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KRAS is a key intermediate in EGFR-activated signaling1
KRAS is important in growth and cell division2-4
Retrospective analyses of treatment effect in the subset of patients with mCRC containing KRAS mutations enrolled in randomized clinical trials
First-line Treatment Studies3,5-8
Second- and Third-line Treatment Studies3,9-11
|ITT: intent to treat; mAb: EGFR monoclonal antibody; PFS: progression-free survival; ORR: overall response rate; OS: overall survival.|
|*||Results from the primary efficacy endpoint are in bold. A given endpoint is designated as “decreased” if there was a numerically smaller result and as “increased” if there was a numerically higher result in the mAb group than in the control group.|
Vectibix® (panitumumab) is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.
The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®.
Vectibix® is not indicated for the treatment of patients with KRAS mutation-positive mCRC or for whom KRAS mCRC status is unknown. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in codon 12 or 13.
IMPORTANT SAFETY INFORMATION
WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS
Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].
Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)].
In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. 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®. Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling.
Infusion reactions, manifesting as anaphylactoid reactions, bronchospasm, and hypotension, can occur following Vectibix® administration. Terminate the infusion for severe infusion reactions.
Vectibix® is not indicated for use in combination with chemotherapy. In a phase 3 study of patients with KRAS mutation-positive mCRC (n = 440) evaluating Vectibix® in combination with infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) compared to FOLFOX alone as first-line therapy for mCRC, shortened overall survival time was observed in the mutant KRAS mCRC population after 294 deaths (HR = 1.24, 95% CI: 0.98-1.57).
In an interim analysis of Study 2, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival 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/dermatitis acneiform (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 4%) and included fatal events in three (< 1%) Vectibix®-treated patients.
In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.
Severe diarrhea and dehydration, which may lead to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.
Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Patients with a history or evidence of interstitial pneumonitis, pulmonary fibrosis, were excluded from most clinical trials. Therefore, the estimated risk in a general population that includes such patients is uncertain. Cases of interstitial lung disease (ILD), including fatalities, have been reported in patients treated with Vectibix®. Interrupt Vectibix® therapy for the acute onset or worsening of pulmonary symptoms. Discontinue Vectibix® therapy if ILD is confirmed.
In a randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate treatment (eg, oral or intravenous electrolyte repletion) as needed.
Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months after the last dose.
Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix®. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.
Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus and has the potential to cause fetal harm when administered to pregnant women.
Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen's Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll.
Discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.
The most common adverse reactions (≥ 20%) of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, diarrhea, including diarrhea resulting in dehydration, and constipation.
The most serious adverse reactions of Vectibix® are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.
References: 1. Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol. 2002;20:1s-13s. 2. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 2007;7:295-308. 3. Vectibix® (panitumumab) prescribing information, Amgen. 4. Andreyev HJ, Norman AR, Cunningham D, Oates JR, Clarke PA. Kirsten ras mutations in patients with colorectal cancer: the multicenter "RASCAL" study. J Natl Cancer Inst. 1998;90:675-684. 5. Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408-1417. 6. Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663-671. 7. Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009;27:672-680. 8. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360:563-572. 9. Langer C, Kopit J, Awad M, et al. Analysis of K-RAS mutations in patients with metastatic colorectal cancer receiving cetuximab in combination with irinotecan: results from the EPIC trial. Ann Oncol. 2008;19(suppl 8):viii133. Abstract. 10. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757-1765. 11. Data on file, Amgen; 2007.