Earlier this year, avelumab was approved for use in combination with axitinib for the first-line treatment of patients with advanced renal cell carcinoma.^1,2

Supporting Efficacy Data

Approval was based on findings in the open-label phase III -JAVELIN Renal 101 trial (ClinicalTrials.gov identifier NCT02684006).^2,3 In the trial, 886 patients with untreated advanced renal cell carcinoma regardless of tumor programmed cell death ligand 1 (PD-L1) expression were randomly assigned to receive avelumab at 10 mg/kg via intravenous infusion every 2 weeks plus oral axitinib at 5 mg twice daily (n = 442) or sunitinib at 50 mg once daily orally for 4 weeks followed by 2 weeks off (n = 444) until radiographic disease progression or unacceptable toxicity.

The primary efficacy endpoints were progression-free survival assessed by blinded independent central review and overall survival in patients with PD-L1–positive tumors. A significant improvement in progression-free survival was observed with avelumab/axitinib vs sunitinib in patients with PD-L1–positive tumors (hazard ratio [HR] = 0.61, 95% confidence interval = 0.48–0.79). A significant improvement in progression-free survival with avelumab/axitinib was also observed in the total population (median = 13.8 vs 8.4 months, HR = 0.69, P = .0002) at interim analysis. With a median overall survival follow-up of 19 months, overall survival data were immature, with death occurring in 27% of the total population. An objective response was observed in 51.4% vs 25.7% of all patients.

How It Works

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. Binding of PD-L1 to the programmed cell death protein 1 (PD-1) and B7.1 receptors found on T cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production. Avelumab binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 and B7.1. This interaction releases the inhibitory effects of PD-L1 on the immune response, resulting in the restoration of immune responses, including antitumor immune responses. Avelumab has also been shown to induce antibody-dependent cell-mediated cytotoxicity in vitro. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.

How It Is Used

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. Full prescribing information for axitinib should be reviewed prior to initiation of treatment. Patients should be premedicated with an antihistamine and acetaminophen prior to the first four infusions of avelumab; premedication should be administered for subsequent doses based on clinical judgment and the presence/severity of prior infusion reactions.

Detailed information regarding clinical and laboratory monitoring guidelines for early detection of adverse reactions to avelumab and recommended management, including immunosuppressant treatment guidelines, are provided in product labeling. Product labeling provides detailed information on dose modification for the following adverse reactions: hepatitis, including specific modifications for use in combination with axitinib; colitis; endocrinopathies, including but not limited to hypothyroidism, hyperthyroidism, adrenal insufficiency, and hyperglycemia; nephritis and renal dysfunction; other immune-mediated adverse reactions, including but not limited to myocarditis, pancreatitis, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, bullous dermatitis, Stevens-Johnson syndrome/toxic epidermal necrolysis, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, hypophysitis, iritis, and encephalitis; and infusion-related reactions.

Safety Profile

The JAVELIN Renal 101 trial excluded patients with autoimmune disease other than type 1 diabetes mellitus, vitiligo, psoriasis, or thyroid disorders not requiring immunosuppressive treatment.

The most common adverse events of any grade in the avelu-mab/axitinib group (≥ 30% of patients) were diarrhea (62% vs 48% with sunitinib), fatigue (53% vs 54%), hypertension (50% vs 36%), musculoskeletal pain (40% vs 33%), nausea (34% vs 39%), mucositis (34% vs 35%), palmar-plantar erythrodysesthesia (33% vs 34%), and dysphonia (31% vs 3%). The most common grade 3 or 4 adverse events included hypertension (26% vs 17%), hepatotoxicity (9% vs 3.6%), and diarrhea (8% vs 2.7%). Major cardiac adverse events occurred in 7% of patients receiving the combination. An oral prednisone dose equivalent to ≥ 40 mg daily for an immune--mediated adverse event was given to 11% of patients.

Serious adverse events occurred in 35% of patients receiving avelumab/axitinib, with the most common being diarrhea, dyspnea, hepatotoxicity, venous thromboembolic disease, acute kidney injury, and pneumonia. Dose interruptions or reductions due to adverse events, excluding interruptions of avelumab due to infusion-related reactions, occurred in 76% of patients. Avelumab was interrupted in 50%, most commonly due to diarrhea. Axitinib was interrupted in 66% and dose reduced in 19%, most commonly due to diarrhea, hypertension, palmar-plantar erythrodysesthesia, and hepatotoxicity. Adverse events led to discontinuation of either avelumab or axitinib in 22% of patients, with the most common causes being hepatotoxicity and infusion-related reaction. Fatal adverse events occurred in 1.8% of patients, including sudden cardiac death, stroke, myocarditis, and necrotizing pancreatitis.

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. Patients should be advised not to breastfeed while receiving avelumab. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves avelumab plus axitinib for renal cell carcinoma. Available at www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-avelumab-plus-axitinib-renal-cell-carcinoma. Accessed September 9, 2019.

2. Bavencio (avelumab) injection prescribing information, EMD Serono, Inc, May 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/761049s006lbl.pdf. Accessed September 9, 2019.

3. 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.