Pembrolizumab in MSI-H or dMMR Solid Tumors: ‘First Tissue/Site-Agnostic’ Approval by FDA


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On May 23, 2017, pembrolizumab (Keytruda) was granted accelerated approval for treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) solid tumors progressing following prior treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR colorectal cancer progressing following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.1,2 The U.S. Food and Drug Administration (FDA) has termed the approval the “first tissue/ site-agnostic approval.”

Product labeling states the safety and effectiveness of pembrolizumab in pediatric patients with MSI-H central nervous system cancers have not been established.

Supporting Efficacy Data

The approval was based on findings of durable responses among 149 patients with MSI-H or dMMR cancers in 5 single-arm multicohort multicenter trials (KEYNOTE-016, -164, -012, -028, and -158). Patients received pembrolizumab at 200 mg every 3 weeks or 10 mg/kg every 2 weeks. Treatment continued for up to 24 months or until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, or was associated with a decline in performance status.

A total of 90 patients had colorectal cancer and 59 patients had 14 other cancer types. The median age of patients was 55 years (36% ≥ 65 years); 56% were male; 77% were white, 19% Asian, and 2% black; Eastern Cooperative Oncology Group performance status was 0 in 36% and 1 in 64%; 98% had metastatic disease and 2% had locally advanced unresectable disease; the median number of prior therapies for metastatic or unresectable disease was 2; and 84% of those with metastatic colorectal cancer and 53% of those with other solid tumors had received at least 2 prior lines of therapy.

OF NOTE

Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; and embryofetal toxicity.

In 135 patients, MSI-H or dMMR tumor status was prospectively determined using local laboratory-developed investigational polymerase chain reaction (PCR) for MSI-H status or immunohistochemistry (IHC) for dMMR. In the remaining 14 patients, MSI-H status was determined in retrospective assessment of 415 tumor samples using a central laboratory–developed PCR test. Overall, 47 patients had dMMR cancer identified by IHC, 60 had MSI-H identified by PCR, and 42 had positive findings on both tests.

The objective response rate on blinded independent central radiologist review according to Response Evaluation Criteria in Solid Tumors 1.1 was 39.6% (95% confidence interval = 31.7%–47.9%), with a complete response in 11 patients (7.4%). The median duration of response was not reached, with durations ranging from 1.6+ to 22.7+ months and responses lasting ≥ 6 months in 78% of responders. Response rates were 36% in patients with colorectal cancer and 46% in those with other cancer types. Treatment efficacy in pediatric patients with MSI-H cancers is extrapolated from the results in the adult population.

How It Works

Binding of programmed cell death ligand 1 (PD-L1) and PD-L2 to the programmed cell death protein 1 (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, 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

The recommended dose of pembrolizumab in this indication is 200 mg for adults or 2 mg/kg (up to a maximum of 200 mg) for children via intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Specific management guidelines for immune-mediated adverse events are provided in the warnings/precautions section of product labeling. Pembrolizumab treatment should be withheld for grade 2 pneumonitis, grade 2 or 3 colitis, grade 3 or 4 endocrinopathies,

ACCELERATED APPROVAL OF PEMBROLIZUMAB

  • Pembrolizumab (Keytruda) was granted accelerated approval for treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors progressing following prior treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR colorectal cancer progressing following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
  • The recommended dose of pembrolizumab in this indication is 200 mg for adults or 2 mg/ kg (up to a maximum of 200 mg) for children via intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

grade 4 hematologic toxicity in those with classical Hodgkin lymphoma, grade 2 nephritis, aspartate transaminase (AST) or alanine transaminase (ALT) level > 3 to 5 times or total bilirubin level >1.5 to 3 times upper limit of normal (ULN), and any other severe or grade 3 treatment-related adverse reaction. Treatment can be resumed when adverse reactions recover to grade 0 or 1.

Pembrolizumab should be permanently discontinued for grade 3 or 4 infusion-related reactions, any life-threatening adverse reaction, grade 3 or 4 pneumonitis or recurrent grade 2 pneumonitis, grade 3 or 4 nephritis, AST or ALT level > 5 times or total bilirubin level > 3 times ULN, AST or ALT level increases of ≥ 50% persisting for ≥ 1 week in patients with liver metastasis who began treatment with grade 2 increased AST or ALT level, inability to reduce corticosteroid dose to ≤ 10 mg/d of prednisone or equivalent within 12 weeks, persistent grade 2 or 3 adverse reactions that do not recover to grade 0 or 1 within 12 weeks of the last dose, and any recurrent severe or grade 3 treatment-related adverse reaction.

Safety Profile

Specific adverse event and laboratory abnormality data in patients with MSI-H or dMMR cancers are not provided in the product labeling. In overall experience with pembrolizumab, the most common adverse events (≥ 20% of patients) include fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation, and nausea. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies (including hypophysitis, thyroid disorders, and type 1 diabetes), immune-mediated nephritis, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryofetal toxicity. Patients should be monitored for hepatic, renal, and thyroid function and for hyperglycemia. Breastfeeding women should discontinue pembrolizumab treatment or breastfeeding. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm. Accessed January 22, 2018.

2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck and Co, Inc, May 2017. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s014lbl.pdf. Accessed January 22, 2018.


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