What is the role of Pembrolizumab (pembrolizumab) and related drugs in the treatment of metastatic cancer?

From the Guidelines

Pembrolizumab is a recommended treatment option for patients with metastatic cancer, specifically those with MSI-H or dMMR solid tumors, including prostate cancer, who have progressed on prior treatment and have no satisfactory alternative treatment options, as evidenced by a recent study published in 2023 1.

Key Points

• Pembrolizumab, an anti-PD1 antibody, has been FDA-approved for the treatment of patients with unresectable or metastatic MSI-H or dMMR solid tumors who have progressed on prior treatment and have no satisfactory alternative treatment options.
• The recommended adult dose of pembrolizumab is 200 mg intravenously every 3 weeks or 400 mg every 6 weeks, continuing until disease progression or unacceptable toxicity occurs.
• Common side effects of pembrolizumab include fatigue, pruritus, diarrhea, anorexia, constipation, nausea, rash, fever, cough, dyspnea, and musculoskeletal pain, as well as potential immune-mediated side effects such as colitis, hepatitis, endocrinopathies, pneumonitis, or nephritis.
• Treatment decisions should be based on the specific cancer type, PD-L1 expression levels (when applicable), and the patient's overall health status, as these factors significantly influence response rates.

Evidence

• A study published in 2023 1 reported an objective response rate of 40% (59/149) in patients with MSI-H or dMMR solid tumors treated with pembrolizumab.
• The KEYNOTE-199 study, a multicohort, open-label phase II study, reported an overall response rate of 5% (95% CI, 2%–11%) in patients with PD-L1–positive mCRPC treated with pembrolizumab 1.
• Another study published in 2019 1 reported an objective response rate of 17.4% (95% CI, 5.0%–38.8%) in patients with advanced, progressive prostate cancer treated with pembrolizumab.

Recommendations

• Pembrolizumab should be considered as a treatment option for patients with metastatic cancer, specifically those with MSI-H or dMMR solid tumors, who have progressed on prior treatment and have no satisfactory alternative treatment options.
• Patients should be monitored regularly for potential side effects and immune-mediated adverse events.
• Treatment decisions should be individualized based on the patient's specific cancer type, PD-L1 expression levels, and overall health status.

From the FDA Drug Label

Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

The role of Pembrolizumab and related drugs in the treatment of metastatic cancer is to:

• Block the interaction between PD-1 and its ligands PD-L1 and PD-L2
• Release PD-1 pathway-mediated inhibition of the immune response
• Enhance anti-tumor immune response Key points about Pembrolizumab include:
• It is a monoclonal antibody that targets the PD-1 receptor
• It has been shown to decrease tumor growth in syngeneic mouse tumor models
• It can be used in combination with other treatments, such as kinase inhibitors, to enhance its effects 2 2

From the Research

Role of Pembrolizumab in Metastatic Cancer Treatment

• Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor, preventing its interaction with ligands and allowing for increased immune response and potentially increased anticancer immune activity 3.
• It has been approved by the FDA for the treatment of unresectable or metastatic melanoma in treatment-refractory patients, with objective response rates of 26-38% and acceptable toxicity profiles 3, 4.
• Pembrolizumab has also been studied in combination with radiotherapy for metastatic non-small-cell lung cancer, with results showing increased responses and outcomes compared to pembrolizumab alone 5.
• The optimal sequencing of therapy, including the use of pembrolizumab as first-line immunotherapy or in combination with other therapies, is still being evaluated through randomized trials 6.

Efficacy and Safety of Pembrolizumab

• Studies have shown that pembrolizumab is effective in treating advanced or unresectable melanoma, with responses seen in 25% to 40% of patients, depending on dose and setting 3, 6.
• The most common immune-mediated adverse reactions associated with pembrolizumab include hypothyroidism, pneumonitis, and hyperthyroidism 4.
• Real-world experience with pembrolizumab has confirmed its effectiveness and safety in treating advanced melanoma, with median progression-free survival and overall survival of 2.4 and 5.5 months, respectively 7.

Combination Therapy with Pembrolizumab

• The combination of pembrolizumab with radiotherapy has shown promising results in metastatic non-small-cell lung cancer, with increased responses and outcomes compared to pembrolizumab alone 5.
• There is a strong rationale to combine immune checkpoint inhibitors, such as pembrolizumab with ipilimumab, and to combine immune therapies with targeted therapy agents, which is being evaluated through randomized trials 6.