In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On May 9, 2017, avelumab (Bavencio) was granted accelerated approval for treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.1,2
Supporting Efficacy Data
Approval was based on the finding of durable responses in a single-arm trial in which 242 patients received avelumab at 10 mg/kg intravenously every 2 weeks until radiographic or clinical disease progression or unacceptable toxicity. All patients received premedication with an antihistamine and acetaminophen prior to each avelumab dose. Patients were included regardless of programmed cell death ligand 1 (PD-L1) status.
Patients had a median age of 68 years (range = 30–89 years), 72% were male, 80% were white, all had an Eastern Cooperative Oncology Group performance status of 0 or 1, 44% had nonbladder urothelial carcinoma (23% with upper tract disease), 83% had visceral metastases (34% with liver metastases), 4% had disease progression following platinum-containing neoadjuvant or adjuvant therapy alone, 47% had received cisplatin-based regimens alone, and 32% had received carboplatin-based regimens alone.
The most common serious adverse reactions to avelumab are immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, adrenal insufficiency, hypo- and hyperthyroidism, diabetes, nephritis, and life-threatening infusion-related reactions.
Confirmed response was observed in 30 of 226 patients followed for ≥ 13 weeks (13.3%, 95% confidence interval [CI] = 9.1%–18.4%), including a complete response in 9 (4.0%), and in 26 of 151 patients followed for ≥ 6 months (16.1%, 95% CI = 10.8%–22.8%), including a complete response in 9 (5.6%). The median time to response was 2.0 months (range = 1.3–11.0 months). The median response duration was not reached in patients followed for ≥ 13 weeks or ≥ 6 months, with response durations ranging from 1.4+ to 17.4+ months in both groups.
Among responders followed for ≥ 13 weeks, 22 (73%) had an ongoing response of 6 months or longer and 4 (13%) had an ongoing response of 12 months or longer. Among the responders followed for ≥ 6 months, 22 (85%) had ongoing responses of 6 months or longer, and 4 (15%) had ongoing responses of 12 months or longer. With the use of a clinical trial assay to assess PD-L1 expression (16% of patients not evaluable), no clear differences in response rates were observed based on PD-L1 tumor expression.
How It Works
Avelumab is a PD-L1–blocking human immunoglobulin G1 lambda monoclonal antibody. PD-L1 expressed on tumor cells and tumor-infiltrating immune cells can contribute to inhibition of 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. By binding PD-L1, avelumab blocks the interaction between PD-L1 and its receptors; this interaction releases the inhibitory effects of PD-L1 on the immune response, resulting in restoration of immune responses, including antitumor immune responses. Avelumab has also been shown to induce antibody-dependent cell-mediated cytotoxicity in vitro and decreased tumor growth via PD-L1 inhibition in syngeneic mouse models.
How It Is Used
The recommended dose of avelumab is 10 mg/kg via intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Patients should be premedicated with an antihistamine and acetaminophen prior to the first four infusions; premedication should be administered for subsequent doses based on clinical judgment and the presence/severity of prior infusion reactions.
The most common serious adverse reactions to avelumab are immune-mediated adverse reactions and life-threatening infusion-related 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 the product labeling.
Dose modifications for immune-mediated adverse reactions include withholding and subsequent resuming of treatment in patients with complete or partial resolution (grade 0–1) after corticosteroid treatment and taper for the following: grade 2 pneumonitis; aspartate transaminase (AST) or alanine transaminase (ALT) elevation to > 3 up to 5 times the upper limit of normal (ULN) or total bilirubin > 1.5 and up to 3 times ULN; grade 2 or 3 diarrhea or colitis; grade 3 or 4 endocrinopathies; serum creatinine > 1.5 and up to 6 times ULN; and moderate or severe clinical signs or symptoms of other immune-mediated adverse reactions (including but not limited to myocarditis, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, bullous dermatitis, Stevens-Johnson syndrome/toxic epidermal necrolysis, pancreatitis, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, hypophysitis, iritis, and encephalitis). For grade 1 or 2 infusion-related reactions, infusion should be interrupted or the infusion rate slowed.
Treatment should be permanently discontinued for the following: grade 3 or 4 pneumonitis or recurrent grade 2 pneumonitis; AST or ALT elevation > 5 times ULN or total bilirubin > 3 times ULN; grade 4 or recurrent grade 3 diarrhea or colitis; serum creatinine > 6 times ULN; life-threatening immune-related adverse reactions (excluding endocrinopathies); recurrent severe immune-mediated adverse reactions; requirement of ≥ 10 mg/d of prednisone or equivalent for > 12 weeks; persistent grade 2 or 3 immune-mediated adverse reactions lasting ≥ 12 weeks; and grade 3 or 4 infusion-related reactions.
Safety data reflected in the warnings/precautions for avelumab treatment are from 2 trials in which 1,738 patients received doses of 10 mg/kg every 2 weeks, including 88 patients with metastatic Merkel cell carcinoma and the 242 patients with locally advanced/metastatic urothelial carcinoma within the JAVELIN solid tumor trial (N = 1,650). As noted, the most common serious adverse reactions to avelumab are immune-mediated, including pneumonitis, colitis, hepatitis, adrenal insufficiency, hypo- and hyperthyroidism, diabetes, nephritis, and life-threatening infusion-related reactions.
In the study in urothelial carcinoma, the most common adverse events of any grade were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), and nausea (24%). Grade 3 or 4 adverse events occurred in 59% of patients, with the most common being fatigue (7%), hypertension/hypertensive crisis (5%), and urinary tract infection (5%). The most common grade 3 or 4 laboratory abnormalities were hyponatremia (16%), increased gamma-glutamyltransferase (12%), lymphopenia (11%), and hyperglycemia (9%).
Serious adverse events occurred in 41% of patients, with the most frequent (> 2% of patients) being urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, creatinine increased/renal failure, dehydration, hematuria/urinary tract hemorrhage, intestinal obstruction/small intestine obstruction, and pyrexia. A total of 11 patients (4.5%) received an oral prednisone dose equivalent to ≥ 40 mg daily for an immune-mediated adverse event.
Treatment was temporarily discontinued in 29% of patients (excluding temporary dose interruption for infusion-related reactions when infusion was restarted the same day), with the most common causes being diarrhea, fatigue, dyspnea, urinary tract infection, and rash. Adverse events led to discontinuation of treatment in 12%, with fatigue being the only cause occurring in more than 1% of patients. Adverse events led to death in 14 patients (6%), with causes including pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, and gastrointestinal adverse events.
Avelumab carries warnings/precautions for immune-related pneumonitis, immune-mediated hepatitis, immune-mediated colitis, immune-mediated endocrinopathies, immune-mediated nephritis and renal dysfunction, infusion-related reactions, and embryofetal toxicity. ■
1. U.S. Food and Drug Administration: FDA grants accelerated approval to avelumab for urothelial carcinoma. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm557162.htm. Accessed September 18, 2017.
2. Bavencio (avelumab) injection prescribing information, EMD Serono, Inc, May 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761078s000lbl.pdf. Accessed September 18, 2017.