The FDA has granted an accelerated approval to pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with classical Hodgkin lymphoma (cHL) who are refractory or have relapsed after 3 or more lines of therapy.
The approval is based on data from the nonrandomized, open-label KEYNOTE-087 trial, in which, at a median follow-up of 9.4 months, the overall response rate (ORR) with pembrolizumab was 69% (95% CI, 62-75). The ORR included complete responses in 22% of patients and partial responses in 47% of patients. The median duration of response was 11.1 months (range, 0+ to 11.1) among the 145 responding patients.
The specific pembrolizumab regimens approved are 200 mg every 3 weeks for adults and 2 mg/kg (up to 200 mg) every 3 weeks for pediatric patients. This is the first FDA indication for pembrolizumab in a hematologic malignancy.
“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,” Craig Moskowitz, MD, clinical director, division of hematologic oncology, Memorial Sloan Kettering Cancer Center, said in a statement. “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.”
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 (Adcetris; 83%), and radation 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.
There is not enough data for pembrolizumab in pediatric patients, and so the efficacy was extrapolated from the findings for the adult cHL population.
For safety data, the FDA asessed a study of 40 pediatric patients with advanced melanoma, PD-L1–positive advanced, relapsed, or refractory solid tumors, or lymphoma. The safety profile in the pediatric patients was consistent to that observed in adults. Some adverse events occurred at a higher rate (≥15% difference) in children than in adults, including fatigue, vomiting, abdominal pain, hypertransaminasemia, and hyponatremia. Pembrolizumab exposure at a dose of 2 mg/kg every 3 weeks in these pediatric patients was comparable to that observed in adults.
Pembrolizumab’s label has also been updated with a new "Warning and Precaution" for complications of allogeneic hematopoietic stem cell transplantation after treatment with the PD-1 inhibitor. The warning informs healthcare professionals to monitor patients closely for early signals of transplant-related complications, such as hyperacute GVHD, grade 3/4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions.
The acclerated approval of pembrolizumab in cHL is contingent upon the results of a confirmatory trial verifying the benefit of the PD-1 inhibitor in this setting.
Pembrolizumab has approvals in melanoma, lung cancer, and head and neck cancer. Other applications for approval are pending with the FDA in bladder cancer and microsatellite instability-high cancer, as a monotherapy, and in combination with chemotherapy for patients with lung cancer.
“The results from KEYNOTE-087 showed that most patients with relapsed or refractory classical Hodgkin lymphoma responded to treatment with Keytruda, and 22% experienced complete remission,” Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, said in a statement. “Today’s approval—the first for Keytruda in a hematologic malignancy—reinforces the hope that immunotherapy will prove useful in a wide variety of cancers.”