Panitumumab

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 pa

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. ( 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

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). ( 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 [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 g

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