In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On June 16, 2020, pembrolizumab was granted accelerated approval for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden–high (TMB-H; ≥ 10 mutations/megabase [mut/Mb]) solid tumors. Suitability was determined by an U.S. Food and Drug Administration (FDA)-approved test, which determined the tumors have progressed following prior treatment, for patients who have no satisfactory alternative treatment options.^1,2 (The safety and effectiveness of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established.)

The FDA simultaneously approved the FoundationOneCDx assay as a companion diagnostic for pembrolizumab.

Supporting Efficacy Data

Approval was based on a prospectively planned retrospective analysis of 10 cohorts of patients with various previously treated unresectable or metastatic TMB-H solid tumors who were enrolled in the multicenter, nonrandomized, open-label KEYNOTE-158 trial (ClinicalTrials.gov identifier NCT02628067).² Patients received pembrolizumab at 200 mg intravenously (IV) every 3 weeks until disease progression or unacceptable toxicity.

The main efficacy outcome measures were overall response rate and duration of response in patients who received at least one dose of pembrolizumab. Assessment was by blinded independent central review according to Response Evaluation Criteria in Solid Tumors version 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Of the 1,050 patients included in the efficacy analysis, 790 had sufficient tissue for TMB testing based on protocol-specified testing requirements; of these patients, 102 (13%) had tumors identified as TMB-H, defined as TMB ≥ 10 mut/Mb.

Among the 102 patients, objective response was observed in 30 (29%), with a complete response in 4%. The median duration of response was not reached, with response lasting for at least 12 months in 57% of responders and at least 24 months in 50%. Among 70 patients with TMB ≥ 13 mut/Mb, objective response was observed in 26 (37%), with a complete response in 3%. The median duration of response was not reached, with response lasting for at least 12 months in 58% of responders and at least 24 months in 50%.

How It Works

Binding of PD-L1 and PD-L2 to the PD-1 receptor found on T cells inhibits T-cell proliferation and cytokine production. Pembrolizumab is an anti–PD-1 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2 ligands, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response. Upregulation of PD-1 ligands is observed in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse models, inhibition of PD-1 activity resulted in decreased tumor growth.

How It Is Used

Limitations of use: The safety and effectiveness of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established. For the TMB-H indication, patients must be selected for treatment based on TMB-H status in tumor specimens as determined by an FDA-approved test.

In the current indication, the recommended dose of pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks via 30-minute IV infusion in adult patients and 2 mg/kg every 3 weeks (up to a maximum of 200 mg) via 30-minute IV infusion in pediatric patients, with treatment continued until disease progression, unacceptable toxicity, or for up to 24 months.

No dose reductions of pembrolizumab are recommended. Treatment should be withheld or discontinued to manage adverse reactions. Pembrolizumab infusion should be interrupted or slowed for grade 1 or 2 infusion-related reactions and permanently discontinued for grade 3 or 4 reactions. Specific management guidelines for immune-mediated adverse events are provided in the warnings/precautions section of product labeling, which also contains recommended dosing modifications, including withholding, resuming, and discontinuing treatment, for a variety of adverse reactions.

Safety Profile

The median duration of exposure to pembrolizumab in patients with TMB-H cancer enrolled in KEYNOTE-158 was 4.9 months (range = 0.03–35.2 months). Product labeling provides no specific data on adverse events or laboratory abnormalities in the TMB-H population receiving pembrolizumab. It states that adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received pembrolizumab as a single agent. The most common adverse events of any grade (at least 20% of patients) observed in patients receiving pembrolizumab as a single agent in clinical trials have been fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions.

Pembrolizumab has warnings/precautions for immune-mediated pneumonitis; immune-mediated colitis; immune-mediated hepatitis (and hepatotoxicity in combination with axitinib); immune-mediated endocrinopathies (including hypophysitis, thyroid disorders, and type 1 diabetes); immune-mediated nephritis; immune-mediated skin adverse reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis); other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation before and after pembrolizumab treatment; and embryofetal toxicity. Treatment of patients with multiple myeloma with a PD-1– or PD-L1–blocking antibody in combination with a thalidomide analog plus dexamethasone is not recommended outside of controlled clinical trials. Patients should be monitored for hepatic, renal, and thyroid function and for hyperglycemia. Patients should be advised not to breastfeed while receiving pembrolizumab. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves pembrolizumab for adults and children with TMB-H solid tumors. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors. Accessed June 26, 2020.

2. Keytruda (pembrolizumab) injection prescribing information, Merck & Co,June 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s071s090lbl.pdf. Accessed June 26, 2020.