6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3) and Warnings and Precautions (5.1)]
Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS-Mutant mCRC Receiving Vectibix Monotherapy or in Combination with Oxaliplatin-based Chemotherapy [see Indications and Usage (1) and Warnings and Precautions (5.2)]
Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)]
Infusion Reactions [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)]
Acute Renal Failure [see Warnings and Precautions (5.5)]
Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)]
Photosensitivity [see Warnings and Precautions (5.7)]
Ocular Toxicities [see Warnings and Precautions (5.8)]
Increased Mortality and Toxicity with Vectibix in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)]

6.1 Clinical Trials Experience

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

The data described in WARNINGS AND PRECAUTIONS reflect exposure to Vectibix in four clinical trials in which patients received Vectibix: Study 20020408, an open-label, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC; Study 20050203, a randomized, controlled trial (N = 1183) in patients with wild-type KRAS mCRC that evaluated Vectibix in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone; CodeBreaK 300, a randomized controlled trial (N = 160) evaluating Vectibix in combination with sotorasib versus the investigator's choice of standard of care (trifluridine/tipiracil or regorafenib) in patients with KRAS G12C-mutated mCRC; and CodeBreak 101, an open-label, non-randomized trial evaluating sotorasib as a monotherapy and in combination with other drugs in patients with KRAS G12C-mutated advanced solid tumors, including patients with KRAS G12C-mutated mCRC who received Vectibix in combination with sotorasib (N = 79). Safety data for Study 20050203 are limited to 656 patients with wild-type KRAS mCRC. The safety profile of Vectibix in patients with wild-type RAS mCRC is similar with that seen in patients with wild-type KRAS mCRC. Safety data for CodeBreaK 300 are limited to 47 patients who received Vectibix in combination with sotorasib 960 mg.

Vectibix Monotherapy

In Study 20020408, the most common adverse reactions (≥ 20%) with Vectibix were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.

The most common (> 5%) serious adverse reactions in the Vectibix arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2).

For Study 20020408, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered to patients with mCRC as a monotherapy at the recommended dose and schedule (6 mg/kg every 2 weeks).

Table 1. Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 20020408)
	Study 20020408
System Organ Class Preferred Term	Vectibix Plus Best Supportive Care (N = 229)		Best Supportive Care (N = 234)
	Any Grade n (%)	Grade 3-4 n (%)	Any Grade n (%)	Grade 3-4 n (%)
Eye Disorders
Growth of eyelashes	13 (6)
Gastrointestinal Disorders
Nausea	52 (23)	2 (< 1)	37 (16)	1 (< 1)
Diarrhea	49 (21)	4 (2)	26 (11)
Vomiting	43 (19)	6 (3)	28 (12)	2 (< 1)
Stomatitis	15 (7)		2 (< 1)
General Disorders and Administration Site Conditions
Fatigue	60 (26)	10 (4)	34 (15)	7 (3)
Mucosal inflammation	15 (7)	1 (< 1)	2 (< 1)
Infections and Infestations
Paronychia	57 (25)	4 (2)
Respiratory, Thoracic, and Mediastinal Disorders
Dyspnea	41 (18)	12 (5)	30 (13)	8 (3)
Cough	34 (15)	1 (< 1)	17 (7)
Skin and Subcutaneous Tissue Disorders
Erythema	150 (66)	13 (6)	2 (< 1)
Pruritus	132 (58)	6 (3)	4 (2)
Acneiform dermatitis	131 (57)	17 (7)	2 (< 1)
Rash	51 (22)	3 (1)	2 (< 1)
Skin fissures	45 (20)	3 (1)	1 (< 1)
Exfoliative rash	41 (18)	4 (2)
Acne	31 (14)	3 (1)
Dry skin	23 (10)
Nail disorder	22 (10)
Skin exfoliation	21 (9)	2 (< 1)
Skin ulcer	13 (6)	1 (< 1)

Adverse reactions in Study 20020408 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%).

In Study 20020408, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was severe (NCI-CTC Grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC Grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions (5.1)].

In Study 20020408 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix; and the median time to resolution after the last dose of Vectibix was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix-treated patients [see Dosage and Administration (2.3)].

Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported.

Vectibix in Combination with FOLFOX Chemotherapy

The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 20050203 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One Grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix.

Table 2. Adverse Reactions (≥ 5% Difference) Observed in Patients with Wild-type KRAS Tumors Treated with Vectibix and FOLFOX Chemotherapy Compared to FOLFOX Chemotherapy Alone (Study 20050203)
System Organ Class Preferred Term	Vectibix Plus FOLFOX (n = 322)		FOLFOX Alone (n = 327)
System Organ Class Preferred Term	Any Grade n (%)	Grade 3-4 n (%)	Any Grade n (%)	Grade 3-4 n (%)
Eye Disorders
Conjunctivitis	58 (18)	5 (2)	10 (3)
Gastrointestinal Disorders
Diarrhea	201 (62)	59 (18)	169 (52)	29 (9)
Stomatitis	87 (27)	15 (5)	42 (13)	1 (< 1)
General Disorders and Administration Site Conditions
Mucosal inflammation	82 (25)	14 (4)	53 (16)	1 (< 1)
Asthenia	79 (25)	16 (5)	62 (19)	11 (3)
Infections and Infestations
Paronychia	68 (21)	11 (3)
Investigations
Weight decreased	58 (18)	3 (< 1)	22 (7)
Metabolism and Nutrition Disorders
Anorexia	116 (36)	14 (4)	85 (26)	6 (2)
Hypomagnesemia	96 (30)	21 (7)	26 (8)	1 (< 1)
Hypokalemia	68 (21)	32 (10)	42 (13)	15 (5)
Dehydration	26 (8)	8 (2)	10 (3)	5 (2)
Respiratory, Thoracic, and Mediastinal Disorders
Epistaxis	46 (14)		30 (9)
Skin and Subcutaneous Tissue Disorders
Rash	179 (56)	55 (17)	24 (7)	1 (< 1)
Acneiform dermatitis	104 (32)	33 (10)
Pruritus	75 (23)	3 (< 1)	14 (4)
Dry skin	68 (21)	5 (2)	13 (4)
Erythema	50 (16)	7 (2)	14 (4)
Skin fissures	50 (16)	1 (< 1)	1 (< 1)
Alopecia	47 (15)		30 (9)
Acne	44 (14)	10 (3)	1 (< 1)
Nail disorder	32 (10)	4 (1)	4 (1)
Palmar-plantar erythrodysesthesia syndrome	30 (9)	4 (1)	9 (3)	2 (< 1)

Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were flushing (3% vs < 1%), abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%).

Infusion Reactions

Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC Grade 3-4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)].

Vectibix in Combination with Sotorasib

The safety of Vectibix in combination with sotorasib was evaluated in the CodeBreaK 300 study [see Clinical Studies (14.4)]. Patients with KRAS G12C-mutated mCRC received Vectibix 6 mg/kg intravenous every 2 weeks in combination with sotorasib 960 mg orally once daily (N = 47), Vectibix 6 mg/kg intravenous every 2 weeks in combination with sotorasib 240 mg orally once daily (N = 50), or the investigator's choice of standard of care (SOC) consisting of trifluridine/tipiracil or regorafenib (N = 50). Among the 47 patients who received Vectibix in combination with sotorasib 960 mg, 36% were exposed to Vectibix for 6 months or longer and 4.3% were exposed for greater than 12 months.

The median age of patients who received Vectibix in combination with sotorasib 960 mg was 63 years (range: 37-79 years); 38% were age 65 years or older; 49% were female; 79% were White, and 13% were Asian.

Serious adverse reactions occurred in 26% of patients receiving Vectibix in combination with sotorasib 960 mg. Serious adverse reactions in ≥ 2 patients receiving Vectibix in combination with sotorasib 960 mg were sepsis (6%) and intestinal obstruction (4.3%). Fatal adverse reactions occurred in 2 patients (4.3%) receiving Vectibix in combination with sotorasib 960 mg, consisting of cardiac arrest and sepsis (1 patient each).

Permanent discontinuation of Vectibix due to an adverse reaction occurred in 1 patient for decreased corrected calcium.

Dosage interruptions of Vectibix due to an adverse reaction occurred in 38% of patients. Adverse reactions which required dosage interruption in ≥ 2 patients were rash, hypomagnesemia, and keratitis.

Dosage reductions of Vectibix due to an adverse reaction occurred in 17% of patients. The adverse reaction which required dose reduction in ≥ 2 patients was rash.

The most common adverse reactions (≥ 20%) in patients receiving Vectibix in combination with sotorasib 960 mg were rash, dry skin, diarrhea, stomatitis, fatigue and musculoskeletal pain.

The most common Grade 3 or 4 laboratory abnormalities in ≥ 2 patients (4.3%) were decreased magnesium, decreased potassium, decreased corrected calcium, and increased potassium.

Table 3 and Table 4 summarize the adverse reactions and laboratory abnormalities, respectively, identified in CodeBreaK 300.

Table 3. Adverse Reactions (≥ 10%) in Patients with KRAS G12C-Mutated CRC who Received Vectibix in Combination with Sotorasib in CodeBreaK 300
Adverse Reaction	Vectibix 6 mg/kg in combination with sotorasib 960 mg N = 47		Trifluridine/tipiracil or regorafenib N = 50
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
* Rash includes dermatitis acneiform, dermatosis, drug eruption, eczema, erythema, hand dermatitis, rash, rash erythematous, rash maculo-papular, rash papular, rash pruritic, rash pustular, and skin toxicity. † Dry skin includes dry skin, xerosis, and xeroderma. ‡ Nail disorders include nail avulsion, nail cuticle fissure, nail disorder, nail toxicity, and paronychia. § Diarrhea includes diarrhea, gastroenteritis, and diarrhea hemorrhagic. ¶ Stomatitis includes mucosal inflammation, stomatitis, mouth ulceration, angular cheilitis, and cheilitis. # Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, and hepatic pain. Þ Fatigue includes asthenia and fatigue. ß Musculoskeletal pain includes arthralgia, back pain, myalgia, musculoskeletal chest pain, bone pain, and pain in extremity. à Hemorrhage includes epistaxis, gastrointestinal hemorrhage, vaginal hemorrhage, rectal hemorrhage, hematochezia, hemorrhage, hemorrhage urinary tract, hematospermia, and hematuria. è Conjunctivitis includes conjunctival hyperemia, conjunctivitis, and conjunctivitis allergic.
Skin and Subcutaneous Tissue Disorders
Rash*	87	26	8	2
Dry skin†	28	0	2	0
Pruritis	17	0	4	0
Nail Disorder‡	17	0	0	0
Skin fissure	13	0	0	0
Palmar-plantar erythrodysesthesia syndrome	13	0	10	4
Gastrointestinal Disorders
Diarrhea§	28	6	26	0
Stomatitis¶	26	0	14	0
Nausea	17	2.1	36	4
Constipation	15	2.1	10	0
Abdominal pain#	15	0	18	2
Vomiting	13	2.1	10	2
General disorders
FatigueÞ	21	0	34	2
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painß	21	2.1	14	2
Hematological Disorders
Hemorrhageà	13	2.1	2	0
Eye Disorders
Conjunctivitisè	11	0	2	0

Table 4. Select Laboratory Abnormalities (≥ 20%) that Worsened from Baseline in Patients with KRAS G12C-Mutated CRC who Received Vectibix in Combination with Sotorasib in CodeBreaK 300*
Laboratory Abnormalities	Vectibix 6 mg/kg + Sotorasib		Trifluridine/tipiracil or Regorafenib
Laboratory Abnormalities	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
* The denominator used to calculate the rate varied from 44 to 46 in the Vectibix + sotorasib arm and 18 to 50 in the trifluridine/tipiracil or regorafenib arm based on the number of patients with a baseline value and at least one post-treatment value.
Chemistry
Magnesium decreased	76	24	8	0
Calcium (corrected) decreased	74	4.3	46	0
Aspartate aminotransferase increased	39	0	22	2
Alkaline phosphatase increased	33	2.2	33	0
Creatinine kinase increased	30	2.3	7	0
Alanine aminotransferase increased	28	0	16	2
Potassium decreased	26	7	12	0
Albumin decreased	26	2.2	22	0
Urine protein increased	23	0	22	6
Potassium increased	22	4.3	6	0
Glucose decreased	22	0	2	0
Hematology
Hemoglobin decreased	30	0	58	6
Lymphocytes decreased	26	2.2	56	8
White blood cells decreased	24	0	48	14

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Vectibix. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders: Skin necrosis, angioedema, life-threatening and fatal bullous mucocutaneous disease [see Boxed Warning, Dosage and Administration (2.3) and Warnings and Precautions (5.1)]
Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)]
Eye disorders: Keratitis/ulcerative keratitis, corneal perforation [see Warnings and Precautions (5.8)]