The FDA ( Food and Drug Administration ) has approved Keytruda ( Pembrolizumab ) for the treatment of adults and pediatric patients with unresectable or metastatic tumor mutational burden-high ( TMB-H ) solid tumors, whose tumors have progressed after previous treatment and who have no satisfactory alternative treatment options.
The FDA also approved the FoundationOne CDx assay as a companion diagnostic for Keytruda.
Efficacy was investigated in a prospectively planned retrospective analysis of 10 cohorts of patients with various previously treated unresectable or metastatic TMB-H solid tumors enrolled in the multicenter, nonrandomized, open-label, KEYNOTE-158 trial.
In the trial, TMB status was assessed using the FoundationOne CDx assay with prespecified cut points of 10 or more and 13 or more mutations per megabase ( mut/Mb ).
A total of 1,050 patients were included in the efficacy analysis, but TMB was analyzed in the subset of 790 patients with enough tissue for testing based on protocol-specified testing requirements.
Of the 790 patients, 102 ( 13% ) had tumors identified as TMB-H ( defined as greater than or equal to 10 mut/Mb ).
Tumor response was assessed every nine weeks for the first 12 months and every 12 weeks thereafter.
Patients received 200 mg of Pembrolizumab every three weeks until unacceptable toxicity or disease progression occurred.
The main efficacy outcome measures were overall response rate ( ORR ) and duration of response ( DOR ) as assessed by blinded independent central review according to Response Evaluation Criteria in Solid Tumors ( RECIST ) Version 1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.
The ORR for patients with TMB-H tumors was 29% ( 95% CI, 21-39% ), with a 4% complete response rate and 25% partial response rate.
After a median follow-up of 11.1 months, the median DOR had not been reached ( range, 2.2+ to 34.8+ months ).
Response durations were 12 months or longer in 57% of patients and more than 24 months in 50% of patients.
Adverse events occurring in the patients with TMB-H cancer were similar to those in patients with other solid tumors who received Pembrolizumab as a single agent.
The most common adverse effects with Pembrolizumab are fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain and abdominal pain.
Pembrolizumab also is associated with immune-mediated adverse effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and skin reactions. ( Xagena )
Source: Merck ( MSD ), 2020