THE U.S. FOOD and Drug Administration (FDA) granted accelerated approval to pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma or who have relapsed after two or more prior lines of therapy on June 13, 2018. The newest indication for the programmed cell death protein 1 (PD-1)-blocking antibody followed by 1 day the FDA’s approval of pembrolizumab for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express programmed cell death ligand 1 (PD-L1; combined positive score [CPS] ≥ 1) as determined by an FDA-approved test.
Primary Mediastinal Large B-Cell Lymphoma
PEMBROLIZUMAB’S APPROVAL in the setting of primary mediastinal large B-cell lymphoma was based on data from 53 patients with relapsed or refractory disease enrolled in a multicenter, open-label, single-arm trial, KEYNOTE-170 (ClinicalTrials.gov identifier NCT02576990). Patients were treated with pembrolizumab at 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression or for up to 24 months for patients who did not have disease progression.
The overall response rate was 45% (95% confidence interval [CI] = 32%–60%), including 11% complete responses and 34% partial responses. The median duration of response was not reached within the follow-up period (median = 9.7 months). The median time to first objective response was 2.8 months. Pembrolizumab is not recommended for treatment of patients with primary mediastinal large B-cell lymphoma who require urgent cytoreductive therapy.
The recommended pembrolizumab dose for treatment of adults with primary mediastinal large B-cell lymphoma is 200 mg every 3 weeks. The recommended dose in pediatric patients is 2 mg/kg (up to a maximum of 200 mg) every 3 weeks.
Advanced Cervical Cancer
THE FDA APPROVED pembrolizumab for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥ 1) as determined by an FDA-approved test. The recommended pembrolizumab dose for treatment of cervical cancer is 200 mg every 3 weeks.
The FDA also concurrently approved PD-L1 IHC 22C3 pharmDx as a companion diagnostic.
Pembrolizumab was investigated in 98 patients with recurrent or metastatic cervical cancer enrolled in a single cohort of KEYNOTE-158 (ClinicalTrials.gov identifier NCT02628067), a multicenter, nonrandomized, open-label, multicohort trial. Patients were treated with pembrolizumab intravenously at a dose of 200 mg every 3 weeks until unacceptable toxicity or documented disease progression. Among the 98 patients, approval was based on 77 patients (79%) who had tumors that expressed PD-L1 with a CPS ≥ 1 and who had received at least 1 line of chemotherapy for metastatic disease. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx Kit.
The major efficacy outcomes were objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by blinded independent central review, and response duration. With a median follow-up time of 11.7 months, the objective response rate in 77 patients was 14.3% (95% CI = 7.4%–24.1%), including 2.6% complete responses and 11.7% partial responses.
The estimated median response duration based on 11 patients with a response by independent review was not reached (range = 4.1–18.6+ months); 91% had a response duration of at least 6 months. No responses were observed in patients whose tumors did not have PD-L1 expression (CPS < 1).
Safety and Toxicity
THE MOST COMMON adverse reactions in ≥ 10% of patients with primary mediastinal large B-cell lymphoma treated in the KEYNOTE-170 trial were musculoskeletal pain, upper respiratory tract infection, pyrexia, fatigue, cough, dyspnea, diarrhea, abdominal pain, nausea, arrhythmia, and headache. Pembrolizumab was discontinued or interrupted due to adverse reactions in 8% and 15% of patients, respectively. Serious adverse reactions occurred in 26% of patients.
The most common adverse reactions in at least 10% of patients with cervical cancer enrolled in KEYNOTE-158 were fatigue, pain, pyrexia, peripheral edema, musculoskeletal pain, diarrhea/colitis, abdominal pain, nausea, vomiting, constipation, decreased appetite, hemorrhage, urinary tract infections, infections, rash, hypothyroidism, headache, and dyspnea. Pembrolizumab was discontinued due to adverse reactions in 8% of patients.
Serious adverse reactions occurred in 39% of patients. The most frequent serious adverse reactions reported included anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections (except urinary tract infections; 4.1%).
For more information about pembrolizumab and other newly approved drugs and indications, visit FDA.gov. The FDA’s Oncology Centers of Excellence provides further information about recent drug approvals on its podcast D.I.S.C.O. (Drug Information Soundcast in Clinical Oncology). ■