^ 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 [see Adverse Reactions (6.1, 6.2)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)].
^
PRINCIPAL DISPLAY PANEL
Single-Dose Vial
NDC55513-956-01
AMGEN®
Vectibix®
(panitumumab)
Injection
400 mg
Each 20 mL single-dose vial
of Vectibix® contains 400 mg
panitumumab in a sterile,
preservative-free solution
(pH 5.8) containing 117 mg
sodium chloride and 136 mg
sodium acetate in Water for
Injection, USP.
Store at 2° to 8°C.
Do not freeze or shake.
Protect from direct sunlight.
Rx Only
^ Photosensitivity
Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix.
^ 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.
^ Patient Counseling Information
Discuss the following with patients prior to treatment with Vectibix:
^ Description
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.
^ Preparation And Administration
For intravenous infusion only. Do not administer Vectibix as an intravenous push or bolus.
^ 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.
^ 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.
^ Overdosage
Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.
^ 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.
^ Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of Vectibix or of other panitumumab products.
During the 23-week treatment period of Vectibix as a monotherapy in Studies 20080763, 20020408, 20030194 and other clinical trials, the incidence of anti-panitumumab antibodies was 5.2% (74/1417). Of the 74 patients who tested positive for anti-panitumumab antibodies, 18.9% (14/74) had neutralizing antibodies against panitumumab.
During the 23-week treatment period of Vectibix in combination with chemotherapy in Studies 20050203, 20070509, 20050181 and other clinical trials, the incidence of anti-panitumumab antibodies was 3.2% (47/1470). Of the 47 patients who tested positive for anti-panitumumab antibodies, 14.9% (7/47) had neutralizing antibodies against panitumumab.
There was no identified clinically significant effect of anti-panitumumab-antibodies on panitumumab pharmacokinetics following monotherapy. The effect of anti-panitumumab antibodies on the pharmacokinetics, following combination therapy, and on the safety and effectiveness of panitumumab has not been fully characterized.
^3 Dosage Forms And Strengths
Injection: 100 mg/5 mL (20 mg/mL) colorless solution in single-dose vial.
Injection: 400 mg/20 mL (20 mg/mL) colorless solution in single-dose vial.
^ 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)].
^ 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 < 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 (< 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.
^ Kras G c-mutated Mcrc
The efficacy of Vectibix in combination with sotorasib was evaluated in CodeBreaK 300 [NCT 05198934], a multicenter, randomized, open-label, active-controlled study conducted in previously treated patients with KRAS G12C-mutated mCRC. Key eligibility criteria included patients 18 years of age or older, who had received at least one prior line of therapy for mCRC, and who had received prior fluoropyrimidine, oxaliplatin, and irinotecan for metastatic disease unless there was a medical contraindication.
All patients were also required to have KRAS G12C-mutated mCRC prospectively identified in tumor tissue samples using the QIAGEN therascreen® KRAS RGQ PCR performed in a central laboratory. Other eligibility criteria included an ECOG PS of ≤ 2, and at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
A total of 160 patients with previously treated mCRC with the KRAS G12C mutation were randomized 1:1:1 to receive Vectibix 6 mg/kg intravenously every 2 weeks and sotorasib 960 mg orally daily (N = 53), or Vectibix 6 mg/kg intravenously every 2 weeks and sotorasib 240 mg orally daily (N = 53), or investigator's choice of SOC consisting of trifluridine/tipiracil, or regorafenib (N = 54). Randomization was stratified by prior anti-angiogenic therapy (yes or no), time from initial diagnosis of metastatic disease to randomization (≥ 18 months; < 18 months), and ECOG status (0 or 1 versus 2). Patients received treatment until disease progression, lack of clinical benefit or intolerance to treatment. Sotorasib discontinuation required Vectibix discontinuation [see Dosage and Administration (2.3)].
The major efficacy outcome measure was PFS as evaluated by Blinded Independent Central Review (BICR) according to RECIST 1.1. Additional efficacy outcome measures included OS, Overall Response Rate (ORR), and duration of response (DOR). The efficacy results presented below are limited to Vectibix in combination with the recommended sotorasib dosage of 960 mg daily.
Of the 107 patients randomized to either Vectibix in combination with sotorasib 960 mg once daily or the control arm, the median age was 64 years (range: 34-81 years); 46% were age 65 years or older; 50% were female; 74% were White; 17% were Asia; and 97% of the patients had ECOG PS 0 or 1. The primary site of disease was colon (69%) or rectum (31%). The median number of prior lines of therapy for metastatic disease was 2. Of these patients, 100% received prior fluoropyrimidine, 99% received prior oxaliplatin, 93% received prior irinotecan and 18% of patients had received prior trifluridine/tipiracil, or regorafenib.
The trial demonstrated a statistically significant improvement in PFS for patients randomized to Vectibix in combination with sotorasib 960 mg compared to the investigator's choice SOC. The final analysis of OS was not statistically significant.
The final analysis of PFS for patients randomized to Vectibix in combination with sotorasib 240 mg compared to investigator's choice of SOC was not statistically significant.
The efficacy results from CodeBreaK 300 are summarized in Table 9 and Figure 5.
^ 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.
^ 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.
^Warning: Dermatologic Toxicity
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 Dosage and Administration (2.3), Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
^ 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.
^4 Contraindications
None.
^ 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.
^ How Supplied/storage And Handling
Vectibix is supplied as a sterile, colorless, preservative-free solution containing 20 mg/mL panitumumab in a single-dose vial. Vectibix is provided as one vial per carton.
^ Geriatric Use
Of the 737 patients who received Vectibix monotherapy for recurrent or refractory mCRC [see Clinical Studies (14.1)], 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix monotherapy.
Of the 322 patients who received Vectibix plus FOLFOX, for wild-type KRAS-mutated mCRC [see Clinical Studies (14.2)], 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients.
In a pooled analysis of 132 patients who received Vectibix in combination with sotorasib 960 mg for KRAS G12C-mutated mCRC, 30% were 65 and over while 9% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) compared to younger patients treated with Vectibix in combination with sotorasib.
^6 Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the label:
^ 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)].
^ Pharmacokinetics
Panitumumab administered as a monotherapy exhibits nonlinear pharmacokinetics.
Following single-dose administrations of panitumumab as 1-hour infusions, the area under the concentration-time curve (AUC) increased in a greater than dose-proportional manner, and clearance (CL) of panitumumab decreased from 30.6 to 4.6 mL/day/kg as the dose increased from 0.75 to 9 mg/kg. However, at doses above 2 mg/kg, the AUC of panitumumab increased in an approximately dose-proportional manner.
Following the recommended dose regimen (6 mg/kg given once every 2 weeks as a 1-hour infusion), panitumumab concentrations reached steady-state levels by the third infusion with mean (± SD) peak and trough concentrations of 213 ± 59 and 39 ± 14 mcg/mL, respectively. The mean (± SD) AUC0-tau and CL were 1306 ± 374 mcg•day/mL and 4.9 ± 1.4 mL/kg/day, respectively. The elimination half-life was approximately 7.5 days (range: 3.6 to 10.9 days).
No clinically significant differences in the pharmacokinetics of panitumumab were observed based on age (21 to 88 years), sex, race (White, Black, and Asian), mild or moderate renal impairment (CrCL 30 to 89 mL/min), mild or moderate hepatic impairment (total bilirubin ≤ 3 × ULN and any AST), and EGFR membrane-staining intensity (1+, 2+, and 3+) in tumor cells.
^ Carcinogenesis, Mutagenesis, Impairment Of Fertility
No carcinogenicity or mutagenicity studies of panitumumab have been conducted. It is not known if panitumumab can impair fertility in humans. Prolonged menstrual cycles and/or amenorrhea occurred in normally cycling, female cynomolgus monkeys treated weekly with 1.25 to 5 times the recommended human dose of panitumumab (based on body weight). Menstrual cycle irregularities in panitumumab-treated female monkeys were accompanied by both a decrease and delay in peak progesterone and 17β-estradiol levels. Normal menstrual cycling resumed in most animals after discontinuation of panitumumab treatment. A no-effect level for menstrual cycle irregularities and serum hormone levels was not identified. The effects of panitumumab on male fertility have not been studied; however, no adverse effects were observed microscopically in reproductive organs from male cynomolgus monkeys treated for 26 weeks with panitumumab at doses of up to approximately 5-fold the recommended human dose (based on body weight).
^ 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)].
^ 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.
^ 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 [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].