PANITUMUMAB: 10,876 Adverse Event Reports & Safety Profile

Panitumumab is an epidermal growth factor receptor (EGFR) antagonist for intravenous use. Panitumumab is a human IgG2 kappa monoclonal antibody with an approximate molecular weight of 147 kDa that is produced in genetically engineered mammalian (Chinese hamster ovary) cells. Vectibix (panitumumab) Injection for intravenous use is a sterile, colorless solution with a pH range of 5.6 to 6.0, which may contain a small amount of visible translucent-to-white, amorphous, proteinaceous particles. Each single-dose 5 mL vial contains 100 mg of panitumumab, 34 mg sodium acetate, 29 mg sodium chloride, and Water for Injection, USP. Each single-dose 20 mL vial contains 400 mg of panitumumab, 136 mg sodium acetate, 117 mg sodium chloride, and Water for Injection, USP.

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. ( 1 , 14.2 ) As monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy. ( 1 , 14.1 ) 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 ) *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 , 2.1 , 5.2 , 12.1 , 14.3 ).

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) ] .

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). ( 2 ) 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 )

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3 , 2.4) ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Studies (14.4) ]</span> . 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.

None. None

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) ] Most common adverse reactions (≥ 20%) of Vectibix as monotherapy are skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. ( 6.1 ) Most common adverse reactions (≥ 20%) in clinical trials of Vectibix in combination with FOLFOX chemotherapy are diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. ( 6.1 ) Most common adverse reactions (≥ 20%) in clinical trials of Vectibix in combination with sotorasib are 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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&apos;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)

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 All Grades (%)

Grade

3 or 4 (%)

All

Grades (%)

Grade

3 or 4 (%) Skin and Subcutaneous Tissue Disorders Rash 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. 87 26 8 2 Dry skin Dry skin includes dry skin, xerosis, and xeroderma. 28 0 2 0 Pruritis 17 0 4 0 Nail Disorder Nail 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 Diarrhea Diarrhea includes diarrhea, gastroenteritis, and diarrhea hemorrhagic. 28 6 26 0 Stomatitis Stomatitis 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 pain Abdominal 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 Fatigue Fatigue includes asthenia and fatigue. 21 0 34 2 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Musculoskeletal pain includes arthralgia, back pain, myalgia, musculoskeletal chest pain, bone pain, and pain in extremity. 21 2.1 14 2 Hematological Disorders Hemorrhage Hemorrhage includes epistaxis, gastrointestinal hemorrhage, vaginal hemorrhage, rectal hemorrhage, hematochezia, hemorrhage, hemorrhage urinary tract, hematospermia, and hematuria. 13 2.1 2 0 Eye Disorders Conjunctivitis Conjunctivitis 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 300 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.

Laboratory Abnormalities Vectibix

6 mg/kg + Sotorasib Trifluridine/tipiracil or Regorafenib 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

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 <span class="opacity-50 text-xs">[see Boxed Warning , Dosage and Administration (2.3) and Warnings and Precautions (5.1) ]</span> Immune system disorders: Infusion reaction <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) and Warnings and Precautions (5.4) ]</span> Eye disorders: Keratitis/ulcerative keratitis, corneal perforation <span class="opacity-50 text-xs">[see Warnings and Precautions (5.8) ]</span>

AND PRECAUTIONS Dermatologic and Soft Tissue Toxicity: Monitor for dermatologic and soft tissue toxicities. Reduce dose for recurrent Grade 3 toxicity and withhold or discontinue Vectibix for severe or life-threatening complications. Limit sun exposure. ( 2.3 , 5.1 , 5.7 ) 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. ( 2.1 , 5.2 )

Electrolyte

Depletion/Monitoring: Monitor electrolytes and institute appropriate treatment. ( 5.3 )

Infusion

Reactions: Reduce infusion rate by 50% for mild to moderate reactions; terminate the infusion for severe infusion reactions. ( 2.3 , 5.4 )

Pulmonary Fibrosis/Interstitial

Lung Disease (ILD): Permanently discontinue Vectibix in patients developing ILD. ( 5.6 )

Ocular

Toxicities: Monitor for keratitis, ulcerative keratitis, or corneal perforation. Interrupt or discontinue Vectibix for acute or worsening keratitis, ulcerative keratitis, or corneal perforation. ( 5.8 ) Embryo-fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception during treatment with Vectibix and for 2 months after the last dose. ( 5.10 , 8.1 , 8.3 )

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 Warning and 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 &quot; RAS &quot; <span class="opacity-50 text-xs">[see Indications and Usage (1) , Dosage and Administration (2.1) , Clinical Pharmacology (12.1) and Clinical Studies (14.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Indications and Usage (1) and Clinical Pharmacology (12.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Indications and Usage (1) ]</span> .

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.

5.4 Infusion Reactions In Study 20020408, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC Grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix administration <span class="opacity-50 text-xs">[see Adverse Reactions (6.1 , 6.2) ]</span> . Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

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.

5.7 Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix.

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.

5.9 Increased Mortality and Toxicity with Vectibix in Combination with Bevacizumab and Chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC Grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC Grade 3-4 adverse reactions occurring at a higher rate in Vectibix-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs &lt; 1%), and hypomagnesemia (4% vs 0%). NCI-CTC Grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 3%) and included fatal events in three (&lt; 1%) Vectibix-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy.

5.10 Embryo-fetal Toxicity Based on data from animal studies and its mechanism of action, Vectibix can cause fetal harm when administered to a pregnant woman. When given during organogenesis, panitumumab administration resulted in embryolethality in cynomolgus monkeys at exposures approximately 1.25 to 5 times the recommended human dose. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment, and for at least 2 months after the last dose of Vectibix <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) and Clinical Pharmacology (12.1) ]</span>.