62%–75%) with a complete remission rate of 22% and a partial remission rate of 47%. The median follow-up time was 9.4 months. Among the 145 responding patients, the median duration of response was 11.1 months (range, 0.0+ to 11.1 months).
Adverse Reactions
Pembrolizumab was discontinued due to adverse reactions in 5% of 210 patients with classical Hodgkin lymphoma, and treatment was interrupted due to adverse reactions in 26% of patients. Fifteen percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 16% of patients.
The most frequent serious adverse reactions (≥ 1%) included pneumonia, pneumonitis, pyrexia, dyspnea, graft-vs-host disease, and herpes zoster. Two patients died from causes other than disease progression; one from graft-vs-host disease after subsequent allogeneic stem cell transplant and one from septic shock. The most common adverse reactions (occurring in ≥ 20% of patients) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).
There is limited experience with the drug in pediatric patients. Efficacy for pediatric patients was extrapolated from the results in the adult classical Hodgkin lymphoma population. In a study of 40 pediatric patients with advanced melanoma, programmed cell death ligand 1–positive advanced, relapsed, or refractory solid tumors or lymphoma, patients were treated with pembrolizumab for a median of 43 days (range, 1–414 days), with 24 patients (60%) receiving treatment for 42 days or more. The safety profile in pediatric patients was similar to that seen in adults treated with pembrolizumab. Toxicities that occurred at a higher rate (≥ 15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).
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