Pembrolizumab

Indication. Pembrolizumab is indicated for adult and pediatric patients with unresectable or metastatic, microsatellite instability–high (MSI-H)/microsatellite unstable or mismatch repair–deficient (dMMR) solid tumors whose disease progressed after prior treatment and who have no satisfactory alternative treatment options. The MSI-H phenotype is associated with germline defects in the MLH1, MSH2, MSH6, and PMS2 genes and is the primary phenotype observed in tumors from patients with hereditary nonpolyposis colorectal cancer or Lynch syndrome. Patients can also have the MSI-H phenotype because one of these genes was silenced via DNA methylation. Molecular genetic tests look for microsatellite instability in the tumor tissue, and immunohistochemistry tests for the loss of mismatch repair proteins. For more information, see the Immunotherapy section in Colon Cancer Treatment.

Evidence. The U.S. Food and Drug Administration (FDA) approval was based on data from the following five uncontrolled, multicohort, multicenter, single-arm clinical trials that included 149 patients with MSI-H or dMMR cancers:[1][Level of evidence C3]

These trials included 90 patients with colorectal cancer and 59 patients with other cancers who were diagnosed with one of 14 other cancer types. Patients received either 200 mg of pembrolizumab every 3 weeks or 10 mg/kg of pembrolizumab every 2 weeks.

Efficacy. The major efficacy outcome measures were objective response rate, assessed by blinded independent central radiologist review according to RECIST 1.1, and response duration. The pooled objective response rate was 39.6%. A total of 11 patients (7.4%) had a complete response and 48 patients (32.2%) had a partial response. The objective response rate was 36% in patients with colorectal cancer, and 46% in patients with other cancers (95% confidence interval [CI], 33%–59%).[7,8] Responses lasted 6 months or longer for 78% of patients who responded to pembrolizumab.[1]

Identification of biomarker. For most patients (135 of 149), tumor status was prospectively determined using local laboratory-developed, investigational polymerase chain reaction (PCR) (for MSI-H) or immunohistochemistry (for dMMR).[9] For 14 of the 149 patients, MSI-H status was determined in a retrospective assessment of tumor samples from 415 patients using a central laboratory-developed PCR test.