Vectibix Drug Information

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.

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

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 . 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 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 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.

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.

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 Gastrointestinal Disorders Nausea 52 2 (< 1) 37 1 (< 1) Diarrhea 49 4 26 Vomiting 43 6 28 2 (< 1) Stomatitis 15 2 (< 1) General Disorders and Administration Site Conditions Fatigue 60 10 34 7 Mucosal inflammation 15 1 (< 1) 2 (< 1) Infections and Infestations Paronychia 57 4 Respiratory, Thoracic, and Mediastinal Disorders Dyspnea 41 12 30 8 Cough 34 1 (< 1) 17 Skin and Subcutaneous Tissue Disorders Erythema 150 13 2 (< 1) Pruritus 132 6 4 Acneiform dermatitis 131 17 2 (< 1) Rash 51 3 2 (< 1) Skin fissures 45 3 1 (< 1) Exfoliative rash 41 4 Acne 31 3 Dry skin 23 Nail disorder 22 Skin exfoliation 21 2 (< 1) Skin ulcer 13 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. 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 . 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 5 10 Gastrointestinal Disorders Diarrhea 201 59 169 29 Stomatitis 87 15 42 1 (< 1) General Disorders and Administration Site Conditions Mucosal inflammation 82 14 53 1 (< 1) Asthenia 79 16 62 11 Infections and Infestations Paronychia 68 11 Investigations Weight decreased 58 3 (< 1) 22 Metabolism and Nutrition Disorders Anorexia 116 14 85 6 Hypomagnesemia 96 21 26 1 (< 1) Hypokalemia 68 32 42 15 Dehydration 26 8 10 5 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 46 30 Skin and Subcutaneous Tissue Disorders Rash 179 55 24 1 (< 1) Acneiform dermatitis 104 33 Pruritus 75 3 (< 1) 14 Dry skin 68 5 13 Erythema 50 7 14 Skin fissures 50 1 (< 1) 1 (< 1) Alopecia 47 30 Acne 44 10 1 (< 1) Nail disorder 32 4 4 Palmar-plantar erythrodysesthesia syndrome 30 4 9 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 . Vectibix in Combination with Sotorasib The safety of Vectibix in combination with sotorasib was evaluated in the CodeBreaK 300 study . 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

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 Immune system disorders: Infusion reaction Eye disorders: Keratitis/ulcerative keratitis, corneal perforation

Pregnancy Risk Summary Based on data from animal studies and its mechanism of action, Vectibix can cause fetal harm when administered to pregnant women . Limited available data on the use of Vectibix in pregnant women are not sufficient to inform a risk of adverse pregnancy-related outcomes. Vectibix is a human IgG monoclonal antibody and may be transferred across the placenta during pregnancy. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring . Advise pregnant women of the potential risk to the fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Pregnant cynomolgus monkeys were treated weekly with panitumumab during the period of organogenesis (gestation day 20-50). While no panitumumab was detected in serum of neonates from panitumumab-treated dams, anti-panitumumab antibody titers were present in 14 of 27 offspring delivered at GD 100. There were no fetal malformations or other evidence of teratogenesis noted in the offspring; however, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight).

Pediatric Use The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetics of panitumumab at doses ranging from 2.5 mg/kg intravenous weekly, 6 mg/kg intravenous every 2 weeks, or 9 mg/kg intravenous every 3 weeks were evaluated in 28 pediatric patients. Panitumumab exposures were comparable in adult and adolescent patients of 12 to 17 years of age.

Limited data suggested that pediatric patients of 2 to < 12 years of age had lower panitumumab exposure and higher clearance than that in adolescent patients following 6 mg/kg intravenous administration of Vectibix. There was no evidence of an anti-tumor treatment effect in these patients.

Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.