Bavencio

DESCRIPTION

Avelumab is a programmed death ligand1 (PD-L1) blocking antibody. Avelumab- is a human IgG1 lambdamonoclonal antibodyproduced in Chinese hamster ovary cells and has a molecular weight of approximately 147 kDa.

Bavencio (avelumab) Injection for intravenous use is a sterile, preservative-free, non-pyrogenic, clear, colorless to slightly yellow solution. Each single-dose vial contains 200 mg avelumab in 10 mL (20 mg/mL). Each mL contains 20 mg avelumab, Dmannitol (51 mg), glacialacetic acid(0.6 mg), polysorbate 20 (0.5 mg), sodium hydroxide (0.3 mg), and Water for Injection. The pH range of the solution is 5.0 – 5.6.

INDICATIONS

Metastatic Merkel Cell Carcinoma

BAVENCIO (avelumab) is indicated for the treatment of adults and pediatric patients 12 years and older with metastaticMerkel cell carcinoma(MCC)。这表明在accelerat批准ed approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials [seeClinical Studies].

局部晚期或转移性移行细胞Carcinoma

First-Line Maintenance Treatment of Urothelial Carcinoma

BAVENCIO is indicated for the maintenance treatment of patients with locally advanced or metastatic urothelialcarcinoma(UC) that has not progressed with first-line platinum-containingchemotherapy[seeClinical Studies].

Previously-Treated Urothelial Carcinoma

BAVENCIO is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who:

• Have disease progression during or following platinum-containing chemotherapy
• Have disease progression within 12 months of neoadjuvant oradjuvanttreatment with platinum-containing chemotherapy [seeClinical Studies].

Advanced Renal Cell Carcinoma

BAVENCIO in combination with axitinib is indicated for the first-line treatment of patients with advancedrenal cell carcinoma(RCC) [seeClinical Studies].

DOSAGE AND ADMINISTRATION

Premedication

Premedicate patients with an antihistamine and withacetaminophenprior to the first 4 infusions of BAVENCIO. Premedication should be administered for subsequent BAVENCIO doses based upon clinical judgment and presence/severity of prior infusion reactions [seeDOSAGE AND ADMINISTRATIONand警告AND PRECAUTIONS].

Recommended Dosage For MCC

The recommended dose of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

Recommended Dosage For UC

The recommended dose of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

Recommended Dosage For RCC

The recommended dose of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks in combination with axitinib 5 mg orally taken twice daily (12 hours apart) with or without food until disease progression or unacceptable toxicity. When axitinib is used in combination with BAVENCIO, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of two weeks or longer. Review the Full Prescribing Information for axitinib prior to initiation.

Dose Modifications

No dose reduction for BAVENCIO is recommended. In general, withhold BAVENCIO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue BAVENCIO for life-threatening (Grade 4) immune-mediated adverse reactions,recurrentsevere (Grade 3) immune-mediated reactions that require systemicimmunosuppressivetreatment, or an inability to reducecorticosteroiddose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids.

Dosage modifications for BAVENCIO for adverse reactions that require management different from these general guidelines are summarized in Table 1.

Table 1: Recommended Monotherapy Dosage Modifications for Adverse Reactions

Adverse Reaction	Severity*	Dosage Modification
Immune-Mediated Adverse Reactions [see警告AND PRECAUTIONS]
Pneumonitis	Grade 2	Withholda
	Grade 3 or 4	Permanently discontinue
Colitis	Grade 2 or 3	Withholda
	Grade 4	Permanently discontinue
没有t型肝炎umor involvement of the liver For liver enzyme elevations in patients treated with combination therapy, see Table 2	AST or ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN	Withholda
	AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN	Permanently discontinue
Hepatitis with tumor involvement of the liverb	Baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN	Withholda
	AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN	Permanently discontinue
Endocrinopathies	Grade 3 or 4	Withhold until clinically stable or permanently discontinue depending on severity
Nephritis with Renal Dysfunction	Grade 2 or 3 increased blood creatinine	Withholda
	Grade 4 increased blood creatinine	Permanently discontinue
Exfoliative Dermatologic Conditions	Suspected SJS, TEN, or DRESS	Withholda
	Confirmed SJS, TEN, or DRESS	Permanently discontinue
Myocarditis	Grade 2, 3 or 4	Permanently discontinue
Neurological Toxicities	Grade 2	Withholda
	Grade 3 or 4	Permanently discontinue
Other Adverse Reactions
Infusion-related reactions [see警告AND PRECAUTIONS]	Grade 1 or 2	Interrupt or slow the rate of infusion
	Grade 3 or 4	Permanently discontinue
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal, SJS = Stevens-Johnson syndrome, TEN = toxic epidermal necrosis, DRESS = drug rash with eosinophilia and systemic symptoms * Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 aResume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating corticosteroids. bIf AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue BAVENCIO based on recommendations for hepatitis where there is no tumor involvement of the liver.

表2给出了剂量dif的修改ferent from those described above in Table 1 for BAVENCIO used as monotherapy or in the Full Prescribing Information for the drug administered in combination.

Table 2: Recommended Specific Dosage Modifications for Adverse Reactions for Combination Therapy [see WARNINGS AND PRECAUTIONS]

Treatment	Adverse Reaction	Severity*	Dosage Modification
BAVENCIO in combination with axitinib	Liver enzyme elevations	ALT or AST at least 3 times ULN but less than 10 times ULN without concurrent total bilirubin at least 2 times ULN	Withhold both BAVENCIO and axitinib until adverse reactions recover to Grades 0-1a Consider rechallenge with BAVENCIO or axitinib or sequential rechallenge with both BAVENCIO and axitinib after recovery**
		ALT or AST at least 10 times ULN or more than 3 times ULN with concurrent total bilirubin at least 2 times ULN	Permanently discontinue both BAVENCIO and axitiniba
* Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 ** Dose reduction according to the axitinib Full Prescribing Information should be considered if rechallenging with axitinib. aConsider corticosteroid therapy

Preparation And Administration

Preparation

• Visually inspect vial for particulate matter and discoloration. BAVENCIO is a clear, colorless to slightly yellow solution. Discard vial if the solution is cloudy, discolored, or contains particulate matter.
• Withdraw the required volume of BAVENCIO from the vial(s) and inject it into a 250 mL infusion bag containing either 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection.
• Gently invert the bag to mix the diluted solution and avoid foaming or excessive shearing.
• Inspect the solution to ensure it is clear, colorless, and free of visible particles.
• Discard any partially used or empty vials.

Storage Of Diluted BAVENCIO Solution

Protect from light.

Store diluted BAVENCIO solution:

• At room temperature up to 77°F (25°C) for no more than 4 hours from the time of dilution. Or
• Under refrigeration at 36°F to 46°F (2°C to 8°C) for no more than 24 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.

Do not freeze or shake diluted solution.

Administration

• Administer the diluted solution over 60 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micron).
• Do not co-administer other drugs through the same intravenous line.

HOW SUPPLIED

Dosage Forms And Strengths

Injection: 200 mg/10 mL (20 mg/mL), clear, colorless to slightly yellow solution in a single-dose vial.

Storage And Handling

BAVENCIO (avelumab) Injectionis a sterile, preservative-free, and clear, colorless to slightly yellow solution for intravenous infusion supplied as a single-dose vial of 200 mg/10 mL (20 mg/mL), individually packed into a carton (NDC44087-3535-1).

Store refrigerated at 36°F to 46°F (2°C to 8°C) in original package to protect from light.

Do not freeze or shake the vial.

The vial stopper is not made with natural rubber latex.

Manufactured by: EMD Serono, Inc. Rockland, MA 02370 U.S.A. Marketed by: EMD Serono, Inc. and Pfizer Inc., NY, NY 10017. Â Revised: Jul 2022

SIDE EFFECTS

以下临床明显的不良反应ions are described elsewhere in the labeling:

• Severe and fatal immune-mediated adverse reactions [see警告AND PRECAUTIONS]
• Infusion-related reactions [see警告AND PRECAUTIONS]
• Complications of allogeneic HSCT [see警告AND PRECAUTIONS]
• Major adverse cardiovascular events [see警告AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to BAVENCIO 10 mg/kg intravenously every 2 weeks as a single agent in 1738 patients enrolled in the JAVELIN Merkel 200 and JAVELIN Solid Tumor trials and to BAVENCIO 10 mg/kg intravenously every 2 weeks in combination with axitinib 5 mg orally twice daily in 489 patients enrolled in the JAVELIN Renal 100 and JAVELIN Renal 101 trials. In the BAVENCIO monotherapy population, 24% of patients were exposed for ≥ 6 months and 7% were exposed for ≥ 12 months. The population characteristics of BAVENCIO in combination with axitinib are shown below. When BAVENCIO was used in combination with axitinib, 70% of patients were exposed for ≥ 6 months and 31% were exposed for ≥ 12 months. The following criteria were used to classify an adverse reaction as immune-mediated: onset within 90 days after last dose of BAVENCIO, no spontaneous resolution within 7 days of onset, treatment with corticosteroids or other immunosuppressant or hormone replacement therapy, biopsy consistent with immune-mediated reaction, and no other clear etiology.

Metastatic Merkel Cell Carcinoma

The data described below reflect exposure to BAVENCIO 10 mg/kg intravenously every 2 weeks in 88 patients with metastatic MCC enrolled in the JAVELIN Merkel 200 trial. Patients with any of the following were excluded: autoimmune disease; medical conditions requiring systemic immunosuppression; prior organ or allogeneic stem cell transplantation; prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies; central nervous system (CNS) metastases; infection with HIV, hepatitis B, or hepatitis C; or ECOG performance score > 2.

The median duration of exposure to BAVENCIO was 4 months (range: 2 weeks to 21 months). Forty percent of patients received BAVENCIO for more than 6 months and 14% were treated for more than one year [seeClinical Studies]. The study population characteristics were: median age of 73 years (range: 33 to 88), 74% male, 92% White, ECOG performance score of 0 (56%) or 1 (44%), and 65% of patients had one prior anti-cancer therapy for metastatic MCC and 35% had two or more prior therapies.

BAVENCIO was permanently discontinued for adverse reactions in six (7%) patients; adverse reactions resulting in permanent discontinuation were ileus, Grade 3 transaminitis, Grade 3 creatine kinase elevation, tubulointerstitial nephritis, and Grade 3 pericardial effusion. BAVENCIO was temporarily discontinued in 21 (24%) patients for adverse events, excluding temporary dose interruption for infusion-related reactions where infusion was restarted the same day. The most common adverse reaction requiring dose interruption was anemia. Serious adverse reactions that occurred in more than one patient were acute kidney injury, anemia, abdominal pain, ileus, asthenia, and cellulitis. The most common adverse reactions (≥ 20%) were fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema.

Table 3 and Table 4 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, that occurred in patients receiving BAVENCIO.

Table 3: Adverse Reactions in ≥ 10% of Patients Receiving BAVENCIO in the JAVELIN Merkel 200 Trial

Adverse Reactions	BAVENCIO (N=88)
	All Grades %	Grade 3-4 %
General Disorders
Fatiguea	50	2
Infusion-related reactionb	22	0
Peripheral edemac	20	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal paind	32	2
Arthralgia	16	1
Gastrointestinal Disorders
Diarrhea	23	0
Nausea	22	0
Constipation	17	1
Abdominal paine	16	2
Vomiting	13	0
Skin and Subcutaneous Tissue Disorders
Rashf	22	0
Pruritusg	10	0
Metabolism and Nutrition Disorders
Decreased appetite	20	2
Decreased weight	15	0
Respiratory, Thoracic and Mediastinal Disorders
Cough	18	0
Dyspneah	11	1
Nervous System Disorders
Dizziness	14	0
Headache	10	0
Vascular Disorders
Hypertension	13	6
aFatigue is a composite term that includes fatigue and asthenia. bInfusion-related reaction is a composite term that includes drug hypersensitivity, hypersensitivity, chills, pyrexia, back pain, and hypotension. cPeripheral edema is a composite term that includes peripheral edema and peripheral swelling. dMusculoskeletal pain is a composite term that includes back pain, myalgia, neck pain, pain in extremity. eAbdominal pain is a composite term that includes abdominal pain and abdominal pain upper. fRash is a composite term that includes rash maculo-papular, erythema, and dermatitis bullous. gPruritus is a composite term that includes pruritus and pruritus generalized. hDyspnea is a composite term that includes dyspnea and dyspnea exertional.

Table 4: Selected Treatment-Emergent* Laboratory Abnormalities in Patients Receiving BAVENCIO in the JAVELIN Merkel 200 Trial

Laboratory Tests	Any Grade (N=88) %	Grade 3-4 (N=88) %
Chemistry
Increased aspartate aminotransferase (AST)	34	1
Increased alanine aminotransferase (ALT)	20	5
Increased lipase	14	4
Increased amylase	8	1
Increased bilirubin	6	1
Hyperglycemia**	-	7
Hematology
Anemia	35	9
Lymphopenia	49	19
Thrombocytopenia	27	1
Neutropenia	6	1
* Treatment emergent consists of new onset of laboratory abnormality or worsening of baseline laboratory abnormality. ** Hyperglycemia limited to Grade ≥ 3 events since fasting measurements were not obtained routinely.

局部晚期或转移性移行细胞Carcinoma

First-Line Maintenance Treatment Of Urothelial Carcinoma

The safety of BAVENCIO was evaluated in the JAVELINBladder100 trial where patients received BAVENCIO 10 mg/kg every 2 weeks plus bestsupportive care(BSC) (N=344) or BSC alone (N=345). Patients withautoimmunediseases or conditions requiring systemicimmunosuppressionwere excluded.

In the BAVENCIO plus BSC arm, 47% were exposed to BAVENCIO for > 6 months and 28% were exposed for > 1 year [seeClinical Studies].

The median age of patients treated with BAVENCIO plus BSC was 69 years (range: 37 to 90), 63% of patients were 65 years or older, 76% were male, 67% were White, and theECOGperformance score was 0 (61%) or 1 (39%).

A fatal adverse reaction (sepsis) occurred in one (0.3%) patient receiving BAVENCIO plus BSC.

Serious adverse reactions occurred in 28% of patients receiving BAVENCIO plus BSC. Serious adverse reactions in ≥ 1% of patients includedurinary tract infection(including kidney infection,pyelonephritis, and urosepsis) (6.1%), pain (including abdominal, back, bone,flank, extremity, andpelvic pain) (3.2%), acute kidney injury (1.7%),hematuria(1.5%), sepsis (1.2%), and infusion-related reaction (1.2%).

Permanent discontinuation due to an adverse reaction of BAVENCIO plus BSC occurred in 12% of patients. Adverse reactions resulting in permanent discontinuation of BAVENCIO in > 1% of patients weremyocardial infarction(includingacute myocardial infarctionand troponin T increased) (1.5%) and infusion-related reaction (1.2%).

Dose interruptions due to an adverse reaction, excluding temporary interruptions of BAVENCIO infusions due to infusion-related reactions, occurred in 41% of patients receiving BAVENCIO plus BSC. Adverse reactions leading to interruption of BAVENCIO in > 2% of patients wereurinary tractinfection (including pyelonephritis) (4.7%) and blood creatinine increased (including acute kidney injury, renal impairment, and renal failure) (3.8%).

The most common adverse reactions (≥ 20%) in patients receiving BAVENCIO plus BSC were fatigue, musculoskeletal pain, urinary tract infection, and rash.

Thirty-one (9%) patients treated with BAVENCIO plus BSC received an oral prednisone dose equivalent to ≥ 40 mg daily for an immune-mediated adverse reaction [see警告AND PRECAUTIONS].

Table 5 summarizes adverse reactions that occurred in ≥ 10% of patients treated with BAVENCIO plus BSC.

Table 5: Adverse Reactions (≥ 10%) of Patients Receiving BAVENCIO plus BSC (JAVELIN Bladder 100 Trial)

Adverse Reactions	BAVENCIO plus BSC (N=344)		BSC (N=345)
	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %
General Disorders and Administration Site Conditions
Fatiguea	35	1.7	13	1.7
Pyrexia	15	0.3	3.5	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painb	24	1.2	15	2.6
Arthralgia	16	0.6	6	0
Skin and Subcutaneous Tissue Disorders
Rashc	20	1.2	2.3	0
Pruritus	17	0.3	1.7	0
Infections and Infestations
Urinary tract infectiond	20	6	11	3.8
Gastrointestinal Disorders
Diarrhea	17	0.6	4.9	0.3
Constipation	16	0.6	9.0	0
Nausea	16	0.3	6	0.6
Vomiting	13	1.2	3.5	0.6
Respiratory, Thoracic and Mediastinal Disorders
Coughe	14	0.3	4.6	0
Metabolism and Nutrition Disorders
Decreased appetite	14	0.3	7	0.6
Endocrine disorders
Hypothyroidism	12	0.3	0.6	0
Injury, Poisoning and Procedural Complications
Infusion-related reaction	10	0.9	0	0
aFatigue is a composite term that includes fatigue, asthenia and malaise. bMusculoskeletal pain is a composite term that includes musculoskeletal pain, back pain, myalgia, and neck pain. cRash is a composite term that includes rash, rash maculo-papular, erythema, dermatitis acneiform, eczema, erythema multiforme, rash erythematous, rash macular, rash papular, rash pruritic, drug eruption and lichen planus. dUrinary tract infection is a composite term that includes urinary tract infection, urosepsis, cystitis, kidney infection, pyuria, pyelonephritis, bacteriuria, pyelonephritis acute, urinary tract infection bacterial, and Escherichia urinary tract infection. eCough is a composite term that includes cough and productive cough.

患者接受pre-medication anti-histamine and acetaminophen prior to each infusion. Infusion-related reactions occurred in 10% (Grade 3: 0.9%) of patients treated with BAVENCIO plus BSC.

Table 6: Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 10% of Patients Receiving BAVENCIO plus BSC (JAVELIN Bladder 100 Trial)

Laboratory Abnormality	BAVENCIO plus BSC*		BSC*
	Any Grade %	Grade 3-4 %	Any Grade %	Grade 3-4 %
Chemistry
Blood triglycerides increased	34	2.1	28	1.2
Alkaline phosphatase increased	30	2.9	20	2.3
Blood sodium decreased	28	6	20	2.6
Lipase increased	25	8	16	6
Aspartate aminotransferase (AST) increased	24	1.7	12	0.9
Blood potassium increased	24	3.8	16	0.9
Alanine aminotransferase (ALT) increased	24	2.6	12	0.6
Blood cholesterol increased	22	1.2	16	0.3
Serum amylase increased	21	5	12	1.8
CPK increased	19	2.4	12	0
Phosphate decreased	19	3.2	15	1.2
Hematology
Hemoglobin decreased	28	4.4	18	3.2
White blood cell decreased	20	0.6	10	0
Platelet count decreased	18	0.6	12	0.3
*Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: BAVENCIO plus BSC group (range: 339 to 344 patients) and BSC group (range: 329 to 341 patients).

Previously-Treated Urothelial Carcinoma

The safety of BAVENCIO was evaluated in 242 patients with locally advanced or metastatic UC receiving BAVENCIO at 10 mg/kg every 2 weeks in the UC cohorts of the JAVELIN Solid Tumor trial. Patients received pre-medication with an anti-histamineand acetaminophen prior to each infusion. The median duration of exposure to BAVENCIO was 12 weeks (range: 2 weeks to 92 weeks) [seeClinical Studies].

Fourteen patients (6%) who were treated with BAVENCIO experienced either pneumonitis,respiratory failure, sepsis/urosepsis,cerebrovascular accident, orgastrointestinaladverse events, which led to death.

Grade 1-4 serious adverse reactions were reported in 41% of patients. The most frequent serious adverse reactions reported in ≥ 2% of patients were urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, creatinine increased/renal failure, dehydration, hematuria/urinary tracthemorrhage,intestinal obstruction/small intestineobstruction, and pyrexia.

Permanent discontinuation due to an adverse reaction for BAVENCIO occurred in 12% of patients. The adverse reaction that resulted in permanent discontinuation in > 1% of patients was fatigue.

Dose interruptions due to an adverse reaction, excluding temporary interruptions due to infusion-related reactions, occurred in 29% of patients receiving BAVENCIO. Adverse reactions leading to interruption of BAVENCIO in > 1% of patients were diarrhea, fatigue,dyspnea, urinary tract infection, and rash.

The most common Grade 3 and 4 adverse reactions (≥ 3%) wereanemia, fatigue,hyponatremia,hypertension, urinary tract infection, and musculoskeletal pain.

The most common adverse reactions (≥ 20%) were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.

Eleven (4.5%) patients received an oral prednisone dose equivalent to ≥ 40 mg daily for an immune-mediated adverse reaction [see警告AND PRECAUTIONS].

Advanced Renal Cell Carcinoma

BAVENCIO评估在标枪再保险的安全nal 101. Patients withautoimmune diseaseother than type Idiabetes mellitus,vitiligo,psoriasis, orthyroiddisorders not requiring immunosuppressive treatment were excluded. Patients received BAVENCIO 10 mg/kg every 2 weeks administered in combination with axitinib 5 mg twice daily (N=434) or sunitinib 50 mg once daily for 4 weeks followed by 2 weeks off (N=439).

In the BAVENCIO plus axitinib arm, 70% were exposed to BAVENCIO for ≥ 6 months and 29% were exposed for ≥ 1 year in JAVELIN Renal 101 [seeClinical Studies].

The median age of patients treated with BAVENCIO in combination with axitinib was 62 years (range: 29 to 83), 38% of patients were 65 years or older, 71% were male, 75% were White, and the ECOG performance score was 0 (64%) or 1 (36%).

Fatal adverse reactions occurred in 1.8% of patients receiving BAVENCIO in combination with axitinib. These included sudden cardiac death (1.2%),stroke(0.2%),myocarditis(0.2%), and necrotizingpancreatitis(0.2%).

Serious adverse reactions occurred in 35% of patients receiving BAVENCIO in combination with axitinib. Serious adverse reactions in ≥ 1% of patients included diarrhea (2.5%), dyspnea (1.8%), hepatotoxicity (1.8%), venous thromboembolic disease (1.6%), acute kidney injury (1.4%), andpneumonia(1.2%).

Permanent discontinuation due to an adverse reaction of either BAVENCIO or axitinib occurred in 22% of patients: 19% BAVENCIO only, 13% axitinib only, and 8% both drugs. The most common adverse reactions (> 1%) resulting in permanent discontinuation of BAVENCIO or the combination were hepatotoxicity (6%) and infusion-related reaction (1.8%).

Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of BAVENCIO infusions due to infusion-related reactions, occurred in 76% of patients receiving BAVENCIO in combination with axitinib. This includes interruption of BAVENCIO in 50% of patients. Axitinib was interrupted in 66% and dose reduced in 19% of patients. The most common adverse reaction (> 10%) resulting in interruption of BAVENCIO was diarrhea (10%) and the most common adverse reactions resulting in either interruption or dose reduction of axitinib were diarrhea (19%), hypertension (18%),palmar-plantarerythrodysesthesia (18%), and hepatotoxicity (10%).

The most common adverse reactions (≥ 20%) in patients receiving BAVENCIO in combination with axitinib were diarrhea, fatigue, hypertension, musculoskeletal pain, nausea,mucositis, palmar-plantar erythrodysesthesia,dysphonia, decreased appetite,hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache.

Forty-eight (11%) patients treated with BAVENCIO in combination with axitinib received an oral prednisone dose equivalent to ≥ 40 mg daily for an immune-mediated adverse reaction [see警告AND PRECAUTIONS].

Table 7 summarizes adverse reactions that occurred in ≥ 20% of BAVENCIO in combination with axitinib-treated patients.

Table 7: Adverse Reactions (≥ 20%) of Patients Receiving BAVENCIO in Combination with Axitinib (JAVELIN Renal 101 Trial)

Adverse Reactions	BAVENCIO plus Axitinib (N=434)		Sunitinib (N=439)
	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %
Gastrointestinal Disorders
Diarrheaa	62	8	48	2.7
Nausea	34	1.4	39	1.6
Mucositisb	34	2.8	35	2.1
Hepatotoxicityc	24	9	18	3.6
Abdominal paind	22	1.4	19	2.1
General Disorders and Administration Site Conditions
Fatiguee	53	6	54	6
Vascular Disorders
Hypertensionf	50	26	36	17
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal paing	40	3.2	33	2.7
Skin and Subcutaneous Tissue Disorders
Palmar-plantar erythrodysesthesia	33	6	34	4
Rashh	25	0.9	16	0.5
Respiratory, Thoracic and Mediastinal Disorders
Dysphonia	31	0.5	3.2	0
Dyspneai	23	3	16	1.8
Cough	23	0.2	19	0
Metabolism and Nutrition Disorders
Decreased appetite	26	2.1	29	0.9
Endocrine Disorders
Hypothyroidism	25	0.2	14	0.2
Nervous System Disorders
Headache	21	0.2	16	0.2
aDiarrhea is a composite term that includes diarrhea, autoimmune colitis, and colitis. bMucositis is a composite term that includes mucosal inflammation and stomatitis. cHepatotoxicity is a composite term that includes ALT increased, AST increased, autoimmune hepatitis, bilirubin conjugated, bilirubin conjugated increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatitis, hepatitis fulminant, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, liver disorder, liver injury, and transaminases increased. dAbdominal pain is a composite term that includes abdominal pain, flank pain, abdominal pain upper, and abdominal pain lower. eFatigue is a composite term that includes fatigue and asthenia. fHypertension is a composite term that includes hypertension and hypertensive crisis. gMusculoskeletal pain is a composite term that includes musculoskeletal pain, musculoskeletal chest pain, myalgia, back pain, bone pain, musculoskeletal discomfort, neck pain, spinal pain, and pain in extremity. hRash is a composite term that includes rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, rash erythematous, rash papular, and rash pustular. iDyspnea is a composite term that includes dyspnea, dyspnea exertional and dyspnea at rest.

Other clinically important adverse reactions that occurred in less than 20% of patients in JAVELIN Renal 101 included arthralgia, weight decreased, and chills.

患者接受pre-medication anti-histamine and acetaminophen prior to each infusion. Infusion-related reactions occurred in 12% (Grade 3: 1.6%; no Grade 4) of patients treated with BAVENCIO in combination with axitinib.

Table 8 summarizes selected laboratory abnormalities that occurred in ≥ 20% of BAVENCIO in combination with axitinib-treated patients.

Table 8: Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients Receiving BAVENCIO in Combination with Axitinib (JAVELIN Renal 101 Trial)

Laboratory Abnormality	BAVENCIO plus Axitinib*		Sunitinib*
	Any Grade %	Grade 3-4 %	Any Grade %	Grade 3-4 %
Chemistry
Blood triglycerides increased	71	13	48	5
Blood creatinine increased	62	2.3	68	1.4
Blood cholesterol increased	57	1.9	22	0.7
Alanine aminotransferase increased (ALT)	50	9	46	3.2
Aspartate aminotransferase increased (AST)	47	7	57	3.2
Blood sodium decreased	38	9	37	10
Lipase increased	37	14	25	7
Blood potassium increased	35	3	28	3.9
Blood bilirubin increased	21	1.4	23	1.4
Hematology
Platelet count decreased	27	0.7	80	15
Hemoglobin decreased	21	2.1	65	8
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: BAVENCIO in combination with axitinib group (range: 413 to 428 patients) and sunitinib group (range: 405 to 433 patients).

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to avelumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Of the 344 patients treated with BAVENCIO 10 mg/kg as an intravenous infusion every 2 weeks plus BSC, 325 were evaluable for treatment-emergent anti-drug antibodies (ADA) and 62 (19.1%) tested positive in the JAVELIN Bladder 100 trial.

Of the 480 patients treated with BAVENCIO 10 mg/kg as an intravenous infusion every 2 weeks in combination with axitinib 5 mg twice daily, 453 were evaluable for treatment-emergent ADA and 66 (15%) tested positive in the JAVELIN Renal 100 and JAVELIN Renal 101 trials.

Patients who tested positive for treatment-emergent ADA had decreased systemic BAVENCIO exposure [seeCLINICAL PHARMACOLOGY]. In exploratory analyses, the effect of ADA on the efficacy or safety could not be determined due to insufficient numbers of patients in the ADA-positive subgroup and confounding variables.

DRUG INTERACTIONS

No Information provided

警告

Included as part of thePRECAUTIONSsection.

PRECAUTIONS

Severe And Fatal Immune-Mediated Adverse Reactions

BAVENCIO is amonoclonalantibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of theimmune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Early identification and management of immune-mediated adverse reactions areessentialto ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue BAVENCIO depending on severity [seeDOSAGE AND ADMINISTRATION]. In general, if BAVENCIO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic corticosteroids (e.g., endocrinopathies anddermatologicreactions) are discussed below.

Immune-Mediated Pneumonitis

BAVENCIO can cause immune-mediated pneumonitis. Immune-mediated pneumonitis occurred in 1.2% (21/1738) of patients receiving BAVENCIO, including fatal (0.1%), Grade 4 (0.1%), Grade 3 (0.3%) and Grade 2 (0.6%) adverse reactions. Pneumonitis led to permanent discontinuation of BAVENCIO in 0.3% and withholding of BAVENCIO in 0.3% of patients.

Systemic corticosteroids were required in all (21/21) patients with pneumonitis. Pneumonitis resolved in 57% (12/21) of the patients. Of the 5 patients in whom BAVENCIO was withheld for pneumonitis, 5 reinitiated treatment with BAVENCIO after symptom improvement; of these, none had recurrence of pneumonitis.

With other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received priorthoracicradiation.

Immune-Mediated Colitis

BAVENCIO can cause immune-mediatedcolitis. The primary component of the immune-mediated colitis consisted of diarrhea.Cytomegalovirus(CMV)感染/活化在pati报道ents with corticosteroid-refractoryimmune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-mediated colitis occurred in 1.5% (26/1738) of patients receiving BAVENCIO, including Grade 3 (0.4%) and Grade 2 (0.7%) adverse reactions. Colitis led to permanent discontinuation of BAVENCIO in 0.5% and withholding of BAVENCIO in 0.5% of patients.

Systemic corticosteroids were required in all (26/26) patients with colitis. Colitis resolved in 69% (18/26) of the patients. Of the 8 patients in whom BAVENCIO was withheld for colitis, 5 reinitiated treatment with BAVENCIO after symptom improvement; of these, 40% had recurrence of colitis.

Hepatotoxicity And Immune-Mediated Hepatitis

BAVENCIO As A Single Agent

BAVENCIO can cause immune-mediatedhepatitis. Immune-mediated hepatitis occurred in 0.9% (16/1738) of patients receiving BAVENCIO, including fatal (0.1%), Grade 3 (0.6%), and Grade 2 (0.1%) adverse reactions. Hepatitis led to permanent discontinuation of BAVENCIO in 0.5% and withholding of BAVENCIO in 0.2% of patients.

Systemic corticosteroids were required in all (16/16) patients with hepatitis. Hepatitis resolved in 56% (9/16) of the patients. Of the 3 patients in whom BAVENCIO was withheld for hepatitis, 3 reinitiated treatment with BAVENCIO after symptom improvement; of these, none had recurrence of hepatitis.

BAVENCIO With Axitinib

BAVENCIO in combination with axitinib can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 ALT and AST elevation compared to BAVENCIO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy. For elevated liver enzymes, interrupt BAVENCIO and axitinib and consider administering corticosteroids as needed [seeDOSAGE AND ADMINISTRATION].

In patients treated with BAVENCIO in combination with axitinib in the advanced RCC trials, increased ALT and increased AST were reported in 9% (Grade 3) and 7% (Grade 4) of patients. In patients with ALT ≥ 3 times ULN (Grades 2-4, n=82), ALT resolved to Grades 0-1 in 92%. Among the 73 patients who were rechallenged with either BAVENCIO (n=3) or axitinib (n=25) administered as a single agent or with both (n=45), recurrence of ALT ≥3 times ULN was observed in no patient receiving BAVENCIO, 6 patients receiving axitinib, and 15 patients receiving both BAVENCIO and axitinib. Twenty-two (88%) patients with a recurrence of ALT ≥3 ULN subsequently recovered to Grade 0-1 from the event. Immune-mediated hepatitis was reported in 7% of patients including 4.9% with Grade 3 or 4 immune-mediated hepatitis. Hepatotoxicity led to permanent discontinuation in 6.5% and immune-mediated hepatitis led to permanent discontinuation of either BAVENCIO or axitinib in 5.3% of patients. Thirty-four patients were treated with corticosteroids and one patient was treated with a non-steroidalimmunosuppressant.Resolutionof hepatitis occurred in 31 of the 35 patients at the time of data cut-off.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

BAVENCIO can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiatesymptomatic treatment, including hormone replacement, as clinically indicated. Withhold BAVENCIO depending on severity [seeDOSAGE AND ADMINISTRATION].

Immune-mediated adrenal insufficiency occurred in 0.5% (8/1738) of patients receiving BAVENCIO, including Grade 3 (0.1%), and Grade 2 (0.3%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of BAVENCIO in 0.1% and withholding of BAVENCIO in 0.1% of patients.

Systemic corticosteroids were required in all (8/8) patients with adrenal insufficiency. Adrenal insufficiency did not resolve in any patient (0/8). Of the 2 patients in whom BAVENCIO was withheld for adrenal insufficiency, none reinitiated treatment with BAVENCIO.

Hypophysitis

BAVENCIO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache,photophobia, orvisual fielddefects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement, as clinically indicated.

Withhold or permanently discontinue BAVENCIO depending on severity [seeDOSAGE AND ADMINISTRATION].

Immune-mediatedpituitarydisorders occurred in 0.1% (1/1738) of patients receiving BAVENCIO which was a Grade 2 (0.1%) adverse reactions. Hypopituitarism did not lead to withholding of BAVENCIO in this patient. Systemic corticosteroids were not required in this patient.

Thyroid Disorders

BAVENCIO can cause immune-mediated thyroid disorders.Thyroiditiscan present with or withoutendocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism, as clinically indicated. Withhold or permanently discontinue BAVENCIO depending on severity [seeDOSAGE AND ADMINISTRATION].

Thyroiditisoccurred in 0.2% (4/1738) of patients receiving BAVENCIO, including Grade 2 (0.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation or withholding of BAVENCIO in any patients. No patients with thyroiditis required systemic corticosteroids. Thyroiditis did not resolve in any patients (0/4).

Hyperthyroidismoccurred in 0.4% (7/1738) of patients receiving BAVENCIO, including Grade 2 (0.3%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of BAVENCIO in any patients and led to withholding of BAVENCIO in 0.1% of patients. Systemic corticosteroids were required in 29% (2/7) of patients with hyperthyroidism. Hyperthyroidism resolved in 86% (6/7) of the patients. Of the 2 patients in whom BAVENCIO was withheld for hyperthyroidism, 2 reinitiated treatment with BAVENCIO after symptom improvement; of these, none had recurrence of hyperthyroidism.

Hypothyroidismoccurred in 5% (90/1738) of patients receiving BAVENCIO, including Grade 3 (0.2%) and Grade 2 (3.7%) adverse reactions. Hypothyroidism led to permanent discontinuation of BAVENCIO in 0.1% and withholding of BAVENCIO in 0.5% of patients. Systemic corticosteroids were required in 7% (6/90) of patients with hypothyroidism. Hypothyroidism resolved in 4% (4/90) of the patients. Of the 8 patients in whom BAVENCIO was withheld for hypothyroidism, none reinitiated BAVENCIO.

Type I Diabetes Mellitus, which can present with Diabetic Ketoacidosis:Monitor patients forhyperglycemiaor other signs and symptoms ofdiabetes. Initiate treatment withinsulinas clinically indicated. Withhold BAVENCIO depending on severity [seeDOSAGE AND ADMINISTRATION].

Immune-mediated Type I diabetes mellitus occurred in 0.1% (2/1738) of patients receiving BAVENCIO, including Grade 3 (0.1%) adverse reactions. Type I diabetes mellitus led to permanent discontinuation of BAVENCIO in these two patients. Type I diabetes mellitus did not lead to withholding of BAVENCIO in any patient. Systemic corticosteroids were not required in any patient with Type I diabetes mellitus. Type I diabetes mellitus resolved in no patient and all patients required ongoing insulin treatment.

Immune-Mediated Nephritis With Renal Dysfunction

BAVENCIO can cause immune-mediatednephritis.

免疫介导性肾炎和肾功能不全啊ccurred in 0.1% (1/1738) of patients receiving BAVENCIO, which was a Grade 2 (0.1%) adverse reactions. Nephritis with renal dysfunction led to permanent discontinuation of BAVENCIO in this patient. Nephritis did not lead to withholding of BAVENCIO in any patient.

Systemic corticosteroids were required in this patient. Nephritis with renal dysfunction did not resolve in this patient.

Immune-Mediated Dermatologic Adverse Reactions

BAVENCIO can cause immune-mediated rash ordermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome, DRESS, andtoxic epidermal necrolysis(TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue BAVENCIO depending on severity [seeDOSAGE AND ADMINISTRATION].

Immune-mediated dermatologic adverse reactions occurred in 5% (90/1738) of patients receiving BAVENCIO, including Grade 3 (0.1%) and Grade 2 (2.0%) adverse reactions. Dermatologic adverse reactions led to permanent discontinuation of BAVENCIO in 0.3% of patients and withholding of BAVENCIO in 0.4% of patients.

全身糖皮质激素被要求在29% (26 /90) of patients with dermatologic adverse reactions. One patient required the addition of tacrolimus to high-dose corticosteroids. Dermatologic adverse reactions resolved in 41% (37/90) of the patients. Of the 7 patients in whom BAVENCIO was withheld for dermatologic adverse reactions, 3 reinitiated treatment with BAVENCIO after symptom improvement; of these, none had recurrence of dermatologic adverse reaction.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of < 1% (unless otherwise noted) in patients who received BAVENCIO or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Cardiac/Vascular:Myocarditis,pericarditis,vasculitis.

Gastrointestinal:Pancreatitis to include increases in serumamylaseandlipaselevels,gastritis,duodenitis.

Nervous System:Meningitis,encephalitis,myelitisanddemyelination, myasthenic syndrome/myasthenia gravis(including exacerbation), Guillain-Barré syndrome, nerveparesis, autoimmuneneuropathy.

Ocular:Uveitis,iritis, and otherocularinflammatory toxicities can occur. Some cases can be associated withretinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada like syndrome, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Musculoskeletal and Connective Tissue:Myositis/polymyositis,rhabdomyolysis(and associatedsequelaeincluding renal failure),arthritis,polymyalgiarheumatic.

Endocrine:Hypoparathyroidism.

Other (Hematologic/Immune):Hemolytic anemia,aplastic anemia,hemophagocytic lymphohistiocytosis, systemicinflammatory responsesyndrome,histiocytic necrotizing lymphadenitis(Kikuchi lymphadenitis),sarcoidosis,immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

BAVENCIO can cause severe or life-threatening infusion-related reactions [seeADVERSE REACTIONS]. Premedicate with antihistamine and acetaminophen prior to the first 4 infusions. Monitor patients for signs and symptoms of infusion-related reactions including pyrexia, chills, flushing,hypotension, dyspnea,wheezing,back pain, abdominal pain, andurticaria. Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions. Stop the infusion and permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions [seeDOSAGE AND ADMINISTRATIONandADVERSE REACTIONS].

Infusion-related reactions occurred in 25% of patients treated with BAVENCIO including three (0.2%) Grade 4 and nine (0.5%) Grade 3 infusion-related reactions. Ninety-three percent of patients received premedication with antihistamine and acetaminophen. Eleven (92%) of the 12 patients with Grade ≥ 3 reactions were treated with intravenous corticosteroids. Fourteen percent of patients had infusion-related reactions that occurred after the BAVENCIO infusion was completed.

Complications Of Allogeneic HSCT

Fatal and other serious complications can occur in patients who receiveallogeneichematopoieticstem cell transplantation(HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensityconditioning, andsteroid-requiringfebrilesyndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

Major Adverse Cardiovascular Events (MACE)

BAVENCIO结合axitinib会导致severe and fatalcardiovascularevents. Consider baseline and periodic evaluations of leftventricularejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, ordyslipidemia. Discontinue BAVENCIO and axitinib for Grade 3-4 cardiovascular events.

MACEoccurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with axitinib compared to 3.4% treated with sunitinib in a randomized trial, JAVELIN Renal 101. These events included death due to cardiac events (1.4%), Grade 3-4 myocardialinfarction(2.8%), and Grade 3-4congestive heart failure(1.8%). Median time to onset of MACE was 4.2 months (range: 2 days to 24.5 months).

Embryo-Fetal Toxicity

Based on its mechanism of action, BAVENCIO can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. If this drug is used during pregnancy, or if the patient becomes pregnant while taking BAVENCIO, inform the patient of the potential risk to a fetus. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least one month after the last dose of BAVENCIO [seeUse In Specific Populations].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Immune-Mediated Adverse Reactions

Inform patients of the risk of immune-mediated adverse reactions requiring corticosteroids or hormone replacement therapy, including, but not limited to:

• Pneumonitis:建议患者联系医疗提供er immediately for new or worsening cough, chest pain, or shortness of breath [see警告AND PRECAUTIONS].
• Colitis:建议患者联系医疗提供er immediately for diarrhea or severe abdominal pain [see警告AND PRECAUTIONS].
• Hepatitis:建议患者联系医疗提供er immediately forjaundice, severe nausea or vomiting, pain on the right side of abdomen,lethargy, or easy bruising or bleeding [see警告AND PRECAUTIONS].
• Endocrinopathies:建议患者联系医疗提供er immediately for signs or symptoms of adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus [see警告AND PRECAUTIONS].
• Nephritis with Renal Dysfunction:建议患者联系医疗提供er immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see警告AND PRECAUTIONS].
• Dermatologic Adverse Reactions:建议患者联系医疗提供er immediately for signs or symptoms of skin rash, itchy skin, rash with tiny spots andbumps, reddening of skin, blisters or peeling [see警告AND PRECAUTIONS].

Infusion-Related Reactions

建议患者联系医疗提供er immediately for signs or symptoms of potential infusion-related reactions [see警告AND PRECAUTIONS].

Complications Of Allogeneic HSCT

Advise patients of the risk of post-allogeneic hematopoieticstem celltransplantation complications [see警告AND PRECAUTIONS].

Major Adverse Cardiovascular Events

Advise patients receiving BAVENCIO in combination with axitinib to contact their healthcare provider immediately for signs or symptoms of cardiovascular events including but not limited to new or worsening chest discomfort, dyspnea, or peripheral edema [see警告AND PRECAUTIONS].

Embryo-Fetal Toxicity

Advise females of reproductive potential that BAVENCIO can cause fetal harm. Instruct females of reproductive potential to use effective contraception during and for at least one month after the last dose of BAVENCIO [see警告AND PRECAUTIONSandUse In Specific Populations].

Lactation

Advise nursing mothers not to breastfeed while taking BAVENCIO and for at least one month after the final dose [seeUse In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No studies have been conducted to assess the potential of avelumab for genotoxicity or carcinogenicity.

Fertility studies have not been conducted with avelumab; however, an assessment of male and female reproductive organs was included in 3-month repeat-dose toxicity study in Cynomolgus monkeys. Weekly administration of avelumab did not result in any notable effects in the male and female reproductive organs.

Use In Specific Populations

Pregnancy

Risk Summary

Based on its mechanism of action, BAVENCIO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of BAVENCIO in pregnant women [seeCLINICAL PHARMACOLOGY]. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death [seeData]. Human IgG1 immunoglobulins (IgG1) are known to cross the placenta. Therefore, BAVENCIO has the potential to be transmitted from the mother to the developing fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects andmiscarriagein clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Animal reproduction studies have not been conducted with BAVENCIO to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternalimmune toleranceto the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering BAVENCIO during pregnancy include increased rates ofabortionor stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1knockoutmice. Based on its mechanism of action, fetal exposure to BAVENCIO may increase the risk of developing immune-related disorders or altering the normal immune response.

Lactation

Risk Summary

没有信息的存在avelumab in human milk, the effects on the breastfed infant, or the effects on milk production. Since many drugs including antibodies are excreted in human milk, advise a lactating woman not to breastfeed during treatment and for at least one month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.

Females And Males Of Reproductive Potential

Contraception

Based on its mechanism of action, BAVENCIO can cause fetal harm when administered to a pregnant woman [seeUse In Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO.

Pediatric Use

The safety and effectiveness of BAVENCIO have been established in pediatric patients aged 12 years and older for metastatic MCC. Use of BAVENCIO in this age group is supported by evidence from adequate and well-controlled studies of BAVENCIO in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the steady state exposure of avelumab, that drug exposure is generally similar between adults and pediatric patients age 12 years and older for monoclonal antibodies, and that the course of MCC is sufficiently similar in adult and pediatric patients to allow extrapolation of data in adults to pediatric patients. The recommended dose in pediatric patients 12 years of age or greater is the same as that in adults [seeDOSAGE AND ADMINISTRATION,CLINICAL PHARMACOLOGY, andClinical Studies].

Safety and effectiveness of BAVENCIO have not been established in pediatric patients less than 12 years of age.

Geriatric Use

Metastatic Merkel Cell Carcinoma

Clinical studies of BAVENCIO in MCC did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

局部晚期或转移性移行细胞Carcinoma

Of the 344 patients randomized to BAVENCIO 10 mg/kg plus BSC in the JAVELIN Bladder 100 trial, 63% were 65 years or older and 24% were 75 years or older. No overall differences in safety or efficacy were reported between elderly patients and younger patients.

Advanced Renal Cell Carcinoma

的434名患者随机分配到BAVENCIO 10毫克/ kg administered in combination with axitinib 5 mg twice daily in the JAVELIN Renal 101 trial, 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety or efficacy were reported between elderly patients and younger patients.

OVERDOSE

No Information provided

CONTRAINDICATIONS

None.

CLINICAL PHARMACOLOGY

Mechanism Of Action

PD-L1 may be expressed on tumor cells and tumor-infiltrating immune cells and can contribute to the inhibition of the anti-tumor immune response in the tumor microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells andantigenpresenting cells suppressescytotoxicT-cell activity, T-cell proliferation, andcytokineproduction. 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 anti-tumor immune responses. Avelumab has also been shown to induceantibody-dependent cell-mediated cytotoxicity(ADCC) in vitro. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.

Pharmacodynamics

Based on exposure efficacy and exposure safety relationships, there are no expected clinically meaningful differences in the safety or efficacy of BAVENCIO administered every 2 weeks at 800 mg or 10 mg/kg in patients with metastatic Merkel cell carcinoma, in patients with urothelial carcinoma and in patients with advanced renal cell carcinoma.

Pharmacokinetics

Avelumab pharmacokinetics (PK) was assessed using a population PK approach for both single-agent BAVENCIO and BAVENCIO in combination with axitinib. There are no expected clinically meaningful differences in exposure of avelumab administered every 2 weeks at 800 mg or 10 mg/kg in both settings.

BAVENCIO As A Single Agent

The pharmacokinetics of avelumab as a single agent was studied in 1629 patients who received doses ranging from 1 to 20 mg/kg every 2 weeks. The data showed that the exposure of avelumab increased dose-proportionally in the dose range of 10 to 20 mg/kg every 2 weeks. Steady-state concentrations of avelumab were reached after approximately 4 to 6 weeks (2 to 3 cycles) of repeated dosing, and the systemic accumulation was approximately 1.25-fold. The geometric mean volume of distribution at steady state for a subject receiving 10 mg/kg was 4.72 L. The primary elimination mechanism of avelumab is proteolytic degradation. Based on population pharmacokinetic analyses in patients with solid tumors, the total systemic clearance was 0.59 L/day and the terminal half-life was 6.1 days in patients receiving 10 mg/kg. In a post hoc analysis, avelumab clearance was found to decrease over time in patients with MCC, with a mean maximal reduction (% coefficient of variation [CV%]) from baseline value of approximately 32.1% (36.2%), which is not considered clinically important. There was no evidence to suggest a change of avelumab clearance over time in patients with UC.

BAVENCIO With Axitinib

When BAVENCIO 10 mg/kg was administered in combination with axitinib 5 mg, the respective exposures of avelumab and axitinib were comparable to the single agents. There was no evidence to suggest a clinically relevant change of avelumab clearance over time in patients with advanced RCC.

Specific Populations

Body weight was positively correlated with total systemic clearance in population pharmacokinetic analyses. No clinically meaningful differences in pharmacokinetics were observed in the clearance of avelumab based on age; sex; race; PD-L1 status; tumor burden; mild [calculated creatinine clearance (CLcr) 60 to 89 mL/min, n=623 as estimated by the Cockcroft-Gault formula], moderate [CLcr 30 to 59 mL/min, n=320], or severe [CLcr 15 to 29 mL/min, n=4] renal impairment; and mild [bilirubin less than or equal to ULN and AST greater than ULN or bilirubin between 1 and 1.5 times ULN, n=217] or moderate [bilirubin between 1.5 and 3 times ULN, n=4] hepatic impairment. There are limited data from patients with severe hepatic impairment [bilirubin greater than 3 times ULN, n=1], and the effect of severe hepatic impairment on the pharmacokinetics of avelumab is unknown. In patients with advanced UC or advanced RCC, BAVENCIO clearance in patients who tested positive for treatment-emergent ADA was approximately 15% higher as compared to clearance in patients who tested negative for treatment-emergent ADA.

Animal Toxicology And/Or Pharmacology

In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M.tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection withlymphocyticchoriomeningitis virus.

Clinical Studies

Metastatic Merkel Cell Carcinoma

BAVENCIO是朱元璋的疗效和安全性ed in the JAVELIN Merkel 200 trial (NCT02155647), an open-label, single-arm, multi-center study conducted in patients with histologically confirmed metastatic MCC whose disease had progressed on or after chemotherapy administered for distant metastatic disease. The trial excluded patients with autoimmune disease; medical conditions requiring systemic immunosuppression; prior organ or allogeneic stem cell transplantation; prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies; CNS metastases; infection withHIV,hepatitis B, orhepatitis C; or ECOG performance score ≥ 2.

Patients received BAVENCIO 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Patients with radiological disease progression not associated with significant clinical deterioration, defined as no new or worsening symptoms, no change in performance status for greater than 2 weeks, and no need forsalvage therapy, could continue treatment. Tumor response assessments were performed every 6 weeks. The major efficacy outcome measures were confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by a blinded independent central review committee (IRC) and IRC-assessed duration of response. The efficacy analysis was conducted when the last patient enrolled had completed 12 months of follow-up.

A total of 88 patients were enrolled. Baseline patient characteristics were a median age of 73 years (range: 33 to 88), 74% of patients were male, 92% were White, and the ECOG performance score was 0 (56%) or 1 (44%). Seventy-five percent of patients were 65 years or older, 35% were 75 or older, and 3% were 85 or older. Sixty-five percent of patients were reported to have had one prior anti-cancer therapy for metastatic MCC and 35% had two or more prior therapies. Fifty-three percent of patients hadvisceralmetastases. All patients had tumor samples evaluated for PD-L1 expression; of these, 66% were PD-L1-positive (≥ 1% of tumor cells), 18% were PD-L1 negative, and 16% had non-evaluable results by an investigational immunohistochemistry assay. Archival tumor samples were evaluated for Merkel cell polyomavirus (MCV) using an investigational assay; of the 77 patients with evaluable results, 52% had evidence of MCV.

Efficacy results are presented in Table 9. Responses were observed in patients regardless of tumor PD-L1 expression or presence of MCV.

Table 9: Efficacy Results of the JAVELIN Merkel 200 Trial

Efficacy Endpoints	Results (N=88)
Overall Response Rate (ORR)
Overall response rate, (95% CI)	33.0% (23.3%, 43.8%)
Complete response (CR) rate, (95% CI)	11.4% (6.6%, 19.9%)
Partial response (PR) rate, (95% CI)	21.6% (13.5%, 31.7%)
Duration of Response (DOR)	N=29
Range in months	2.8 to 23.3+
Patients with DOR ≥ 6 months, n (%)	25 (86%)
Patients with DOR ≥ 12 months, n (%)	13 (45%)
CI:Confidence interval.

局部晚期或转移性移行细胞Carcinoma

First-Line Maintenance Treatment Of Urothelial Carcinoma

BAVENCIO是朱元璋的疗效和安全性ed in the JAVELIN Bladder 100 trial (NCT02603432), a randomized, multi-center, open-label study conducted in 700 patients withunresectable,局部晚期或转移性移行细胞carcinoma that did not progress with first-line platinum-containing chemotherapy. Patients with autoimmune disease or a medical condition that required immunosuppression were excluded.

Randomizationwas stratified by best response to chemotherapy (CR/PR vs. stable disease [SD]) and site ofmetastasis(visceral vs. non-visceral) at the time of initiating first-line chemotherapy. Patients were randomized (1:1) to receive either BAVENCIO 10 mg/kg intravenous infusion every 2 weeks plus best supportive care (BSC) or BSC alone. Treatment was initiated within 4-10 weeks after the last dose of chemotherapy.

治疗BAVENCIO直到RECIST v1。1-defined progression of disease by Blinded Independent Central Review (BICR) assessment or unacceptable toxicity. Administration of BAVENCIO was permitted beyond RECIST-defined disease progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, 8 weeks after randomization, then every 8 weeks up to 12 months after randomization, and every 12 weeks thereafter until documented confirmed disease progression based on BICR assessment per RECIST v1.1.

Baseline characteristics were well-balanced between arms. Overall, the median age was 69 years (range: 32 to 90), with 66% of patients ≥ 65 years of age and 24% of patients ≥ 75 years of age. Most patients were male (77%). The majority of patients were White (67%) and 22% were Asian. Baseline ECOG PS was 0 (61%) or 1 (39%).

Fifty-six percent (56%) of patients received prior gemcitabine pluscisplatin, 38% of patients received prior gemcitabine plus carboplatin, and 6% of patients received prior gemcitabine plus cisplatin and gemcitabine plus carboplatin. Best response to first-line chemotherapy was CR or PR (72%) or SD (28%). Sites of metastasis prior to chemotherapy were visceral (55%) or non-visceral (45%). Fifty-one (51%) of patients had PD-L1-positive-tumors, 39% of patients had

PD-L1-negative tumors, and 10% of patients had unknown PD-L1 tumor status. Six percent (6%) of patients received another PD-1/PD-L1checkpointinhibitor after discontinuation of treatment in the BAVENCIO plus BSC arm and 44% of patients in the BSC arm.

The major efficacy outcome measure was overall survival (OS) in all randomized patients and patients with PD-L1-positive tumors. The results from a pre-specified interim analysis demonstrated a statistically significant improvement in OS for patients randomized to BAVENCIO plus BSC as compared with BSC alone. An updated OS analysis was conducted when 452 deaths were observed. Consistent results were observed across the pre-specified subgroups of CR/PR versus SD to first-line chemotherapy.

Table 10: Efficacy Results from the JAVELIN Bladder 100 Trial

Efficacy Endpoints	BAVENCIO plus BSC (N=350)	BSC (N=350)
Primary OS
Events (%)	145 (41.4)	179 (51.1)
Median in months	21.4	14.3
(95% CI)	(18.9, 26.1)	(12.9, 17.9)
Hazard ratio (95% CI)	0.69 (0.5	6, 0.86)
p-value*	0.0	01
Updated OS
Events (%)	215 (61.4)	237 (67.7)
Median in months	23.8	15.0
(95% CI)	(19.9, 28.8)	(13.5, 18.2)
Hazard ratio (95% CI)	0.76 (0.6	3, 0.92)
BSC: Best supportive care; CI: Confidence interval; OS: overall survival. * p-value based on 2-sided stratified log-rank.

Figure 1: K-M Estimates for Updated OS from the JAVELIN Bladder 100 Trial

In the pre-specified endpoint of OS among patients with PD-L1-positive tumors (n=358, 51%), the hazard ratio was 0.69 (95% CI: 0.52, 0.90) in the updated OS analysis for patients randomized to BAVENCIO plus BSC versus BSC alone. In an exploratory analysis of patients with PD-L1-negative tumors (n=270, 39%), the updated OS hazard ratio was 0.82 (95% CI: 0.62, 1.09).

Previously-Treated Urothelial Carcinoma

BAVENCIO是朱元璋的疗效和安全性ed in the UC cohorts of the JAVELIN Solid Tumor trial, an open-label, single-arm, multi-center study that included 242 patients with locally advanced or metastatic urothelial carcinoma (UC) with disease progression on or after platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or辅助化疗regimen. Patients with active or history ofcentral nervous systemmetastasis; other malignancies within the last 5 years; organ transplant; conditions requiring therapeutic immune suppression; or active infection with HIV, hepatitis B, or hepatitis C were excluded. Patients with autoimmune disease, other than type I diabetes, vitiligo, psoriasis, or thyroid disease that did not require immunosuppressive treatment, were excluded. Patients were included regardless of their PD-L1 status.

Patients received BAVENCIO at a dose of 10 mg/kg intravenously every 2 weeks until radiographic or clinical progression or unacceptable toxicity. Tumor response assessments were performed every 6 weeks. Efficacy outcome measures included confirmed overall response rate (ORR), as assessed by an Independent Endpoint Review Committee (IERC) using Response

Evaluation Criteria in Solid Tumors (RECIST) v1.1, and duration of response (DOR). Efficacy was evaluated in patients who were followed for a minimum of both 13 weeks and 6 months at the time of data cut-off.

Baseline demographic and disease characteristics for the 226 patients with a minimum of 13 weeks of follow-up were median age 68 years (range: 30 to 89), 72% male, 80% White, and 34% and 66% of patients had an ECOG performance status 0 and 1, respectively. Forty-four percent of patients had non-bladder urothelial carcinoma including 23% of patients with upper tract disease, and 83% of patients had visceral metastases (baseline target and/or non-target lesions present outside of the lymph nodes). Nine (4%) patients had disease progression following prior platinum-containing neoadjuvant oradjuvant therapyonly. Forty-seven percent of patients only received prior cisplatin-based regimens, 32% received only prior carboplatin-based regimens, and 20% received both cisplatin and carboplatin-based regimens. At baseline, 17% of patients had ahemoglobin< 10 g/dL and 34% of patients had liver metastases.

Efficacy results are presented in Table 11. The median time to response was 2.0 months (range: 1.3 to 11.0) among patients followed for either > 13 weeks or > 6 months. Using a clinical trial assay to assess PD-L1 staining, with 16% of patients not evaluable, there were no clear differences in response rates based on PD-L1 tumor expression. Among the total 30 responding patients followed for > 13 weeks, 22 patients (73%) had an ongoing response of 6 months or longer and 4 patients (13%) had ongoing responses of 12 months or longer. Among the total 26 responding patients followed for > 6 months, 22 patients (85%) had ongoing responses of 6 months or longer and 4 patients (15%) had ongoing responses of 12 months or longer.

Table 11: Efficacy Results of the UC Cohorts in the JAVELIN Solid Tumor Trial

Efficacy Endpoints	≥ 13 Weeks Follow-Up (N=226)	≥ 6 Months Follow-Up (N=161)
Confirmed Overall Response Rate (ORR)
Overall Response Rate n (%)	30 (13.3%)	26 (16.1%)
(95% CI)	(9.1, 18.4)	(10.8, 22.8)
Complete Response (CR) n (%)	9 (4.0%)	9 (5.6%)
Partial Response (PR) n (%)	21 (9.3%)	17 (10.6%)
Duration of Response (DOR)
Median, months (range)	NE (1.4+ to 17.4+)	NE (1.4+ to 17.4+)
CI: Confidence interval; NE: Not estimable; + denotes a censored value.

Advanced Renal Cell Carcinoma

The efficacy and safety of BAVENCIO in combination with axitinib was demonstrated in the JAVELIN Renal 101 trial (NCT02684006), a randomized, multicenter, open-label, study of BAVENCIO in combination with axitinib in 886 patients with untreated advanced RCC regardless of tumor PD-L1 expression [intent-to-treat (ITT) population]. Patients with autoimmune disease or conditions requiring systemic immunosuppression were excluded.

Randomization was stratified according to Eastern CooperativeOncologyGroup (ECOG) Performance Status (PS) (0 vs. 1) and region (United States vs. Canada/Western Europe vs. the rest of the world). Patients were randomized (1:1) to one of the following treatment arms:

• BAVENCIO 10 mg/kg intravenous infusion every 2 weeks in combination with axitinib 5 mg twice daily orally (N=442). Patients who tolerated axitinib 5 mg twice daily without Grade 2 or greater axitinib-related adverse events for 2 consecutive weeks could increase to 7 mg and then subsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity.
• Sunitinib 50 mg once daily orally for 4 weeks followed by 2 weeks off (N=444) until radiographic or clinical progression or unacceptable toxicity.

Treatment with BAVENCIO and axitinib continued until RECIST v1.1-defined progression of disease by Blinded Independent Central Review (BICR) assessment or unacceptable toxicity. Administration BAVENCIO and axitinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, after randomization at 6 weeks, then every 6 weeks thereafter up to 18 months after randomization, and every 12 weeks thereafter until documented confirmed disease progression by BICR.

Baseline characteristics were a median age of 61 years (range: 27 to 88), 38% of patients were 65 years or older, 75% were male, 75% were White, and the ECOG PS was 0 (63%) or 1 (37%), respectively. Patient distribution by International Metastatic Renal Cell Carcinoma Database (IMDC) risk groups was 21% favorable, 62% intermediate, and 16% poor.

The major efficacy outcome measures were progression-free survival (PFS), as assessed by an BICR using RECIST v1.1 and overall survival (OS) in patients with PD-L1-positive tumors using a clinical trial assay (PD-L1 expression level ≥ 1%). Since PFS was statistically significant in patients with PD-L1-positive tumors [HR 0.61 (95% CI: 0.48, 0.79)], it was then tested in the ITT population and a statistically significant improvement in PFS in the ITT population was also demonstrated.

With a median overall survival follow-up of 19 months, overall survival data were immature with 27% deaths in the ITT population.

Efficacy results are presented in Table 12 and Figure 2.

Table 12: Efficacy Results from JAVELIN Renal 101 Trial –ITT

Efficacy Endpoints (Based on BICR Assessment)	BAVENCIO plus Axitinib (N=442)	Sunitinib (N=444)
Progression-Free Survival (PFS)
Events (%)	180 (41)	216 (49)
Median in months (95% CI)	13.8 (11.1, NE)	8.4 (6.9, 11.1)
Hazard ratio (95% CI)	0.69 (0.56, 0.84)
p-value*	0.0002
Confirmed Objective Response Rate (ORR)
Objective Response Rate n (%)	227 (51.4)	114 (25.7)
(95% CI)	(46.6, 56.1)	(21.7, 30.0)
Complete Response (CR) n (%)	15 (3.4)	8 (1.8)
Partial Response (PR) n (%)	212 (48)	106 (24)
BICR: Blinded Independent Central Review; CI: Confidence interval; NE: Not estimable. * p-value based on 2-sided stratified log-rank.

Figure 2: K-M Estimates for PFS based on BICR Assessment – ITT

PATIENT INFORMATION

BAVENCIO®
(buh-VEN-see-oh)
(avelumab) injection

What is the most important information I should know about BAVENCIO?

BAVENCIO is a medicine that may treat certain cancers by working with yourimmune system. BAVENCIO can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problem at the same time. These problems may happen anytime during treatment or even after your treatment has ended.

Call or see your healthcare provider right away if you get any new or worsening signs or symptoms, including:

Lung problems.

• cough
• shortness of breath
• chest pain

Intestinal problems.

• diarrhea (loose stools) or more frequent bowel movements than usual
• stools that are black, tarry, sticky, or have blood or mucus
• severe stomach-area (abdomen) pain or tenderness

Liver problems.

• yellowing of your skin or the whites of your eyes
• dark urine (tea colored)
• severe nausea or vomiting
• bleeding or bruising more easily than normal
• pain on the right side of your stomach-area (abdomen)

Hormone gland problems.

• headache that will not go away or unusual
• urinating more often than usual headaches
• hair loss
• eye sensitivity to light
• feeling cold
• eye problems
• constipation
• rapid heartbeat
• your voice gets deeper
• increased sweating
• dizziness orfainting
• extreme tiredness
• changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness
• weight gain or weight loss
• feeling more hungry or thirsty than usual

Kidney problems.

• decrease in your amount of urine
• swelling of your ankles
• loss of appetite
• blood in your urine

Skin problems.

• rash
• painful sores or ulcers in mouth or nose, throat, orgenitalarea
• itching
• fever or flu-like symptoms
• skin blistering or peeling
• swollen lymph nodes

Problems can also happen in other organs and tissues. These are not all of the signs orsymptoms of immune system problems that can happen with BAVENCIO. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include:

• Chest pain, irregular heartbeat, shortness of breath or swelling of ankles
• Confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs
• Double vision, blurry vision, sensitivity to light, eye pain, changes in eye sight
• Persistent or severe muscle pain or weakness, muscle cramps
• Lowred blood cells, bruising.

Infusion-related reactions can sometimes be severe or life-threatening.Signs and symptoms of infusion-related reactions may include:

• chills or shaking
• dizziness
• hives
• feel like passing out
• flushing
• fever
• shortness of breath or wheezing
• back pain
• stomach area (abdomen) pain

Complications, including graft-versus-host-disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic).These complications can be serious and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with BAVENCIO. Your healthcare provider will monitor you for these complications.

Heart problems.When BAVENCIO is used with the medicine axitinib, severe heart problems can happen and can lead to death. Signs and symptoms of heart problems may include:

• swelling of your stomach area (abdomen),
• weight gain legs, hands, feet, or ankles
• pain or discomfort in your arms, back, neck,
• shortness of breath or jaw
• nausea or vomiting
• breaking out in a coldsweat
• new or worsening chest discomfort, including pain or pressure
• feeling lightheaded or dizzy

Getting medical treatment right away may help keep these problems from becoming more serious.Your healthcare provider will check you for these problems during your treatment with BAVENCIO. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with BAVENCIO if you have severe side effects.

What is BAVENCIO?

BAVENCIO is a prescription medicine used to treat:

• a type ofskin cancer默克尔细胞癌(MCC)在成人和children 12 years of age and older. BAVENCIO may be used when your skin cancer has spread.
• a type of cancer in the bladder or urinary tract called urothelial carcinoma (UC) when it has spread or cannot be removed by surgery (advanced UC). BAVENCIO may be used:
  • as maintenance treatment when your cancer has responded or stabilized after you have received platinum-containing chemotherapy as your first treatment.
  • when you have received platinum-containing chemotherapy, and it did not work or is no longer working.
• a type ofkidney cancercalled renal cell carcinoma (RCC). BAVENCIO may be used with the medicine axitinib as your first treatment when your kidney cancer has spread or cannot be removed by surgery (advanced RCC).

It is not known if BAVENCIO is safe and effective in children under the age of 12.

Before you receive BAVENCIO, tell your healthcare provider about all of your medical conditions, including if you:

• have immune system problems such as Crohn’s disease,ulcerative colitis, orlupus
• have received an organ transplant
• have received or plan to receive a stem cell transplant that usesdonorstem cells(allogeneic)
• have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome
• have heart problems orhigh blood pressure
• have a highcholesterollevel in your blood
• are pregnant or plan to become pregnant. BAVENCIO can harm your unborn baby.
  Females who are able to become pregnant:
  • You should use an effective method of birth control during your treatment and for at least 1 month after the last dose of BAVENCIO. Talk to your healthcare provider about birth control methods that you can use during this time.
• are breastfeeding or plan to breastfeed. It is not known if BAVENCIO passes into your breast milk. Do not breastfeed during treatment and for at least 1 month after the final dose of BAVENCIO.

Tell your healthcare provider about all the medicines you take,including prescription and overthe-counter medicines, vitamins, and herbal supplements.

How will I receive BAVENCIO?

• Your healthcare provider will give you BAVENCIO into your vein through an intravenous (IV) line over 60 minutes.
• BAVENCIO is usually given every 2 weeks.
• Your healthcare provider will give you medicines before the first 4 infusions and then as needed to help reduce infusion reactions.
• Your healthcare provider will decide how many treatments you need.
• Your healthcare provider will do blood tests to check you for certain side effects.
• If you miss an appointment, call your healthcare provider as soon as possible to reschedule your appointment.

What are the possible side effects of BAVENCIO?

BAVENCIO can cause serious side effects, including:

• See “What is the most important information I should know about BAVENCIO?”

The most common side effects of BAVENCIO in people with MCC include:

• feeling tired
• infusion-related reactions including chills, fever, and back pain
• muscle and bone pain
• rash
• diarrhea
• decreased appetite
• nausea
• swelling in your hands, feet, or ankles

The most common side effects of BAVENCIO as maintenance treatment in people with UC whose cancer responded or stabilized after platinum-containing chemotherapy as first treatment include:

• feeling tired
• urinary tract infection
• muscle and bone pain
• rash

The most common side effects of BAVENCIO in people with UC after platinum-containing chemotherapy that did not work, or is no longer working, include:

• feeling tired
• muscle and bone pain
• infusion-related reactions including chills, fever, back pain, redness, and shortness of breath
• nausea
• decreased appetite
• urinary tract infection

The most common side effects of BAVENCIO when given with axitinib in people with RCC include:

• diarrhea
• hoarseness
• feeling tired
• decreased appetite
• high blood pressure
• low levels ofthyroid hormone
• muscle and bone pain
• rash
• nausea
• shortness of breath
• mouth sores
• cough
• liver problems
• stomach area (abdomen) pain
• blisters or rash on the palms of your hands and soles of your feet
• headache

These are not all the possible side effects of BAVENCIO.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800FDA-1088.

General information about the safe and effective use of BAVENCIO.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about BAVENCIO, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about BAVENCIO that is written for health professionals.

What are the ingredients in BAVENCIO?

Active ingredient:avelumab

Inactive ingredients:D-mannitol, glacial acetic acid, polysorbate 20, sodium hydroxide, and Water for Injection

This Medication Guide has been approved by the U.S. Food and Drug Administration.