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mechanism of action is HER1 Antagonists [MoA]

Vectibix

(Panitumumab)

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Dosage & Administration

RAS

Wild-Type mCRC: Administer 6 mg/kg every 14 days as an intravenous infusion over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg). (

2 DOSAGE AND ADMINISTRATION

RAS

Wild-Type mCRC: Administer 6 mg/kg every 14 days as an intravenous infusion over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg).
*

KRAS G12C

-mutated mCRC: Administer 6 mg/kg every 14 days as an intravenous infusion over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg) in combination with sotorasib.

2.1 Patient Selection

RAS

Wild-Type mCRC

Prior to initiation of treatment with Vectibix as monotherapy, assess

RAS

mutational status in colorectal tumors and confirm the absence of a

RAS

mutation in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of both

KRAS

and

NRAS

KRAS

G12C-mutated mCRC

Prior to initiation of treatment with Vectibix in combination with sotorasib, confirm the presence of the

KRAS G12C

mutation using an FDA-approved test.

Information on FDA-approved tests for the detection of

RAS

mutations in patients with mCRC is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage

RAS

Wild-Type mCRC

The recommended dosage of Vectibix is 6 mg/kg, administered as an intravenous infusion every 14 days until disease progression or unacceptable toxicity

[see Dosage and Administration (2.4)]

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions

[see Warnings and Precautions (5.4)]

KRAS G12C

-mutated mCRC

Administer the first sotorasib dose prior to the first Vectibix infusion.

The recommended dosage for Vectibix in combination with sotorasib is 6 mg/kg, administered as an intravenous infusion every 14 days until disease progression, unacceptable toxicity, or until sotorasib is withheld or discontinued

[see Dosage and Administration (2.3, 2.4)]

. Refer to the sotorasib full prescribing information for recommended sotorasib dosing information.

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions

[see Warnings and Precautions (5.4)]

2.3 Dose Modifications

Dose Modifications for Vectibix in Combination with Sotorasib

When Vectibix is administered in combination with sotorasib, if treatment with sotorasib is temporarily withheld or permanently discontinued, temporarily withhold or permanently discontinue Vectibix, respectively

[see Clinical Studies (14.4)]

Refer to the sotorasib full prescribing information for dose modifications for adverse reactions associated with the use of sotorasib.

Dose Modifications for Specific Adverse Reactions Associated with the Use of Vectibix

Infusion Reactions

[see Warnings and Precautions (5.4)and Adverse Reactions (6.1, 6.2)]

* Reduce infusion rate by 50% in patients experiencing a mild or moderate (Grade 1 or 2) infusion reaction for the duration of that infusion.
* Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix.

Dermatologic Toxicity

[see Boxed Warning, Warnings and Precautions (5.1)and Adverse Reactions (6.1, 6.2)]

* Upon first occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < Grade 3, reinitiate Vectibix at the original dose.
* Upon the second occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < Grade 3, reinitiate Vectibix at 80% of the original dose.
* Upon the third occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < Grade 3, reinitiate Vectibix at 60% of the original dose.
* Upon the fourth occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix.

Permanently discontinue Vectibix following the occurrence of a Grade 4 dermatologic reaction or for a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses.

2.4 Preparation and Administration

For intravenous infusion only. Do

not

administer Vectibix as an intravenous push or bolus.

Preparation

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration. Vectibix solution is colorless and may contain a small amount of visible translucent-to-white, amorphous, proteinaceous particles. Do not use if the solution is discolored or cloudy, or if foreign matter is present.

Prepare the solution for infusion, using aseptic technique, as follows:

* Do not shake the vial.
* Use a 21-gauge or larger gauge (smaller bore) hypodermic needle to withdraw the necessary amount of Vectibix for a dose of 6 mg/kg. Do not use needle-free devices (e.g., vial adapters) to withdraw vial contents.
* Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium chloride injection, USP. Do not exceed a final concentration of 10 mg/mL.
* Mix diluted solution by gentle inversion.
* Discard any unused portion of the vial.

Administration

* Administer using a low-protein-binding 0.2 µm or 0.22 µm in-line filter.
* Vectibix must be administered via infusion pump.
* Flush line before and after Vectibix administration with 0.9% sodium chloride injection, USP, to avoid mixing with other drug products or intravenous solutions. Do not mix Vectibix with, or administer as an infusion with, other medicinal products. Do not add other medications to solutions containing panitumumab.
* Infuse doses of 1000 mg or lower over 60 minutes through a peripheral intravenous line or indwelling intravenous catheter. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes.

* Use the diluted infusion solution of Vectibix within 6 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36° to 46°F). DO NOT FREEZE.

)
*

KRAS G12C

-mutated mCRC: Administer 6 mg/kg every 14 days as an intravenous infusion over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg) in combination with sotorasib. (

2 DOSAGE AND ADMINISTRATION

RAS

Wild-Type mCRC: Administer 6 mg/kg every 14 days as an intravenous infusion over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg).
*

KRAS G12C

-mutated mCRC: Administer 6 mg/kg every 14 days as an intravenous infusion over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg) in combination with sotorasib.

2.1 Patient Selection

RAS

Wild-Type mCRC

Prior to initiation of treatment with Vectibix as monotherapy, assess

RAS

mutational status in colorectal tumors and confirm the absence of a

RAS

mutation in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of both

KRAS

and

NRAS

KRAS

G12C-mutated mCRC

Prior to initiation of treatment with Vectibix in combination with sotorasib, confirm the presence of the

KRAS G12C

mutation using an FDA-approved test.

Information on FDA-approved tests for the detection of

RAS

mutations in patients with mCRC is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage

RAS

Wild-Type mCRC

The recommended dosage of Vectibix is 6 mg/kg, administered as an intravenous infusion every 14 days until disease progression or unacceptable toxicity

[see Dosage and Administration (2.4)]

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions

[see Warnings and Precautions (5.4)]

KRAS G12C

-mutated mCRC

Administer the first sotorasib dose prior to the first Vectibix infusion.

[see Dosage and Administration (2.3, 2.4)]

. Refer to the sotorasib full prescribing information for recommended sotorasib dosing information.

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions

[see Warnings and Precautions (5.4)]

2.3 Dose Modifications

Dose Modifications for Vectibix in Combination with Sotorasib

[see Clinical Studies (14.4)]

Refer to the sotorasib full prescribing information for dose modifications for adverse reactions associated with the use of sotorasib.

Dose Modifications for Specific Adverse Reactions Associated with the Use of Vectibix

Infusion Reactions

[see Warnings and Precautions (5.4)and Adverse Reactions (6.1, 6.2)]

Dermatologic Toxicity

[see Boxed Warning, Warnings and Precautions (5.1)and Adverse Reactions (6.1, 6.2)]

2.4 Preparation and Administration

For intravenous infusion only. Do

not

administer Vectibix as an intravenous push or bolus.

Preparation

Prepare the solution for infusion, using aseptic technique, as follows:

Administration

)

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Vectibix Prescribing Information

Dermatologic Toxicity:

Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC Grade 3 and higher) in 15% of patients receiving Vectibix monotherapy

[see

2.3 Dose Modifications

Dose Modifications for Vectibix in Combination with Sotorasib

[see Clinical Studies (14.4)]

Refer to the sotorasib full prescribing information for dose modifications for adverse reactions associated with the use of sotorasib.

Dose Modifications for Specific Adverse Reactions Associated with the Use of Vectibix

Infusion Reactions

[see Warnings and Precautions (5.4)and Adverse Reactions (6.1, 6.2)]

Reduce infusion rate by 50% in patients experiencing a mild or moderate (Grade 1 or 2) infusion reaction for the duration of that infusion.
Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix.

Dermatologic Toxicity

[see Boxed Warning, Warnings and Precautions (5.1)and Adverse Reactions (6.1, 6.2)]

Upon first occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < Grade 3, reinitiate Vectibix at the original dose.
Upon the second occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < Grade 3, reinitiate Vectibix at 80% of the original dose.
Upon the third occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < Grade 3, reinitiate Vectibix at 60% of the original dose.
Upon the fourth occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix.

5.1 Dermatologic and Soft Tissue Toxicity

Vectibix can cause dermatologic toxicity, which may be severe. Clinical manifestations included, but were not limited to, acneiform dermatitis, pruritis, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.

Among 229 patients who received Vectibix as monotherapy, dermatologic toxicity occurred in 90% including Grade 3 (15%). Among 585 patients who received Vectibix in combination with FOLFOX, dermatologic toxicity occurred in 96% including Grade 4 (1%) and Grade 3 (32%). In 126 patients receiving Vectibix in combination with sotorasib across clinical studies, dermatologic toxicities occurred in 94%, including Grade 3 (16%) of patients.

Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications

[see Boxed Warningand Adverse Reactions (6.1, 6.2)]

. Dose modifications for Vectibix concerning dermatologic toxicity are provided

[see Dosage and Administration (2.3)]

and

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 (%)
Skin and Subcutaneous Tissue Disorders
RashRash 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.	87	26	8	2
Dry skinDry skin includes dry skin, xerosis, and xeroderma.	28	0	2	0
Pruritis	17	0	4	0
Nail DisorderNail disorders include nail avulsion, nail cuticle fissure, nail disorder, nail toxicity, and paronychia.	17	0	0	0
Skin fissure	13	0	0	0
Palmar-plantar erythrodysesthesia syndrome	13	0	10	4
Gastrointestinal Disorders
DiarrheaDiarrhea includes diarrhea, gastroenteritis, and diarrhea hemorrhagic.	28	6	26	0
StomatitisStomatitis includes mucosal inflammation, stomatitis, mouth ulceration, angular cheilitis, and cheilitis.	26	0	14	0
Nausea	17	2.1	36	4
Constipation	15	2.1	10	0
Abdominal painAbdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, and hepatic pain.	15	0	18	2
Vomiting	13	2.1	10	2
General disorders
FatigueFatigue includes asthenia and fatigue.	21	0	34	2
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painMusculoskeletal pain includes arthralgia, back pain, myalgia, musculoskeletal chest pain, bone pain, and pain in extremity.	21	2.1	14	2
Hematological Disorders
HemorrhageHemorrhage includes epistaxis, gastrointestinal hemorrhage, vaginal hemorrhage, rectal hemorrhage, hematochezia, hemorrhage, hemorrhage urinary tract, hematospermia, and hematuria.	13	2.1	2	0
Eye Disorders
ConjunctivitisConjunctivitis includes conjunctival hyperemia, conjunctivitis, and conjunctivitis allergic.	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 300The 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.
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 (%)
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

]

Indications and Usage ( 1 INDICATIONS AND USAGE Vectibix is an epidermal growth factor receptor (EGFR) antagonist indicated for the treatment of: Adult patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test) Metastatic Colorectal Cancer (mCRC): In combination with FOLFOX for first-line treatment. As monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy. KRAS G12C-mutated Metastatic Colorectal Cancer (mCRC) In combination with sotorasib, for the treatment of adult patients with KRAS G12C- mutated mCRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. *Limitations of Use: Vectibix is not indicated for the treatment of patients with RAS -mutant mCRC unless used in combination with sotorasib in KRAS G12C-mutated mCRC. Vectibix is not indicated for the treatment of patients with mCRC for whom RAS mutation status is unknown . Metastatic Colorectal Cancer (mCRC) RAS Wild-Type mCRC Vectibix is indicated for the treatment of adult patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test) metastatic colorectal cancer (mCRC) [see Dosage and Administration (2.1)] : As first-line therapy in combination with FOLFOX [see Clinical Studies (14.2)] . As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1)] . KRAS G12C -mutated mCRC Vectibix, in combination with sotorasib, is indicated for the treatment of adult patients with KRAS G12C- mutated mCRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy [see Dosage and Administration (2.1)and Clinical Studies (14.4)] . Limitations of Use : Vectibix is not indicated for the treatment of patients with RAS -mutant mCRC unless used in combination with sotorasib in KRAS G12C-mutated mCRC. Vectibix is not indicated for the treatment of patients with mCRC for whom RAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), Clinical Pharmacology (12.1)and Clinical Studies (14.3)] . )	01/2025
Dosage and Administration ( 2.1 Patient Selection RAS Wild-Type mCRC Prior to initiation of treatment with Vectibix as monotherapy, assess RAS mutational status in colorectal tumors and confirm the absence of a RAS mutation in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of both KRAS and NRAS . KRAS G12C-mutated mCRC Prior to initiation of treatment with Vectibix in combination with sotorasib, confirm the presence of the KRAS G12C mutation using an FDA-approved test. Information on FDA-approved tests for the detection of RAS mutations in patients with mCRC is available at: http://www.fda.gov/CompanionDiagnostics. , 2.2 Recommended Dosage RAS Wild-Type mCRC The recommended dosage of Vectibix is 6 mg/kg, administered as an intravenous infusion every 14 days until disease progression or unacceptable toxicity [see Dosage and Administration (2.4)] . Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions [see Warnings and Precautions (5.4)] . KRAS G12C -mutated mCRC Administer the first sotorasib dose prior to the first Vectibix infusion. The recommended dosage for Vectibix in combination with sotorasib is 6 mg/kg, administered as an intravenous infusion every 14 days until disease progression, unacceptable toxicity, or until sotorasib is withheld or discontinued [see Dosage and Administration (2.3, 2.4)] . Refer to the sotorasib full prescribing information for recommended sotorasib dosing information. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions [see Warnings and Precautions (5.4)] . , 2.3 Dose Modifications Dose Modifications for Vectibix in Combination with Sotorasib When Vectibix is administered in combination with sotorasib, if treatment with sotorasib is temporarily withheld or permanently discontinued, temporarily withhold or permanently discontinue Vectibix, respectively [see Clinical Studies (14.4)] . Refer to the sotorasib full prescribing information for dose modifications for adverse reactions associated with the use of sotorasib. Dose Modifications for Specific Adverse Reactions Associated with the Use of Vectibix Infusion Reactions [see Warnings and Precautions (5.4)and Adverse Reactions (6.1, 6.2)] Reduce infusion rate by 50% in patients experiencing a mild or moderate (Grade 1 or 2) infusion reaction for the duration of that infusion. Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix. Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1)and Adverse Reactions (6.1, 6.2)] Upon first occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < Grade 3, reinitiate Vectibix at the original dose. Upon the second occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < Grade 3, reinitiate Vectibix at 80% of the original dose. Upon the third occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < Grade 3, reinitiate Vectibix at 60% of the original dose. Upon the fourth occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix. Permanently discontinue Vectibix following the occurrence of a Grade 4 dermatologic reaction or for a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses. )	01/2025
Warnings and Precautions ( 5.1 Dermatologic and Soft Tissue Toxicity Vectibix can cause dermatologic toxicity, which may be severe. Clinical manifestations included, but were not limited to, acneiform dermatitis, pruritis, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Among 229 patients who received Vectibix as monotherapy, dermatologic toxicity occurred in 90% including Grade 3 (15%). Among 585 patients who received Vectibix in combination with FOLFOX, dermatologic toxicity occurred in 96% including Grade 4 (1%) and Grade 3 (32%). In 126 patients receiving Vectibix in combination with sotorasib across clinical studies, dermatologic toxicities occurred in 94%, including Grade 3 (16%) of patients. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warningand Adverse Reactions (6.1, 6.2)] . Dose modifications for Vectibix concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)] . , 5.2 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 Vectibix monotherapy or in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with colorectal cancer that harbor somatic RAS mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as " RAS " [see Indications and Usage (1), Dosage and Administration (2.1), Clinical Pharmacology (12.1)and Clinical Studies (14.3)] . Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents [see Indications and Usage (1)and Clinical Pharmacology (12.1)] . Additionally, in Study 20050203, 272 patients with RAS- mutant mCRC tumors received Vectibix in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis , overall survival (OS) was shorter (HR = 1.21, 95% CI: 1.01-1.45) in patients with RAS- mutant mCRC who received Vectibix and FOLFOX versus FOLFOX alone [see Indications and Usage (1)] . , 5.3 Electrolyte Depletion/Monitoring Vectibix can cause progressively decreasing serum magnesium levels leading to severe (Grade 3 or 4) hypomagnesemia. Among 229 patients who received Vectibix as monotherapy, decreased magnesium occurred in 38% including Grade 4 (1.3%) and Grade 3 (2.6%). Among 585 patients who received Vectibix in combination with FOLFOX, decreased magnesium occurred in 51% including Grade 4 (5%) and Grade 3 (6%). In 126 patients receiving Vectibix in combination with sotorasib across clinical studies, decreased magnesium occurred in 69%, including Grade 4 (2.4%) and Grade 3 (14%). Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix treatment, periodically during Vectibix treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. , 5.5 Acute Renal Failure Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix. Among 229 patients who received Vectibix as monotherapy, acute renal failure occurred in 2% including Grade 3 or 4 (2%). Among 585 patients who received Vectibix in combination with FOLFOX, acute renal failure occurred in 2% including Grade 3 or 4 (2%). In 126 patients receiving Vectibix in combination with sotorasib across clinical studies, acute renal failure occurred in 3.2% including Grade 3 (0.8%). Monitor patients for diarrhea and dehydration, provide supportive care (including anti-emetic or anti-diarrheal therapy) as needed, and withhold Vectibix if necessary. , 5.6 Pulmonary Fibrosis/Interstitial Lung Disease (ILD) Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. Grade 1 ILD/pneumonitis occurred in 0.8% (1/126) of patients enrolled in clinical studies of Vectibix in combination with sotorasib. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix therapy. Discontinue Vectibix therapy if ILD is confirmed. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix versus the risk of pulmonary complications must be carefully considered. , 5.8 Ocular Toxicities Serious cases of keratitis, ulcerative keratitis, and corneal perforation have occurred with Vectibix use. Among 585 patients who received Vectibix in combination with FOLFOX, keratitis occurred in 0.3%. In 126 patients receiving Vectibix in combination with sotorasib across clinical studies, keratitis occurred in 1.6%, ulcerative keratitis occurred in 0.8%, and vernal keratoconjunctivitis in 0.8% (all were Grade 1-2). Monitor for evidence of keratitis, ulcerative keratitis, or corneal perforation. Interrupt or discontinue Vectibix therapy for acute or worsening keratitis, ulcerative keratitis, or corneal perforation. )	01/2025

Vectibix is an epidermal growth factor receptor (EGFR) antagonist indicated for the treatment of:

Adult patients with wild-type

RAS

(defined as wild-type in both

KRAS

and

NRAS

as determined by an FDA-approved test) Metastatic Colorectal Cancer (mCRC)*:

In combination with FOLFOX for first-line treatment. (

1 INDICATIONS AND USAGE

Vectibix is an epidermal growth factor receptor (EGFR) antagonist indicated for the treatment of:

Adult patients with wild-type

RAS

(defined as wild-type in both

KRAS

and

NRAS

as determined by an FDA-approved test) Metastatic Colorectal Cancer (mCRC)*:

In combination with FOLFOX for first-line treatment.
As monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy.

KRAS

G12C-mutated Metastatic Colorectal Cancer (mCRC)*

In combination with sotorasib, for the treatment of adult patients with
KRAS G12C-
mutated mCRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

*Limitations of Use: Vectibix is not indicated for the treatment of patients with

RAS

-mutant mCRC unless used in combination with sotorasib in

KRAS

G12C-mutated mCRC. Vectibix is not indicated for the treatment of patients with mCRC for whom

RAS

mutation status is unknown .

Metastatic Colorectal Cancer (mCRC)

RAS
Wild-Type mCRC

Vectibix is indicated for the treatment of adult patients with wild-type
RAS
(defined as wild-type in both
KRAS
and
NRAS
as determined by an FDA-approved test) metastatic colorectal cancer (mCRC)
[see Dosage and Administration (2.1)]
:
- As first-line therapy in combination with FOLFOX
  [see Clinical Studies (14.2)]
  .
- As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy
  [see Clinical Studies (14.1)]
  .
KRAS G12C
-mutated mCRC

Vectibix, in combination with sotorasib, is indicated for the treatment of adult patients with
KRAS G12C-
mutated mCRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy
[see Dosage and Administration (2.1)and Clinical Studies (14.4)]
.

Limitations of Use

: Vectibix is not indicated for the treatment of patients with

RAS

-mutant mCRC unless used in combination with sotorasib in

KRAS

G12C-mutated mCRC. Vectibix is not indicated for the treatment of patients with mCRC for whom

RAS

mutation status is unknown

[see Dosage and Administration (2.1), Warnings and Precautions (5.2), Clinical Pharmacology (12.1)and Clinical Studies (14.3)]

14.2 First-line mCRC in Combination with FOLFOX Chemotherapy

Study 20050203 (NCT00364013)

Study 20050203 was a multicenter, open-label trial that randomized (1:1) patients with mCRC who were previously untreated in the metastatic setting and who had received no prior oxaliplatin to receive Vectibix every 14 days in combination with FOLFOX or to FOLFOX alone every 14 days. Vectibix was administered at 6 mg/kg over 60 minutes prior to administration of chemotherapy. The FOLFOX regimen consisted of oxaliplatin 85 mg per m²IV infusion over 120 minutes and leucovorin (dl-racemic) 200 mg per m²intravenous infusion over 120 minutes at the same time on day 1 using a Y-line, followed on day 1 by 5-FU 400 mg per m²intravenous bolus. The 5-FU bolus was followed by a continuous infusion of 5-FU 600 mg per m²over 22 hours. On day 2, patients received leucovorin 200 mg per m²followed by the bolus dose (400 mg per m²) and continuous infusion of 5-FU (600 mg per m²) over 22 hours. Study 20050203 excluded patients with known central nervous system metastases, clinically significant cardiac disease, interstitial lung disease, or active inflammatory bowel disease. The prespecified major efficacy measure was PFS in the subgroup of patients with wild-type

KRAS

mCRC as assessed by a blinded independent central review of imaging. Other key efficacy measures included OS and ORR.

In Study 20050203, in the wild-type

KRAS

subgroup (n = 656), 64% of patients were men, 92% White, 2% Black, and 4% Hispanic or Latino. Sixty-six percent of patients had colon cancer and 34% had rectal cancer. ECOG performance was 0 in 56% of patients, 1 in 38% of patients, and 2 in 6% of patients. Median age was 61.5 years.

The efficacy results in Study 20050203 in patients with wild-type

KRAS

mCRC are presented in Table 7 below.

Table 7. Results in Patients with Wild-type KRAS mCRC (Study 20050203)
Wild-type KRAS population	Primary Analysis
Wild-type KRAS population	Vectibix plus FOLFOX (n = 325)	FOLFOX Alone (n = 331)
PFS
Median (months) (95% CI)	9.6 (9.2, 11.1)	8 (7.5, 9.3)
Hazard ratio (95% CI) p-value	0.8 (0.66, 0.97) p = 0.02
ORR
% (95% CI)	54% (48%, 59%)	47% (41%, 52%)

Exploratory Analysis of OS

An exploratory analysis of OS with updated information based on events in 82% of patients with wild-type

KRAS

mCRC estimated the treatment effect of Vectibix plus FOLFOX compared with FOLFOX alone on OS (Figure 3). Median OS among 325 patients with wild-type

KRAS

mCRC who received Vectibix plus FOLFOX was 23.8 months (95% CI: 20.0, 27.7) vs 19.4 months (95% CI: 17.4, 22.6) among 331 patients who received FOLFOX alone (HR = 0.83, 95% CI: 0.70, 0.98).

Figure 3. Kaplan-Meier Plot of Overall Survival in Patients with Wild-type KRAS mCRC (Study 20050203)

Retrospective exploratory analyses in the RAS wild-type subgroup

Among the 656 patients with wild-type

KRAS

exon 2 mCRC,

RAS

mutation status was assessed for 620 patients using Sanger bidirectional sequencing and Surveyor^®/WAVE^®analysis. Of these 620 patients, approximately 17% of patients (n = 104) tumors harbored mutations in

KRAS

exons 3 or 4 or in

NRAS

exons 2, 3, and 4.

Retrospective subset analyses were then conducted among the subset of patients without

RAS

mutations (n = 512) as described above.

In the wild-type

RAS

subgroup, 65% of patients were men and 91% were White, 2% Black, and 5% Hispanic or Latino. Sixty-five percent of patients had colon cancer and 35% had rectal cancer. ECOG performance was 0 in 57% of patients, 1 in 37% of patients, and 2 in 6% of patients. Median age was 61 years.

Table 8. Results in Patients with Wild-Type RAS mCRC (Study 20050203)
Wild-type RAS population	Primary Analysis
Wild-type RAS population	Vectibix plus FOLFOX (n = 259)	FOLFOX Alone (n = 253)
PFS
Median (months) (95% CI)	10.1 (9.3, 12.0)	7.9 (7.2, 9.3)
Hazard ratio (95% CI)	0.72 (0.58, 0.90)
OS OS with updated information based on events in 82% of patients
Median (months) (95% CI)	25.8 (21.7; 29.7)	20.2 (17.5; 23.6)
Hazard ratio (95% CI)	0.77 (0.64; 0.94)
ORR
% (95% CI)	58% (51%, 64%)	45% (39%, 51%)

Figure 4. Kaplan-Meier Plot of Overall Survival in Patients with Wild-Type RAS-mCRC (Study 20050203)

)

As monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy. (

1 INDICATIONS AND USAGE

Vectibix is an epidermal growth factor receptor (EGFR) antagonist indicated for the treatment of:

Adult patients with wild-type

RAS

(defined as wild-type in both

KRAS

and

NRAS

as determined by an FDA-approved test) Metastatic Colorectal Cancer (mCRC)*:

In combination with FOLFOX for first-line treatment.
As monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy.

KRAS

G12C-mutated Metastatic Colorectal Cancer (mCRC)*

In combination with sotorasib, for the treatment of adult patients with
KRAS G12C-
mutated mCRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

*Limitations of Use: Vectibix is not indicated for the treatment of patients with

RAS

-mutant mCRC unless used in combination with sotorasib in

KRAS

G12C-mutated mCRC. Vectibix is not indicated for the treatment of patients with mCRC for whom

RAS

mutation status is unknown .

Metastatic Colorectal Cancer (mCRC)

RAS
Wild-Type mCRC

Vectibix is indicated for the treatment of adult patients with wild-type
RAS
(defined as wild-type in both
KRAS
and
NRAS
as determined by an FDA-approved test) metastatic colorectal cancer (mCRC)
[see Dosage and Administration (2.1)]
:
- As first-line therapy in combination with FOLFOX
  [see Clinical Studies (14.2)]
  .
- As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy
  [see Clinical Studies (14.1)]
  .
KRAS G12C
-mutated mCRC

Vectibix, in combination with sotorasib, is indicated for the treatment of adult patients with
KRAS G12C-
mutated mCRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy
[see Dosage and Administration (2.1)and Clinical Studies (14.4)]
.

Limitations of Use

: Vectibix is not indicated for the treatment of patients with

RAS

-mutant mCRC unless used in combination with sotorasib in

KRAS

G12C-mutated mCRC. Vectibix is not indicated for the treatment of patients with mCRC for whom

RAS

mutation status is unknown

[see Dosage and Administration (2.1), Warnings and Precautions (5.2), Clinical Pharmacology (12.1)and Clinical Studies (14.3)]

14.1 Recurrent or Refractory mCRC

The safety and efficacy of Vectibix was demonstrated in Study 20020408, an open-label, multinational, randomized, controlled trial of 463 patients with EGFR-expressing, metastatic carcinoma of the colon or rectum, in Study 20080763, an open-label, multicenter, multinational, randomized trial of 1010 patients with wild-type

KRAS

mCRC, and in Study 20100007, an open-label, multicenter, multinational, randomized trial of 377 patients with wild-type

KRAS

mCRC.

Study 20020408 (NCT00113763)

Patients in Study 20020408 were required to have progressed on or following treatment with a regimen(s) containing a fluoropyrimidine, oxaliplatin, and irinotecan; progression was confirmed by an independent review committee (IRC) masked to treatment assignment for 76% of the patients. Patients were randomized (1:1) to receive panitumumab at a dose of 6 mg/kg given once every 2 weeks plus BSC (N = 231) or BSC alone (N = 232) until investigator-determined disease progression. Randomization was stratified based on Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0 and 1 vs 2) and geographic region (Western Europe, Eastern/Central Europe, or other). Upon investigator-determined disease progression, patients in the BSC-alone arm were eligible to receive panitumumab and were followed until disease progression was confirmed by the IRC.

Based upon IRC determination of disease progression, a statistically significant prolongation in progression free survival (PFS) was observed in patients receiving panitumumab compared to those receiving BSC alone. The mean PFS was 96 days in the panitumumab arm and 60 days in the BSC-alone arm.

The study results were analyzed in the wild-type

KRAS

subgroup where

KRAS

status was retrospectively determined using archived paraffin-embedded tumor tissue.

KRAS

mutation status was determined in 427 patients (92%); of these, 243 (57%) had no detectable

KRAS

mutations in either codons 12 or 13. The hazard ratio for PFS in patients with wild-type

KRAS

mCRC was 0.45 (95% CI: 0.34-0.59) favoring the panitumumab arm. The response rate was 17% for the panitumumab arm and 0% for BSC. There were no differences in OS; 77% of patients in the BSC arm received panitumumab at the time of disease progression.

Study 20080763 (NCT01001377)

Study 20080763 was an open-label, multicenter, multinational, randomized (1:1) clinical trial, stratified by region (North America, Western Europe, and Australia versus rest of the world) and ECOG PS (0 and 1 vs 2) in patients with wild-type

KRAS

mCRC. A total of 1010 patients who received prior treatment with irinotecan, oxaliplatin, and a thymidylate synthase inhibitor were randomized to receive Vectibix 6 mg/kg intravenously over 60 minutes every 14 days or cetuximab 400 mg/m²intravenously over 120 minutes on day 1 followed by 250 mg/m²intravenously over 60 minutes every 7 days. The trial excluded patients with clinically significant cardiac disease and interstitial lung disease. The major efficacy analysis tested whether the OS of Vectibix was noninferior to cetuximab. Data for investigator-assessed PFS and objective response rate (ORR) were also collected. The criteria for noninferiority was for Vectibix to retain at least 50% of the OS benefit of cetuximab based on an OS hazard ratio of 0.55 from the NCIC CTG CO.17 study relative to BSC.

In Study 20080763, 37% of patients were women, 52% were white, 45% were Asian, and 1.3% were Hispanic or Latino. Thirty-one percent of patients were enrolled at sites in North America, Western Europe, or Australia. ECOG performance was 0 in 32% of patients, 1 in 60% of patients, and 2 in 8% of patients. Median age was 61 years. More patients (62%) had colon cancer than rectal cancer (38%). Most patients (74%) had not received prior bevacizumab.

The key efficacy analysis for Study 20080763 demonstrated that Vectibix was statistically significantly noninferior to cetuximab for OS.

The efficacy results for Study 20080763 are presented in Table 5 and Figure 1.

Table 5. Results in Previously Treated Wild-type KRAS mCRC (Study 20080763)
Wild-type KRAS Population	Vectibix (n = 499)Modified intent-to-treat population that included all patients who received at least one dose of therapy	Cetuximab (n = 500)
Overall Survival (OS)
Number of OS events (%)	383 (76.8)	392 (78.4)
Median (months) (95% CI)	10.4 (9.4, 11.6)	10.0 (9.3, 11.0)
Hazard ratio (95% CI)	0.97 (0.84, 1.11)
Progression-Free Survival (PFS)
Median (months) (95% CI)	4.1 (3.2, 4.8)	4.4 (3.2, 4.8)
Hazard ratio (95% CI)	1.00 (0.88, 1.14)
Objective Response Rate (ORR)
% (95% CI)	22% (18%, 26%)	19% (16%, 23%)

Figure 1. Kaplan-Meier Plot of Overall Survival in Patients with Wild-type KRAS mCRC (Study 20080763)

Study 20100007 (NCT01412957)

Study 20100007 was an open-label, multicenter, randomized (1:1) clinical study stratified by ECOG performance status (0 or 1 vs 2) and region (sites in Europe versus Asia versus rest of world) in patients with wild-type

KRAS

mCRC. Eligible patients were required to have received prior therapy with irinotecan, oxaliplatin, and a thymidylate synthase inhibitor, and have wild-type

KRAS

exon 2 mCRC as determined by a clinical trial assay. An assessment for

RAS

status (defined as

KRAS

exons 2, 3, and 4 and

NRAS

exons 2, 3, and 4) using Sanger sequencing was conducted in patients for whom tumor tissue was available.

Patients were randomized to receive Vectibix (6 mg/kg intravenously every 14 days) plus BSC or BSC alone. Patients received Vectibix and BSC or BSC until disease progression, withdrawal of consent, unacceptable toxicity, or death. Patients randomized to BSC were not offered Vectibix at the time of disease progression. The major efficacy outcome measure was OS in patients with wild-type

KRAS

mCRC. Secondary efficacy outcome measures included OS in the subgroup of patients with wild-type

RAS

mCRC; PFS and ORR in patients with wild-type

KRAS

; and PFS and ORR in the subgroup of patients with wild-type

RAS

mCRC.

A total of 377 patients were randomized, 189 to the Vectibix plus BSC arm and 188 to the BSC alone arm. Baseline demographics and disease characteristics were: median age of 61 years (range: 19-82); 57% male; 55% White, 43% Asian; 36% ECOG PS-0, 55% ECOG PS-1; 57% had a primary colon tumor and 43% had a primary rectal tumor; and 32% had prior bevacizumab exposure.

KRAS

tumor mutation status was available for all patients and

RAS

tumor mutation status was available for 86% of the 377 patients. Among the 377 patients, 270 (72%) patients had wild-type

RAS

tumors, 54 (14%) had mutant

RAS

tumors, and 54 (14%) had unknown

RAS

tumor status.

The results of the study demonstrated a statistically significant improvement in OS. The efficacy results for Study 20100007 are presented in Table 6 and Figure 2.

Table 6. Results in Previously Treated Wild-type KRAS and Wild-type RAS mCRC (Study 20100007)
	Wild-type KRAS Population (n = 377)		Wild-type RAS Population (n = 270)
	Vectibix Plus BSC (n = 189)	BSC (n = 188)	Vectibix Plus BSC (n = 142)	BSC (n = 128)
OS
Number of deaths (%)	136 (72)	135 (72)	104 (73)	95 (74)
Median (months) (95% CI)	10 (8.7, 11.4)	7.4 (5.8, 9.3)	10 (8.7, 11.6)	6.9 (5.2, 7.9)
HR (95% CI)	0.73 (0.57, 0.93)		0.7 (0.53, 0.93)
p-value	0.0096		0.0135
PFS
Number of events (%)	182 (96)	162 (86)	137 (97)	113 (88)
Median (months) (95% CI)	3.6 (3.4, 5.3)	1.7 (1.6, 1.9)	5.2 (3.5, 5.3)	1.7 (1.6, 2.2)
HR (95% CI)	0.51 (0.41, 0.64)		0.46 (0.35. 0.59)
p-value	< 0.0001		< 0.0001
ORR % (95% CI)	27 (20.8, 33.9)	1.6 (0.3, 4.6)	31 (23.5, 39.3)	2.3 (0.5, 6.7)

Figure 2. Kaplan-Meier Plot of Overall Survival in Patients with Wild-type RAS mCRC (Study 20100007)

)

KRAS

G12C-mutated Metastatic Colorectal Cancer (mCRC)*

In combination with sotorasib, for the treatment of adult patients with
KRAS G12C-
mutated mCRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. (
1 INDICATIONS AND USAGE
Vectibix is an epidermal growth factor receptor (EGFR) antagonist indicated for the treatment of:
Adult patients with wild-type
RAS
(defined as wild-type in both
KRAS
and
NRAS
as determined by an FDA-approved test) Metastatic Colorectal Cancer (mCRC)*:
In combination with FOLFOX for first-line treatment.
As monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy.
KRAS
G12C-mutated Metastatic Colorectal Cancer (mCRC)*
In combination with sotorasib, for the treatment of adult patients with
KRAS G12C-
mutated mCRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
*Limitations of Use: Vectibix is not indicated for the treatment of patients with
RAS
-mutant mCRC unless used in combination with sotorasib in
KRAS
G12C-mutated mCRC. Vectibix is not indicated for the treatment of patients with mCRC for whom
RAS
mutation status is unknown .
Metastatic Colorectal Cancer (mCRC)
RAS
Wild-Type mCRC

Vectibix is indicated for the treatment of adult patients with wild-type
RAS
(defined as wild-type in both
KRAS
and
NRAS
as determined by an FDA-approved test) metastatic colorectal cancer (mCRC)
[see Dosage and Administration (2.1)]
:
As first-line therapy in combination with FOLFOX
[see Clinical Studies (14.2)]
.
As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy
[see Clinical Studies (14.1)]
.
KRAS G12C
-mutated mCRC

Vectibix, in combination with sotorasib, is indicated for the treatment of adult patients with
KRAS G12C-
mutated mCRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy
[see Dosage and Administration (2.1)and Clinical Studies (14.4)]
.
Limitations of Use
: Vectibix is not indicated for the treatment of patients with
RAS
-mutant mCRC unless used in combination with sotorasib in
KRAS
G12C-mutated mCRC. Vectibix is not indicated for the treatment of patients with mCRC for whom
RAS
mutation status is unknown
[see Dosage and Administration (2.1), Warnings and Precautions (5.2), Clinical Pharmacology (12.1)and Clinical Studies (14.3)]
.
)

*Limitations of Use: Vectibix is not indicated for the treatment of patients with

RAS

-mutant mCRC unless used in combination with sotorasib in

KRAS

G12C-mutated mCRC. Vectibix is not indicated for the treatment of patients with mCRC for whom

RAS

mutation status is unknown (

1 INDICATIONS AND USAGE

Vectibix is an epidermal growth factor receptor (EGFR) antagonist indicated for the treatment of:

Adult patients with wild-type

RAS

(defined as wild-type in both

KRAS

and

NRAS

as determined by an FDA-approved test) Metastatic Colorectal Cancer (mCRC)*:

In combination with FOLFOX for first-line treatment.
As monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy.

KRAS

G12C-mutated Metastatic Colorectal Cancer (mCRC)*

In combination with sotorasib, for the treatment of adult patients with
KRAS G12C-
mutated mCRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

*Limitations of Use: Vectibix is not indicated for the treatment of patients with

RAS

-mutant mCRC unless used in combination with sotorasib in

KRAS

G12C-mutated mCRC. Vectibix is not indicated for the treatment of patients with mCRC for whom

RAS

mutation status is unknown .

Metastatic Colorectal Cancer (mCRC)

RAS
Wild-Type mCRC

Vectibix is indicated for the treatment of adult patients with wild-type
RAS
(defined as wild-type in both
KRAS
and
NRAS
as determined by an FDA-approved test) metastatic colorectal cancer (mCRC)
[see Dosage and Administration (2.1)]
:
- As first-line therapy in combination with FOLFOX
  [see Clinical Studies (14.2)]
  .
- As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy
  [see Clinical Studies (14.1)]
  .
KRAS G12C
-mutated mCRC

Vectibix, in combination with sotorasib, is indicated for the treatment of adult patients with
KRAS G12C-
mutated mCRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy
[see Dosage and Administration (2.1)and Clinical Studies (14.4)]
.

Limitations of Use

: Vectibix is not indicated for the treatment of patients with

RAS

-mutant mCRC unless used in combination with sotorasib in

KRAS

G12C-mutated mCRC. Vectibix is not indicated for the treatment of patients with mCRC for whom

RAS

mutation status is unknown

[see Dosage and Administration (2.1), Warnings and Precautions (5.2), Clinical Pharmacology (12.1)and Clinical Studies (14.3)]

2.1 Patient Selection

RAS

Wild-Type mCRC

Prior to initiation of treatment with Vectibix as monotherapy, assess

RAS

mutational status in colorectal tumors and confirm the absence of a

RAS

mutation in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of both

KRAS

and

NRAS

KRAS

G12C-mutated mCRC

Prior to initiation of treatment with Vectibix in combination with sotorasib, confirm the presence of the

KRAS G12C

mutation using an FDA-approved test.

Information on FDA-approved tests for the detection of

RAS

mutations in patients with mCRC is available at: http://www.fda.gov/CompanionDiagnostics.

5.2 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

Vectibix monotherapy or in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with colorectal cancer that harbor somatic

RAS

mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either

KRAS

NRAS

and hereafter is referred to as "

RAS

[see Indications and Usage (1), Dosage and Administration (2.1), Clinical Pharmacology (12.1)and Clinical Studies (14.3)]

Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of

RAS

mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing

RAS

mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents

[see Indications and Usage (1)and Clinical Pharmacology (12.1)]

Additionally, in Study 20050203, 272 patients with

RAS-

mutant mCRC tumors received Vectibix in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis

overall survival (OS) was shorter (HR = 1.21, 95% CI: 1.01-1.45) in patients with

RAS-

mutant mCRC who received Vectibix and FOLFOX versus FOLFOX alone

[see Indications and Usage (1)]

12.1 Mechanism of Action

The EGFR is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases, including EGFR, HER2, HER3, and HER4. EGFR is constitutively expressed in normal epithelial tissues, including the skin and hair follicle. EGFR is overexpressed in certain human cancers, including colon and rectum cancers. Interaction of EGFR with its normal ligands (e.g., EGF, transforming growth factor-alpha) leads to phosphorylation and activation of a series of intracellular proteins, which in turn regulate transcription of genes involved with cellular growth and survival, motility, and proliferation.

KRAS

(Kirsten rat sarcoma 2 viral oncogene homologue) and

NRAS

(Neuroblastoma

RAS

viral oncogene homologue) are highly related members of the

RAS

oncogene family. Signal transduction through the EGFR can result in activation of the wild-type

KRAS

and

NRAS

proteins; however, in cells with activating

RAS

somatic mutations, the

RAS

-mutant proteins are continuously active and appear independent of EGFR regulation.

Panitumumab binds specifically to EGFR on both normal and tumor cells, and competitively inhibits the binding of ligands for EGFR. Nonclinical studies show that binding of panitumumab to the EGFR prevents ligand-induced receptor autophosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, decreased proinflammatory cytokine and vascular growth factor production, and internalization of the EGFR.

In vitro

assays and

in vivo

animal studies demonstrate that panitumumab inhibits the growth and survival of selected human tumor cell lines expressing EGFR.

In the setting of

KRAS

G12C-mutant CRC, EGFR activation has been identified as a mechanism of resistance to KRAS G12C inhibition. In a murine patient-derived colorectal tumor xenograft model, the combination of panitumumab and sotorasib, a KRAS G12C inhibitor, had increased antitumor activity compared to either panitumumab or sotorasib alone.

14.3
RAS
-Mutant mCRC

Vectibix is not effective for the treatment of patients with

RAS-

mutant mCRC, defined as a

RAS

mutation in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), or exon 4 (codons 117 and 146) of

KRAS

and

NRAS

, except for when Vectibix is used in combination with sotorasib in

KRAS G12C

-mutated mCRC.

In Study 20050203, among patients with

RAS

-mutant tumors, the median PFS was 7.3 months (95% CI: 6.3, 7.9) among 272 patients receiving Vectibix plus FOLFOX and 8.7 months (95% CI: 7.6, 9.4) among patients who received FOLFOX alone (HR = 1.31, 95% CI: 1.07, 1.60). The median OS was 15.6 months (95% CI: 13.4, 17.9) among patients receiving Vectibix plus FOLFOX and 19.2 months (95% CI: 16.7, 21.8) among patients who received FOLFOX alone (HR = 1.25, 95% CI: 1.02, 1.55).

In Study 20100007, among patients with

RAS

-mutant tumors, no differences in OS or PFS were observed between the treatment arms [n = 54; OS HR = 0.99 (95% CI: 0.49, 2.00); PFS HR = 1.03 (95% CI: 0.56, 1.90)].

RAS
Wild-Type mCRC: Administer 6 mg/kg every 14 days as an intravenous infusion over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg). (
2 DOSAGE AND ADMINISTRATION
RAS
Wild-Type mCRC: Administer 6 mg/kg every 14 days as an intravenous infusion over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg).
KRAS G12C
-mutated mCRC: Administer 6 mg/kg every 14 days as an intravenous infusion over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg) in combination with sotorasib.
2.1 Patient Selection
RAS
Wild-Type mCRC
Prior to initiation of treatment with Vectibix as monotherapy, assess
RAS
mutational status in colorectal tumors and confirm the absence of a
RAS
mutation in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of both
KRAS
and
NRAS
.
KRAS
G12C-mutated mCRC
Prior to initiation of treatment with Vectibix in combination with sotorasib, confirm the presence of the
KRAS G12C
mutation using an FDA-approved test.
Information on FDA-approved tests for the detection of
RAS
mutations in patients with mCRC is available at: http://www.fda.gov/CompanionDiagnostics.
2.2 Recommended Dosage
RAS
Wild-Type mCRC
The recommended dosage of Vectibix is 6 mg/kg, administered as an intravenous infusion every 14 days until disease progression or unacceptable toxicity
[see Dosage and Administration (2.4)]
.
Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions
[see Warnings and Precautions (5.4)]
.
KRAS G12C
-mutated mCRC
Administer the first sotorasib dose prior to the first Vectibix infusion.
The recommended dosage for Vectibix in combination with sotorasib is 6 mg/kg, administered as an intravenous infusion every 14 days until disease progression, unacceptable toxicity, or until sotorasib is withheld or discontinued
[see Dosage and Administration (2.3, 2.4)]
. Refer to the sotorasib full prescribing information for recommended sotorasib dosing information.
Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions
[see Warnings and Precautions (5.4)]
.
2.3 Dose Modifications
Dose Modifications for Vectibix in Combination with Sotorasib
When Vectibix is administered in combination with sotorasib, if treatment with sotorasib is temporarily withheld or permanently discontinued, temporarily withhold or permanently discontinue Vectibix, respectively
[see Clinical Studies (14.4)]
.
Refer to the sotorasib full prescribing information for dose modifications for adverse reactions associated with the use of sotorasib.
Dose Modifications for Specific Adverse Reactions Associated with the Use of Vectibix
Infusion Reactions
[see Warnings and Precautions (5.4)and Adverse Reactions (6.1, 6.2)]
Reduce infusion rate by 50% in patients experiencing a mild or moderate (Grade 1 or 2) infusion reaction for the duration of that infusion.
Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix.
Dermatologic Toxicity
[see Boxed Warning, Warnings and Precautions (5.1)and Adverse Reactions (6.1, 6.2)]
Upon first occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < Grade 3, reinitiate Vectibix at the original dose.
Upon the second occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < Grade 3, reinitiate Vectibix at 80% of the original dose.
Upon the third occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < Grade 3, reinitiate Vectibix at 60% of the original dose.
Upon the fourth occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix.
Permanently discontinue Vectibix following the occurrence of a Grade 4 dermatologic reaction or for a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses.
2.4 Preparation and Administration
For intravenous infusion only. Do
not
administer Vectibix as an intravenous push or bolus.
Preparation
Visually inspect parenteral drug products for particulate matter and discoloration prior to administration. Vectibix solution is colorless and may contain a small amount of visible translucent-to-white, amorphous, proteinaceous particles. Do not use if the solution is discolored or cloudy, or if foreign matter is present.
Prepare the solution for infusion, using aseptic technique, as follows:
Do not shake the vial.
Use a 21-gauge or larger gauge (smaller bore) hypodermic needle to withdraw the necessary amount of Vectibix for a dose of 6 mg/kg. Do not use needle-free devices (e.g., vial adapters) to withdraw vial contents.
Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium chloride injection, USP. Do not exceed a final concentration of 10 mg/mL.
Mix diluted solution by gentle inversion.
Discard any unused portion of the vial.
Administration
Administer using a low-protein-binding 0.2 µm or 0.22 µm in-line filter.
Vectibix must be administered via infusion pump.
Flush line before and after Vectibix administration with 0.9% sodium chloride injection, USP, to avoid mixing with other drug products or intravenous solutions. Do not mix Vectibix with, or administer as an infusion with, other medicinal products. Do not add other medications to solutions containing panitumumab.
Infuse doses of 1000 mg or lower over 60 minutes through a peripheral intravenous line or indwelling intravenous catheter. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes.
Use the diluted infusion solution of Vectibix within 6 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36° to 46°F). DO NOT FREEZE.
)
KRAS G12C
-mutated mCRC: Administer 6 mg/kg every 14 days as an intravenous infusion over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg) in combination with sotorasib. (
2 DOSAGE AND ADMINISTRATION
RAS
Wild-Type mCRC: Administer 6 mg/kg every 14 days as an intravenous infusion over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg).
KRAS G12C
-mutated mCRC: Administer 6 mg/kg every 14 days as an intravenous infusion over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg) in combination with sotorasib.
2.1 Patient Selection
RAS
Wild-Type mCRC
Prior to initiation of treatment with Vectibix as monotherapy, assess
RAS
mutational status in colorectal tumors and confirm the absence of a
RAS
mutation in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of both
KRAS
and
NRAS
.
KRAS
G12C-mutated mCRC
Prior to initiation of treatment with Vectibix in combination with sotorasib, confirm the presence of the
KRAS G12C
mutation using an FDA-approved test.
Information on FDA-approved tests for the detection of
RAS
mutations in patients with mCRC is available at: http://www.fda.gov/CompanionDiagnostics.
2.2 Recommended Dosage
RAS
Wild-Type mCRC
The recommended dosage of Vectibix is 6 mg/kg, administered as an intravenous infusion every 14 days until disease progression or unacceptable toxicity
[see Dosage and Administration (2.4)]
.
Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions
[see Warnings and Precautions (5.4)]
.
KRAS G12C
-mutated mCRC
Administer the first sotorasib dose prior to the first Vectibix infusion.
The recommended dosage for Vectibix in combination with sotorasib is 6 mg/kg, administered as an intravenous infusion every 14 days until disease progression, unacceptable toxicity, or until sotorasib is withheld or discontinued
[see Dosage and Administration (2.3, 2.4)]
. Refer to the sotorasib full prescribing information for recommended sotorasib dosing information.
Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions
[see Warnings and Precautions (5.4)]
.
2.3 Dose Modifications
Dose Modifications for Vectibix in Combination with Sotorasib
When Vectibix is administered in combination with sotorasib, if treatment with sotorasib is temporarily withheld or permanently discontinued, temporarily withhold or permanently discontinue Vectibix, respectively
[see Clinical Studies (14.4)]
.
Refer to the sotorasib full prescribing information for dose modifications for adverse reactions associated with the use of sotorasib.
Dose Modifications for Specific Adverse Reactions Associated with the Use of Vectibix
Infusion Reactions
[see Warnings and Precautions (5.4)and Adverse Reactions (6.1, 6.2)]
Reduce infusion rate by 50% in patients experiencing a mild or moderate (Grade 1 or 2) infusion reaction for the duration of that infusion.
Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix.
Dermatologic Toxicity
[see Boxed Warning, Warnings and Precautions (5.1)and Adverse Reactions (6.1, 6.2)]
Upon first occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < Grade 3, reinitiate Vectibix at the original dose.
Upon the second occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < Grade 3, reinitiate Vectibix at 80% of the original dose.
Upon the third occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < Grade 3, reinitiate Vectibix at 60% of the original dose.
Upon the fourth occurrence of a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix.
Permanently discontinue Vectibix following the occurrence of a Grade 4 dermatologic reaction or for a Grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses.
2.4 Preparation and Administration
For intravenous infusion only. Do
not
administer Vectibix as an intravenous push or bolus.
Preparation
Visually inspect parenteral drug products for particulate matter and discoloration prior to administration. Vectibix solution is colorless and may contain a small amount of visible translucent-to-white, amorphous, proteinaceous particles. Do not use if the solution is discolored or cloudy, or if foreign matter is present.
Prepare the solution for infusion, using aseptic technique, as follows:
Do not shake the vial.
Use a 21-gauge or larger gauge (smaller bore) hypodermic needle to withdraw the necessary amount of Vectibix for a dose of 6 mg/kg. Do not use needle-free devices (e.g., vial adapters) to withdraw vial contents.
Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium chloride injection, USP. Do not exceed a final concentration of 10 mg/mL.
Mix diluted solution by gentle inversion.
Discard any unused portion of the vial.
Administration
Administer using a low-protein-binding 0.2 µm or 0.22 µm in-line filter.
Vectibix must be administered via infusion pump.
Flush line before and after Vectibix administration with 0.9% sodium chloride injection, USP, to avoid mixing with other drug products or intravenous solutions. Do not mix Vectibix with, or administer as an infusion with, other medicinal products. Do not add other medications to solutions containing panitumumab.
Infuse doses of 1000 mg or lower over 60 minutes through a peripheral intravenous line or indwelling intravenous catheter. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes.
Use the diluted infusion solution of Vectibix within 6 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36° to 46°F). DO NOT FREEZE.
)

Lactation: Advise women not to breastfeed. (
8.2 Lactation
Risk Summary
There are no data on the presence of panitumumab in human milk or the effects of panitumumab on the breastfed infant or on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential for serious adverse reactions in breastfed infants from Vectibix, advise women not to breastfeed during treatment with Vectibix and for 2 months after the last dose.
)

Vectibix

Dosage & Administration

Vectibix Prescribing Information

Vectibix Prior Authorization Resources

Most recent Vectibix prior authorization forms

Most recent state uniform prior authorization forms

Brand Resources

Benefits investigation

Vectibix PubMed™ News

Vectibix Patient Education

Patient toolkit