Pembrolizumab Plus Axitinib: On April 19, 2019, pembrolizumab (Keytruda) was approved for use in combination with the small-molecule tyrosine kinase inhibitor axitinib (Inlyta) for the first-line treatment of patients with advanced renal cell carcinoma. Approval was based on findings in the phase III KEYNOTE-426 trial (ClinicalTrials.gov identifier NCT02853331).1
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. Binding of 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 is observed in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance.
In renal cell carcinoma, the recommended dose of pembrolizumab is 200 mg via intravenous infusion over 30 minutes every 3 weeks in combination with 5 mg of oral axitinib twice daily until disease progression, unacceptable toxicity, or for pembrolizumab, up to 24 months in patients without disease progression.
In KEYNOTE-426, the most common adverse events of any grade in the pembrolizumab/axitinib group (≥ 30%) were diarrhea, fatigue, or asthenia, hypertension, hepatotoxicity, hypothyroidism, and decreased appetite. Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, skin adverse reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, and other immune-mediated adverse reactions, as well as for infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryofetal toxicity.
Avelumab Plus Axitinib: Earlier this year, avelumab (Bavencio) was approved for use in combination with axitinib for the first-line treatment of patients with advanced renal cell carcinoma. Approval was based on findings in the open-label phase III JAVELIN Renal 101 trial (ClinicalTrials.gov identifier NCT02684006).2
Avelumab is a PD-L1–blocking antibody. PD-L1 may be expressed on tumor cells and tumor-infiltrating immune cells and can contribute to the inhibition of the antitumor immune response in the tumor microenvironment. Avelumab binds PD-L1 and blocks the interaction between PD-L1 and the PD-1 and B7.1 receptors, thereby releasing the inhibitory effects of PD-L1 on the immune response. Avelumab has also been shown to induce antibody-dependent cell-mediated cytotoxicity in vitro.
The recommended dose of avelumab in renal cell carcinoma is 800 mg via intravenous infusion over 60 minutes every 2 weeks in combination with oral axitinib at 5 mg twice daily until disease progression or unacceptable toxicity. When axitinib is used in combination with avelumab, dose increase of axitinib above the initial 5-mg dose may be considered at intervals of 2 weeks or longer.
The most common adverse events of any grade in the avelumab/axitinib group (≥ 30% of patients) were diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, and dysphonia. Avelumab carries warnings/precautions for immune-related pneumonitis; hepatotoxicity and immune-mediated hepatitis; immune-mediated colitis; immune-mediated endocrinopathies; immune-mediated nephritis and renal dysfunction; infusion-related reactions; major cardiovascular adverse events; and embryofetal toxicity.
REFERENCES
1. Rini BI, Plimack ER, Stus V, et al: Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380: 1116-1127, 2019.
2. Motzer RJ, Penkov K, Haanen J, et al: Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380: 1103-1115, 2019.
