Avelumab: Uses, Dosage, Side Effects and Interactions

Avelumab is a cutting-edge immunotherapy drug that has revolutionized the treatment landscape for several advanced cancers. As a fully human IgG1 monoclonal antibody targeting programmed death-ligand 1 (PD-L1), avelumab boosts the body’s immune response against cancer cells, helping patients achieve longer-lasting remissions where traditional treatments often fall short. In this article, we’ll explore the clinical uses of avelumab, its recommended dosing regimens, the side effects patients may experience, and key drug interactions to be aware of.

Uses of Avelumab

Avelumab’s unique mechanism—blocking PD-L1 and unleashing T cells—makes it a vital option for patients with cancers that are difficult to treat. Its versatility has led to approval or investigation in various malignancies, particularly where other therapies have failed or are unsuitable.

Cancer Type	Setting/Line of Therapy	Approval/Trial Status	Source(s)
Merkel cell carcinoma	Metastatic, chemotherapy-refractory	FDA approved	6
Urothelial carcinoma	Metastatic, post-platinum therapy	Accelerated FDA approval	1 10
Non-small-cell lung cancer	Metastatic, post-platinum therapy	Investigational/trials	4 9
Renal-cell carcinoma	Advanced, first-line (with axitinib)	Phase 3 ongoing, promising	7 16
Breast cancer (TNBC)	Advanced/metastatic, after SOC failure	Investigational/trials	2 5
Head and neck cancer	Locally advanced, with chemoradiation	Phase 3 unsuccessful	8
Gastric/GEJ cancer	Advanced, third-line	Phase 3 unsuccessful	11
Ovarian cancer	Recurrent/refractory	Investigational/trials	13

Table 1: Major Indications and Clinical Trial Settings for Avelumab

Approved and Investigational Indications

Merkel Cell Carcinoma (MCC)

• Avelumab is FDA approved for metastatic MCC that has failed prior chemotherapy. As MCC is rare and aggressive, conventional options are limited and often not durable. Avelumab demonstrated durable responses and manageable safety in these patients 6.

Urothelial Carcinoma (UC)

• For patients with locally advanced or metastatic UC who have progressed after platinum-based chemotherapy, avelumab is approved on an accelerated basis in the US. The drug showed meaningful response rates and survival benefit in heavily pretreated populations 1 10.

Renal Cell Carcinoma (RCC)

• Avelumab, in combination with axitinib (a VEGF inhibitor), is being evaluated as a first-line treatment for advanced RCC. Early-phase studies show promising efficacy and a manageable safety profile 7 16.

Non-Small-Cell Lung Cancer (NSCLC)

• While not yet approved, avelumab has shown antitumor activity and an acceptable safety profile in patients with advanced, platinum-treated NSCLC 4.

Triple-Negative Breast Cancer (TNBC) and Other Solid Tumors

• Investigational use in TNBC and other solid tumors has revealed a subset of patients, particularly those with high PD-L1 expression, may benefit from avelumab 2 5 13.

Other Cancers

• Trials in gastric/gastroesophageal junction cancer, head and neck squamous cell carcinoma, and ovarian cancer have been conducted. In some cases (e.g., gastric, head and neck), avelumab did not improve outcomes compared to standard therapies, but safety was generally favorable 8 11 13.

Mechanism of Action

Avelumab blocks PD-L1 on tumor cells, preventing it from binding to PD-1 on T cells. This releases the “brakes” on the immune system, allowing T cells to recognize and destroy cancer cells. Unlike most other PD-1/PD-L1 inhibitors, avelumab is engineered to retain its Fc region, enabling it to mediate antibody-dependent cellular cytotoxicity (ADCC)—a second antitumor mechanism via natural killer (NK) cells 3 5 14.

Selection Criteria

• Patients must have advanced, unresectable, or metastatic cancer, often with prior therapy failure.
• Avelumab is given irrespective of PD-L1 status in many indications, though responses are higher in PD-L1 positive tumors 2 10.
• Adequate organ function and performance status are required 1 4 6.

Dosage of Avelumab

Avelumab’s dosing regimens are designed for both efficacy and safety. The typical administration is straightforward, but dosing may be adjusted in clinical trials or combination therapies.

Indication/Setting	Dose (mg/kg)	Frequency	Source(s)
Standard (most cancers)	10 mg/kg	IV every 2 weeks	1 2 4 6 9 10
With axitinib (RCC, HCC)	10 mg/kg + axitinib	IV every 2 wks + axitinib 5 mg BID	7 16
Chemoradiotherapy (HN cancer)	10 mg/kg	IV every 2 weeks + CRT	8
Dose escalation (trials)	1, 3, 10, 20 mg/kg	IV every 2 weeks	9

Table 2: Common Dosing Regimens for Avelumab

Standard Dosing

• Monotherapy: The recommended dose is 10 mg/kg administered as a 1-hour intravenous infusion every 2 weeks, continued until disease progression or unacceptable toxicity 1 2 4 6 9 10.
• Combination Therapy: When combined with axitinib (5 mg orally twice daily), avelumab is given at 10 mg/kg every 2 weeks for advanced renal cell carcinoma and hepatocellular carcinoma 7 16.

Dosing in Clinical Trials

Early phase studies explored a range of doses (1, 3, 10, and 20 mg/kg). The maximum tolerated dose was not reached, but 10 mg/kg every 2 weeks was chosen for further development based on pharmacokinetics, safety, and target occupancy 9.

Administration Considerations

• Route: Intravenous infusion over 1 hour.
• Duration: Treatment continues until progression, toxicity, or patient withdrawal.
• Premedication: Antihistamines and acetaminophen are often recommended prior to infusion to reduce risk of infusion-related reactions 1 4 6.

Dose Adjustments and Special Populations

• No formal dose adjustments based on age, gender, or mild organ impairment have been established, but patients must have adequate organ function 1 4 6.
• Dose modifications or interruption may be required for severe adverse reactions (see side effects section).

Side Effects of Avelumab

Because avelumab reactivates the immune system, it can cause both general and immune-mediated side effects. Most are manageable, but rare severe reactions can occur.

Side Effect	Frequency/Severity	Notable Details/Examples	Source(s)
Infusion-related reactions	Common (up to 29%)	Generally mild, premedication helps	1 4 6 9 10 16
Fatigue	Common (16–40%)	Usually mild to moderate	1 4 9 10 11
Immune-related AEs	Less common (5–12%), can be severe	Pneumonitis, hepatitis, colitis, endocrinopathies	4 6 9 12
Serious adverse events	Uncommon (6–13%)	Mainly severe immune reactions	1 4 6 9 16
Ocular side effects	Rare (≤1–24%)	Uveitis, dry eye, others	12
Laboratory abnormalities	Rare	Elevated liver enzymes, lipase	1 4 6 9 10 16
Deaths (treatment-related)	Very rare	Often due to severe pneumonitis	1 6 8

Table 3: Major Adverse Effects Associated with Avelumab

Common Side Effects

• Infusion-Related Reactions: These are the most frequent, occurring in up to 29% of patients. Symptoms include chills, fever, flushing, and shortness of breath, and are usually mild to moderate (grade 1–2). Premedication with antihistamines and acetaminophen is effective in reducing incidence 1 4 6 9 10 16.
• Fatigue: Reported in up to 40% of patients, typically mild to moderate 1 4 9 10 11.
• Nausea, influenza-like symptoms, and asthenia are also commonly reported but generally manageable 1 4 9 10 11.

Immune-Related Adverse Events (irAEs)

Avelumab, like other checkpoint inhibitors, can trigger autoimmune-like responses as the immune system becomes more active:

• Pneumonitis, hepatitis, colitis, endocrinopathies (thyroiditis, adrenal insufficiency), nephritis, and skin reactions have all been reported. Most occur in less than 12% of patients, but some can be life-threatening if not managed promptly 4 6 9 12.
• Ophthalmic complications such as uveitis, dry eye, and, rarely, optic neuropathy or inflammatory orbitopathy may occur 12.

Serious and Rare Adverse Events

• Grade 3–4 adverse events are observed in 6–17% of patients. Serious events (grade ≥3) include severe fatigue, autoimmune reactions, and laboratory abnormalities (elevated liver enzymes, creatine phosphokinase) 1 4 6 9 10 16.
• Treatment-related deaths are exceedingly rare and usually result from severe immune-related events like pneumonitis or autoimmune myocarditis 1 6 8 16.

Special Considerations

• Most irAEs are managed with corticosteroids and, if severe, cessation of avelumab 12.
• The risk of immune-related adverse events necessitates careful patient monitoring and prompt management.

Interactions of Avelumab

Understanding potential interactions is critical to maximizing benefit and minimizing harm. Avelumab’s primary interactions involve immunosuppressive drugs and, in combination therapy, with other anticancer agents.

Interacting Agent/Class	Interaction Type/Concern	Clinical Impact/Recommendation	Source(s)
Immunosuppressants	May reduce avelumab efficacy	Avoid concurrent use if possible	1 4 6 12
Combination therapies	Additive toxicity (e.g., hypertension with axitinib)	Monitor closely, dose adjust as needed	7 16
Corticosteroids	May blunt immune response	Use only if clinically necessary	1 12
Ocular medications	For irAEs, may require steroids	Ophthalmologist involvement needed	12

Table 4: Major Drug and Class Interactions with Avelumab

Immunosuppressive Agents

• Concurrent use of systemic immunosuppressants (including corticosteroids, cyclosporine, etc.) can diminish avelumab’s therapeutic effect by blunting immune system activation. These should be avoided unless required to treat severe or life-threatening irAEs 1 4 6 12.

Combination Therapy Interactions

• Avelumab + Axitinib: Used for advanced renal cell carcinoma and hepatocellular carcinoma. This combination can increase the risk of hypertension, palmar-plantar erythrodysesthesia, and liver enzyme abnormalities, requiring careful monitoring and sometimes dose adjustments 7 16.

Management of Immune-Related Adverse Events

• Corticosteroids and immunosuppressants are the mainstay for managing severe irAEs. However, their use can theoretically reduce avelumab’s efficacy, making it essential to balance risk and benefit. Tapering steroids as soon as clinically feasible is recommended 1 12.

Ocular Interactions

• For immune-mediated ocular side effects, topical or periocular corticosteroids are often used, and severe cases may require systemic steroids and discontinuation of therapy. Coordination with ophthalmology is advised 12.

Other Drug Interactions

• No major pharmacokinetic drug interactions have been reported, but patients should inform their care team of all medications, including over-the-counter drugs and supplements.

Conclusion

Avelumab has emerged as a versatile and valuable immunotherapy for patients with advanced or refractory cancers, offering hope where traditional treatments are limited. As with any powerful therapy, understanding its clinical applications, dosing, side effects, and interactions is crucial for optimizing outcomes.

Key Takeaways:

• Diverse Uses: Avelumab is approved for metastatic Merkel cell carcinoma and platinum-refractory urothelial carcinoma, with ongoing trials in other solid tumors.
• Standard Dose: The typical regimen is 10 mg/kg IV every 2 weeks, alone or in combination with other agents.
• Side Effects: Infusion reactions and fatigue are common, while immune-related adverse events—though less frequent—can be serious and require prompt management.
• Interactions: Immunosuppressants may reduce efficacy; additive toxicity can occur in combination regimens; careful monitoring is essential.
• Patient-Centered Care: Avelumab’s benefits must be weighed against its risks, with close monitoring and multidisciplinary management critical to success.

As research continues, avelumab’s role in oncology will likely expand, offering new hope for many patients facing challenging cancers.