- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- Company information
- More information about this medicine
Excipient with known effectEach ml of concentrate contains 0.150 mmol sodium, which is 3.45 mg sodium.For the full list of excipients, see section 6.1.
PosologyThe recommended dose of Vectibix is 6 mg/kg of bodyweight given once every two weeks. Prior to infusion, Vectibix should be diluted in sodium chloride 9 mg/ml (0.9%) solution for injection to a final concentration not to exceed 10 mg/ml (for preparation instructions see section 6.6).Modification of the dose of Vectibix may be necessary in cases of severe (≥ grade 3) dermatological reactions (see section 4.4).
Special populationsThe safety and efficacy of Vectibix have not been studied in patients with renal or hepatic impairment. There is no clinical data to support dose adjustments in the elderly
Paediatric populationThe safety and efficacy of Vectibix in children aged 0 up to 18 years has not been established. No data are available.
Method of administrationVectibix must be administered as an intravenous infusion via an infusion pump, using a low protein binding 0.2 or 0.22 micrometer in-line filter, through a peripheral line or indwelling catheter. The recommended infusion time is approximately 60 minutes. If the first infusion is tolerated, then subsequent infusions may be administered over 30 to 60 minutes. Doses higher than 1000 mg should be infused over approximately 90 minutes (for handling instructions, see section 6.6).The infusion line should be flushed with sodium chloride solution before and after Vectibix administration to avoid mixing with other medicinal products or intravenous solutions.A reduction in the rate of infusion of Vectibix may be necessary in cases of infusion-related reactions (see section 4.4). Vectibix must not be administered as an intravenous push or bolus.For instructions on dilution of the medicinal product before administration, see section 6.6.
Dermatologic reactions and soft tissue toxicityDermatologic related reactions, a pharmacologic effect observed with epidermal growth factor receptor (EGFR) inhibitors, are experienced with nearly all patients (approximately 90%) treated with Vectibix. Severe (NCI-CTC grade 3) skin reactions were reported in 34% and life-threatening (NCI-CTC grade 4) skin reactions in < 1% of patients who received Vectibix in combination with chemotherapy (n = 1536) (see section 4.8). If a patient develops dermatologic reactions that are grade 3 (CTCAE v 4.0) or higher, or that are considered intolerable, the following dose modification is recommended:
|Occurrence of skin symptom(s): ≥ grade 31||Administration of Vectibix||Outcome||Dose regulation|
|Initial occurrence||Hold 1 or 2 doses||Improved (< grade 3)||Continuing infusion at 100% of original dose|
|At the second occurrence||Hold 1 or 2 doses||Improved (< grade 3)||Continuing infusion at 80% of original dose|
|At the third occurrence||Hold 1 or 2 doses||Improved (< grade 3)||Continuing infusion at 60% of original dose|
|At the fourth occurrence||Discontinue||-||-|
Pulmonary complicationsPatients with a history of, or evidence of, interstitial pneumonitis or pulmonary fibrosis were excluded from clinical studies. Cases of interstitial lung disease (ILD), both fatal and non-fatal, have been reported, mainly from the Japanese population. In the event of acute onset or worsening pulmonary symptoms, Vectibix treatment should be interrupted and a prompt investigation of these symptoms should occur. If ILD is diagnosed, Vectibix should be permanently discontinued and the patient should be treated appropriately. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with panitumumab versus the risk of pulmonary complications must be carefully considered.
Electrolyte disturbancesProgressively decreasing serum magnesium levels leading to severe (grade 4) hypomagnesaemia have been observed in some patients. Patients should be periodically monitored for hypomagnesaemia and accompanying hypocalcaemia prior to initiating Vectibix treatment, and periodically thereafter for up to 8 weeks after the completion of treatment (see section 4.8). Magnesium repletion is recommended, as appropriate.Other electrolyte disturbances, including hypokalaemia, have also been observed. Monitoring as above and repletion as appropriate of these electrolytes is also recommended.
Infusion related reactionsAcross monotherapy and combination mCRC clinical studies (n = 2588), infusion-related reactions (occurring within 24 hours of an infusion) were reported in approximately 4% of Vectibix-treated patients, of which < 1% were severe (NCI-CTC grade 3 and grade 4).In the post-marketing setting, serious infusion-related reactions have been reported, including rare post-marketing reports with a fatal outcome. If a severe or life-threatening reaction occurs during an infusion or at any time post-infusion [e.g. presence of bronchospasm, angioedema, hypotension, need for parenteral treatment, or anaphylaxis], Vectibix should be permanently discontinued (see sections 4.3 and 4.8).In patients experiencing a mild or moderate (CTCAE v 4.0 grades 1 and 2) infusion-related reaction the infusion rate should be reduced for the duration of that infusion. It is recommended to maintain this lower infusion rate in all subsequent infusions.Hypersensitivity reactions occurring more than 24 hours after infusion have been reported including a fatal case of angioedema that occurred more than 24 hours after the infusion. Patients should be informed of the possibility of a late onset reaction and instructed to contact their physician if symptoms of a hypersensitivity reaction occur.
Acute renal failureAcute renal failure has been observed in patients who develop severe diarrhoea and dehydration. Patients who experience severe diarrhoea should be instructed to consult a healthcare professional urgently.
Vectibix in combination with irinotecan, bolus 5-fluorouracil, and leucovorin (IFL) chemotherapyPatients receiving Vectibix in combination with the IFL regimen [bolus 5-fluorouracil (500 mg/m2), leucovorin (20 mg/m2) and irinotecan (125 mg/m2)] experienced a high incidence of severe diarrhoea (see section 4.8). Therefore administration of Vectibix in combination with IFL should be avoided (see section 4.5).
Vectibix in combination with bevacizumab and chemotherapy regimensA randomised, open-label, multicentre study of 1,053 patients evaluated the efficacy of bevacizumab and oxaliplatin- or irinotecan-containing chemotherapeutic regimens with and without Vectibix in the first-line treatment of metastatic colorectal cancer. Shortened progression free survival time and increased deaths were observed in the patients receiving Vectibix in combination with bevacizumab and chemotherapy. A greater frequency of pulmonary embolism, infections (predominantly of dermatologic origin), diarrhoea, electrolyte imbalances, nausea, vomiting and dehydration was also observed in the treatment arms using Vectibix in combination with bevacizumab and chemotherapy. An additional analysis of efficacy data by KRAS status did not identify a subset of patients who benefited from Vectibix in combination with oxaliplatin- or irinotecan-based chemotherapy and bevacizumab. A trend towards worse survival was observed with Vectibix in the wild-type KRAS subset of the bevacizumab and oxaliplatin cohort, and a trend towards worse survival was observed with Vectibix in the bevacizumab and irinotecan cohort regardless of KRAS mutational status. Therefore, Vectibix should not be administered in combination with bevacizumab containing chemotherapy (see sections 4.5 and 5.1).Vectibix in combination with oxaliplatin-based chemotherapy in patients with mutant KRAS mCRC or for whom KRAS tumour status is unknownThe combination of Vectibix with oxaliplatin-containing chemotherapy is contraindicated for patients with mutant KRAS mCRC or for whom KRAS mCRC status is unknown. In a phase 3 study (n = 1183, 656 patients with wild-type KRAS and 440 patients with mutant KRAS tumours) evaluating panitumumab in combination with infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) compared to FOLFOX alone as first-line therapy for mCRC, a shortened progression-free survival and overall survival time were observed in patients with mutant KRAS tumours who received panitumumab and FOLFOX (n = 221) vs. FOLFOX alone (n = 219). KRAS mutational status should be determined using a validated test method by an experienced laboratory. If Vectibix is to be used in combination with FOLFOX then it is recommended that mutational status be determined by a laboratory that participates in a KRAS European Quality Assurance program or wild-type status be confirmed in a duplicate test.
Ocular toxicitiesSerious cases of keratitis and ulcerative keratitis have been rarely reported in the post-marketing setting. Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist. If a diagnosis of ulcerative keratitis is confirmed, treatment with Vectibix should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered.Vectibix should be used with caution in patients with a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.
Patients with ECOG 2 performance status treated with Vectibix in combination with chemotherapyFor patients with ECOG 2 performance status, assessment of benefit-risk is recommended prior to initiation of Vectibix in combination with chemotherapy for treatment of mCRC. A positive benefit-risk balance has not been documented in patients with ECOG 2 performance status (see section 5.1).
Elderly patientsNo overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix monotherapy. However, an increased number of serious adverse events were reported in elderly patients treated with Vectibix in combination with FOLFIRI or FOLFOX chemotherapy compared to chemotherapy alone (see section 4.8).
Other precautionsThis medicinal product contains 0.150 mmol sodium (which is 3.45 mg sodium) per ml of concentrate. To be taken into consideration by patients on a controlled sodium diet.
PregnancyThere are no adequate data from the use of Vectibix in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Therefore, Vectibix has the potential to cause foetal harm when administered to pregnant women. Human IgG is known to cross the placental barrier, and panitumumab may therefore be transmitted from the mother to the developing foetus. In women of childbearing potential, appropriate contraceptive measures must be used during treatment with Vectibix, and for 2 months following the last dose. If Vectibix is used during pregnancy or if the patient becomes pregnant while receiving this medicinal product, she should be advised of the potential risk for loss of the pregnancy or potential hazard to the foetus. Women who become pregnant during Vectibix treatment should be encouraged to enrol in Amgen's Pregnancy Surveillance programme. Contact details are provided in section 6 of the Package Leaflet Contents of the pack and other information.
Breast-feedingIt is unknown whether panitumumab is excreted in human breast milk. Because human IgG is secreted into human milk, panitumumab might also be secreted. The potential for absorption and harm to the infant after ingestion is unknown. It is recommended that women do not breast feed during treatment with Vectibix and for 2 months after the last dose. Women who breast-feed during Vectibix treatment should be encouraged to enrol in Amgen's Lactation Surveillance Programme. Contact details are provided in section 6 of the Package Leaflet Contents of the pack and other information.
FertilityAnimal studies have shown reversible effects on the menstrual cycle and reduced female fertility in monkeys (see section 5.3). Panitumumab may impact the ability of a woman to become pregnant.
Summary of safety profileBased on an analysis of all mCRC clinical trial patients receiving Vectibix monotherapy and in combination with chemotherapy (n = 2588), the most commonly reported adverse reactions are skin reactions occurring in 93% of patients. These reactions are related to the pharmacologic effects of Vectibix, and the majority are mild to moderate in nature with 25% severe (grade 3 NCI-CTC) and < 1% life threatening (grade 4 NCI-CTC). For clinical management of skin reactions, including dose modification recommendations, see section 4.4. Very commonly reported adverse reactions occurring in ≥ 20% of patients were gastrointestinal disorders [diarrhoea (50%), nausea (41%), vomiting (27%), constipation (23%) and abdominal pain (23%)]; general disorders [fatigue (37%), pyrexia (20%)]; metabolism and nutrition disorders [anorexia (27%)]; infections and infestations [paronychia (20%)]; and skin and subcutaneous disorders [rash (45%), dermatitis acneiform (39%), pruritus (35%), erythema (30%) and dry skin (22%)].
Tabulated summary of adverse reactionsThe data in the table below describe adverse reactions reported from clinical studies in patients with mCRC who received panitumumab as a single agent or in combination with chemotherapy (n = 2588) and spontaneous reporting. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
|MedDRA system organ class||Very common (≥ 1/10)||Common ( ≥ 1/100 to < 1/10)||Uncommon (≥ 1/1000 to < 1/100)||Rare (≥ 1/10,000 to < 1/1000||Frequency not known*|
|Infections and infestations||Paronychia1||Rash pustular Cellulitis1Folliculitis Localised infection||Eye infection Eyelid infection|
|Blood and lymphatic system disorders||Anaemia||Leukopenia|
|Immune system disorders||Hypersensitivity1||Anaphylactic reaction1|
|Metabolism and nutrition disorders||Hypokalaemia Anorexia Hypomagnesaemia||Hypocalcaemia Dehydration Hyperglycaemia Hypophosphataemia|
|Nervous system disorders||Headache Dizziness|
|Eye disorders||Conjunctivitis||Blepharitis Growth of eyelashes Lacrimation increased Ocular hyperaemia Dry eye Eye pruritus Eye irritation||Eyelid irritation Keratitis1||Ulcerative Keratitis1|
|Vascular disorders||Deep vein thrombosis Hypotension Hypertension Flushing|
|Respiratory, thoracic and mediastinal disorders||Dyspnoea Cough||Pulmonary embolism Epistaxis||Bronchospasm Nasal dryness||Interstitial lung disease|
|Gastrointestinal disorders||Diarrhoea1Nausea Vomiting Abdominal pain Stomatitis Constipation||Rectal haemorrhage Dry mouth Dyspepsia Aphthous stomatitis Cheilitis Gastrooesophageal reflux disease||Chapped lips|
|Skin and subcutaneous tissue disorders||Dermatitis acneiform Rash1,2Erythema Pruritus Dry skin Skin fissures Acne Alopecia||Palmar-plantar erythrodysaesthesia syndrome Skin ulcer Scab Hypertrichosis Onychoclasis Nail disorder||Angioedema1Hirsutism Ingrowing nail Onycholysis||Skin Necrosis1|
|Musculoskeletal and connective tissue disorders||Back pain||Pain in extremity|
|General disorders and administration site conditions||Fatigue Pyrexia Asthenia Mucosal inflammation Oedema peripheral||Chest pain Pain Chills||Infusion-related reaction1|
|Investigations||Weight decreased||Blood magnesium decreased|
Description of selected adverse reactions
Gastrointestinal disordersDiarrhoea when reported was mainly mild or moderate in severity. Severe diarrhoea (NCI-CTC grade 3 and 4) was reported in 2% of patients treated with Vectibix as a monotherapy and in 17% of patients treated with Vectibix in combination with chemotherapy. There have been reports of acute renal failure in patients who develop diarrhoea and dehydration (see section 4.4).
Infusion related reactionsAcross monotherapy and combination mCRC clinical studies (n = 2588), infusion-related reactions (occurring within 24 hours of any infusion), which may include symptoms/signs such as chills, fever or dyspnoea, were reported in approximately 4% of Vectibix-treated patients, of which < 1% were severe (NCI-CTC grade 3 and grade 4).A case of fatal angioedema occurred in a patient with recurrent and metastatic squamous cell carcinoma of the head and neck treated with Vectibix in a clinical trial. The fatal event occurred after re-exposure following a prior episode of angioedema; both episodes occurred greater than 24 hours after administration (see sections 4.3 and 4.4). Hypersensitivity reactions occurring more than 24 hours after infusion have also been reported in the post-marketing setting.For clinical management of infusion-related reactions, see section 4.4.
Skin and subcutaneous tissue disordersSkin rash most commonly occurred on the face, upper chest, and back, but could extend to the extremities. Subsequent to the development of severe skin and subcutaneous reactions, infectious complications including sepsis, in rare cases leading to death, cellulitis and local abscesses requiring incisions and drainage were reported. The median time to first symptom of dermatologic reaction was 10 days, and the median time to resolution after the last dose of Vectibix was 28 days. Paronychial inflammation was associated with swelling of the lateral nail folds of the toes and fingers.Dermatological reactions (including nail effects), observed in patients treated with Vectibix or other EGFR inhibitors, are known to be associated with the pharmacologic effects of therapy. Across all clinical trials, skin reactions occurred in 93% of patients receiving Vectibix as monotherapy or in combination with chemotherapy (n = 2588). These events consisted predominantly of rash and dermatitis acneiform and were mostly mild to moderate in severity. Severe (NCI-CTC grade 3) skin reactions were reported in 34% and life-threatening (NCI-CTC grade 4) skin reactions in < 1% of patients who received Vectibix in combination with chemotherapy (n = 1536). Life threatening and fatal infectious complications including necrotising fasciitis and sepsis have been observed in patients treated with Vectibix (see section 4.4).For clinical management of dermatological reactions, including dose modification recommendations, see section 4.4.In the post-marketing setting, cases of skin necrosis have been reported.
Ocular toxicitiesNon-serious cases of keratitis have been observed in 0.2 to 0.7% of clinical trial patients. In the post-marketing setting, serious cases of keratitis and ulcerative keratitis have been rarely reported (see section 4.4).
Other special populationsNo overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix monotherapy. However, an increased number of serious adverse events were reported in elderly patients treated with Vectibix in combination with FOLFIRI (45% vs 37%) or FOLFOX (52% vs 37%) chemotherapy compared to chemotherapy alone (see Section 4.4). The most increased serious adverse events were diarrhoea in patients treated with Vectibix in combination with either FOLFOX or FOLFIRI, and dehydration and pulmonary embolism when patients were treated with Vectibix in combination with FOLFIRI.The safety of Vectibix has not been studied in patients with renal or hepatic impairment.
Mechanism of actionPanitumumab is a recombinant, fully human IgG2 monoclonal antibody that binds with high affinity and specificity to the human EGFR. EGFR is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including EGFR (HER1/c-ErbB-1), HER2, HER3, and HER4. EGFR promotes cell growth in normal epithelial tissues, including the skin and hair follicle, and is expressed on a variety of tumour cells. Panitumumab binds to the ligand binding domain of EGFR and inhibits receptor autophosphorylation induced by all known EGFR ligands. Binding of panitumumab to EGFR results in internalisation of the receptor, inhibition of cell growth, induction of apoptosis, and decreased interleukin 8 and vascular endothelial growth factor production. The KRAS (Kirsten rat sarcoma 2 viral oncogene homologue) gene encodes a small, GTP-binding protein involved in signal transduction. A variety of stimuli, including that from the EGFR activates KRAS which in turn stimulates other intracellular proteins to promote cell proliferation, cell survival and angiogenesis.Activating mutations in the KRAS gene occur frequently in a variety human tumours and have been implicated in both oncogenesis and tumour progression.
Pharmacodynamic effectsIn vitro assays and in vivo animal studies have shown that panitumumab inhibits the growth and survival of tumour cells expressing EGFR. No anti-tumour effects of panitumumab were observed in human tumour xenografts lacking EGFR expression. The addition of panitumumab to radiation, chemotherapy or other targeted therapeutic agents, in animal studies resulted in an increase in anti-tumour effects compared to radiation, chemotherapy or targeted therapeutic agents alone. Dermatological reactions (including nail effects), observed in patients treated with Vectibix or other EGFR inhibitors, are known to be associated with the pharmacologic effects of therapy (with cross-reference to sections 4.2 and 4.8).
ImmunogenicityAs with all therapeutic proteins, there is potential for immunogenicity. Data on the development of anti-panitumumab antibodies has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies (an ELISA which detects high-affinity antibodies, and a Biosensor Immunoassay which detects both high and low-affinity antibodies). For patients whose sera tested positive in either screening immunoassay, an in vitro biological assay was performed to detect neutralising antibodies.As monotherapy:• The incidence of binding antibodies (excluding predose and transient positive patients) was < 1% as detected by the acid-dissociation ELISA and 3.8% as detected by the Biacore assay;• The incidence of neutralising antibodies (excluding predose and transient positive patients) was < 1%;• Compared with patients who did not develop antibodies, no relationship between the presence of anti-panitumumab antibodies and pharmacokinetics, efficacy and safety has been observed.In combination with irinotecan- or oxaliplatin-based chemotherapy: • The incidence of binding antibodies (excluding predose positive patients) was 1.0% as detected by the acid-dissociation ELISA and < 1% as detected by the Biacore assay;• The incidence of neutralising antibodies (excluding predose positive patients) was < 1%;• No evidence of an altered safety profile was found in patients who tested positive for antibodies to Vectibix.The detection of antibody formation is dependent on the sensitivity and specificity of the assay. The observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease, therefore, comparison of the incidence of antibodies to other products may be misleading.
Clinical efficacy as monotherapyThe efficacy of Vectibix as monotherapy in patients with metastatic colorectal cancer (mCRC) who had disease progression during or after prior chemotherapy was studied in a randomised controlled trial (463 patients) and open-label, single-arm trials (384 patients). A multinational, randomised, controlled trial was conducted in 463 patients with EGFR-expressing metastatic carcinoma of the colon or rectum after confirmed failure of oxaliplatin and irinotecan-containing regimens. Patients were randomised 1:1 to receive Vectibix at a dose of 6 mg/kg given once every two weeks plus best supportive care (not including chemotherapy) (BSC) or BSC alone. Patients were treated until disease progression or unacceptable toxicity occurred. Upon disease progression BSC alone patients were eligible to crossover to a companion study and receive Vectibix at a dose of 6 mg/kg given once every two weeks. Of 463 patients, 63% were male. The median age was 62 years (range 27 to 83), and 99% were Caucasian. Three hundred and ninety-six (86%) patients had a baseline ECOG Performance Status of 0 or 1. Sixty-seven percent of patients had colon cancer and 33% had rectal cancer. The primary endpoint was progression-free survival (PFS). In an analysis adjusting for potential bias from unscheduled assessments, the rate of disease progression or death in patients who received Vectibix was reduced by 40% relative to patients that received BSC [Hazard Ratio = 0.60, (95% CI: 0.49, 0.74), stratified log-rank p < 0.0001]. There was no difference seen in median PFS times as more than 50% of patients progressed in both treatment groups before the first scheduled visit. The study was retrospectively analysed by wild-type KRAS status versus mutant KRAS status. KRAS mutation status was determined by analysis of archived paraffin embedded tumour tissue. Tumour samples obtained from the primary resection of colorectal cancer were analysed for the presence of the seven most common activating mutations in the codon 12 and 13 (Gly12Asp, Gly12Ala, Gly12Val, Gly12Ser, Gly12Arg, Gly12Cys, and Gly13Asp) of the KRAS gene by using an allele-specific polymerase chain reaction. 427 (92%) patients were evaluable for KRAS status of which 184 had mutations. The efficacy results from an analysis adjusting for potential bias from unscheduled assessments are shown in the table below. There was no difference in overall survival (OS) seen in either group.
|Wild-type KRAS population||Mutant KRAS population|
|Vectibix plus BSC||BSC||Vectibix plus BSC||BSC|
|(n = 124)||(n = 119)||(n = 84)||(n = 100)|
|ORR n (%)||17%||0%||0%||0%|
|Response rate (investigator assessed)a (95% CI)||22% (14, 32)||0% (0, 4)|
|Hazard ratio (95% CI)||0.49 (0.37,0.65), p<0.0001||1.07 (0.77,1.48), p=0.6880|
|Difference in median (weeks)||8.0||0.0|
|Rate at week 8||60%||21%||21%||28%|
PFS Patients with mutant and wild-type KRASPFS Patients with wild-type KRAS
Unscheduled tumour assessments were moved to the nearest scheduled timepointPFS Patients with Mutant KRAS
Unscheduled tumour assessments were moved to the nearest scheduled timepoint
Clinical efficacy in combination with chemotherapy
First-line combination with FOLFOXThe efficacy of Vectibix in combination with oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (FOLFOX) was evaluated in a randomised, controlled trial of 1183 patients with mCRC with the primary endpoint of progression-free survival (PFS). Other key endpoints included the overall survival (OS), objective response rate (ORR), time to response, time to progression (TTP), and duration of response. The study was prospectively analysed by tumour KRAS status which was evaluable in 93% of the patients. The efficacy results in patients with wild-type KRAS mCRC and mutant KRAS mCRC are presented in the table below. Vectibix is indicated only for the treatment of wild-type KRAS mCRC (see sections 4.4 and 4.5). The table below also summarises subsequent chemotherapy (irinotecan, oxaliplatin, or fluoropyrimidine) and anti-EGFR therapy. The role of subsequent anti-EGFR therapy or chemotherapy on the estimated OS treatment effect is unknown.
|First-line mCRCwild-type KRAS population||First-line mCRCmutant KRAS population|
|Vectibix plus FOLFOX||FOLFOX||Vectibix plus FOLFOX||FOLFOX|
|(n = 325)||(n = 331)||(n = 221)||(n = 219)|
|% (95% CI)||57% (51%, 63%)||48% (42%, 53%)||40% (33%, 47%)||41% (34%, 48%)|
|Odds ratio (95% CI)||1.47 (1.07, 2.04)||0.98 (0.65,1.47)|
|Median duration of response (months) (95% CI)||10.9 (9.5, 13.3)||8.8 (7.7, 9.6)||7.4 (5.9, 8.3)||8.0 (6.7, 9.6)|
|Median (months) (95% CI)||10.0 (9.3, 11.4)||8.6 (7.5, 9.5)||7.4 (6.9, 8.1)||9.2 (8.1, 9.9)|
|Difference in median (months)||1.4||-1.8|
|Hazard ratio (95% CI); p-value||0.80 (0.67, 0.95); p = 0.0092||1.27 (1.04, 1.55); p = 0.0194|
|Estimated rate at 12 months (95% CI)||44% (38%, 49%)||32% (27%, 38%)||24% (18%, 30%)||30% (24%, 37%)|
|On-treatment PFS hazard ratio (95% CI)a; p-value||0.77 (0.63, 0.92); p = 0.0054||1.32 (1.05, 1.65); p = 0.0158|
|Median (months) (95% CI)||10.8 (9.4,12.5)||9.2 (7.7, 10.0)||7.5 (7.3, 8.9)||9.2 (8.0, 9.7)|
|Hazard ratio (95% CI)||0.76 (0.62, 0.92)||1.24 (0.98,1.58)|
|Median (months) (95% CI)||23.9 (20.3, 27.7)||19.7 (17.6, 22.7)||15.5 (13.1, 17.6)||19.2 (16.5, 21.7)|
|Difference in median (months)||4.2||-3.7|
|Hazard ratio (95% CI); p-value||0.88 (0.73, 1.06); p = 0.1710||1.17 (0.95, 1.45); p = 0.1444|
|Estimated rate at 24 months (95% CI)||50% (44%, 55%)||41% (36%, 47%)||29% (23%, 36%)||39% (32%, 45%)|
|Subjects receiving chemotherapy after the protocol treatment phase (%)||59%||65%||60%||70%|
|Subjects receiving anti-EGFR therapy after the protocol treatment phase - (%)||13%||25%||7%||16%|
|ECOG PS of 0 or 1 (n=616)||ECOG 2 PS (n=40)|
|Vectibix plus FOLFOX||FOLFOX||Vectibix plus FOLFOX||FOLFOX|
|(n=305)||(n=311)||(n = 20)||(n=20)|
|Median PFS (months)||10.8||8.7||4.8||7.5|
|Difference in median (months)||2.1||-2.7|
|PFS Hazard ratio (95% CI); p-value||0.76 (0.64, 0.91); p = 0.0022||1.80 (0.88, 3.69); p = 0.1060|
|Median OS (months)||25.8||20.6||7.0||11.7|
|Difference in median (months)||5.2||-4.7|
|OS Hazard ratio (95% CI); p-value||0.84 (0.69, 1.02); p = 0.0735||1.59 (0.80, 3.16); p = 0.1850|
Second-line combination with FOLFIRIThe efficacy of Vectibix in combination with irinotecan, 5-fluorouracil (5-FU) and leucovorin (FOLFIRI) was evaluated in a randomised, controlled trial of 1186 patients with mCRC with the primary endpoints of overall survival (OS) and progression-free survival (PFS). Other key endpoints included the objective response rate (ORR), time to response, time to progression (TTP), and duration of response. The study was prospectively analysed by tumour KRAS status which was evaluable in 91% of the patients. The efficacy results in patients with wild-type KRAS mCRC and mutant KRAS mCRC are presented in the table below. Eighteen (18) % (n = 115) of patients with wild-type KRAS mCRC had been exposed to prior bevacizumab treatment. PFS and Response Rate were similar regardless of prior bevacizumab treatment. Vectibix is indicated only for the treatment of wild-type KRAS mCRC (see sections 4.4 and 4.5). The table below also summarises subsequent chemotherapy (irinotecan, oxaliplatin, or fluoropyrimidine) and anti-EGFR therapy. The role of subsequent anti-EGFR therapy or chemotherapy on the estimated OS treatment effect is unknown.
|Second-line mCRC wild-type KRAS population||Second-line mCRCmutant KRAS population|
|Vectibix plus FOLFIRI||FOLFIRI||Vectibix plus FOLFIRI||FOLFIRI|
|(n = 303)||(n = 294)||(n = 238)||(n = 248)|
|% (95% CI)||36% (31%, 42%)||10 % (7%, 14%)||13% (9%, 18%)||15% (11%, 20%)|
|Odds ratio (95% CI)||5.50 (3.32, 8.87)||0.93 (0.53, 1.63)|
|Median duration of response (months) (95% CI)||7.6 (6.5, 9.4)||6.6 (5.7, 10.9)||5.8 (5.5, 7.4)||5.3 (4.6, 7.9)|
|Median (months) (95% CI)||6.7 (5.8, 7.4)||4.9 (3.8, 5.5)||5.3 (4.2, 5.7)||5.4 (4.0, 5.6)|
|Difference in median (months)||1.8||-0.1|
|Hazard ratio (95% CI); p-value||0.82 (0.69, 0.97); p = 0.0231||0.95 (0.78, 1.14); p = 0.5611|
|Estimated rate at six months (95% CI)||54% (48%, 60%)||39% (33%, 44%)||40% (34%, 47%)||38% (32%, 44%)|
|On-treatment PFS hazard ratio (95%CI) a; p-value||0.73 (0.60, 0.88); p = 0.001||0.89 (0.72, 1.10); p = 0.2951|
|Median (months) (95% CI)||7.3 (6.0, 7.5)||5.3 (3.9, 5.7)||5.5 (4.5, 5.7)||5.5 (4.8, 5.7)|
|Hazard ratio (95% CI)||0.72 (0.59, 0.88)||0.89 (0.71, 1.11)|
|Median (months) (95% CI)||14.5 (13.0, 16.1)||12.5 (11.2, 14.2)||11.8 (10.4, 13.3)||11.1 (10.3, 12.4)|
|Difference in median (months)||2.0||0.7|
|Hazard ratio (95% CI); p-value||0.92 (0.78, 1.10); p = 0.3660||0.93 (0.77, 1.13); p = 0.4815|
|Estimated rate at 12 months (95% CI)||59% (53%, 64%)||53% (47%, 59%)||49% (42%, 55%)||45% (39%, 51%)|
|Estimated rate at 18 months (95% CI)||40% (34%, 45%)||33% (27%, 39%)||26% (21%, 32%)||24% (19%, 29%)|
|Subjects receiving chemotherapy after the protocol treatment phase (%)||53%||50%||48%||55%|
|Subjects receiving anti-EGFR therapy after the protocol treatment phase - (%)||13%||34%||9%||32%|
First-line combination with bevacizumab and oxaliplatin or irinotecan-based chemotherapyIn a randomised, open label, controlled clinical trial, chemotherapy (oxaliplatin or irinotecan) and bevacizumab were given with and without panitumumab in the first line treatment of patients with metastatic colorectal cancer (n = 1053 [n = 823 oxaliplatin cohort, n = 230 irinotecan cohort]). Panitumumab treatment was discontinued due to a statistically significant reduction in PFS in patients receiving panitumumab observed in an interim analysis. The major study objective was comparison of PFS in the oxaliplatin cohort. In the final analysis, the hazard ratio for PFS was 1.27 (95% CI: 1.06, 1.52). Median PFS was 10.0 (95% CI: 8.9, 11.0) and 11.4 (95% CI: 10.5, 11.9) months in the panitumumab and the non-panitumumab arm, respectively. There was an increase in mortality in the panitumumab arm. The hazard ratio for overall survival was 1.43 (95% CI: 1.11, 1.83). Median overall survival was 19.4 (95% CI: 18.4, 20.8) and 24.5 (95% CI: 20.4, 24.5) in the panitumumab arm and the non-panitumumab arm.An additional analysis of efficacy data by KRAS status did not identify a subset of patients who benefited from panitumumab in combination with oxaliplatin- or irinotecan based chemotherapy and bevacizumab. For the wild-type KRAS subset of the oxaliplatin cohort, the hazard ratio for PFS was 1.36 with 95% CI: 1.04-1.77. For the mutant KRAS subset, the hazard ratio for PFS was 1.25 with 95% CI: 0.91-1.71. A trend for OS favouring the control arm was observed in the wild-type KRAS subset of the oxaliplatin cohort (hazard ratio = 1.89; 95% CI: 1.30, 2.75). A trend towards worse survival was also observed with panitumumab in the irinotecan cohort regardless of KRAS mutational status. Overall, panitumumab treatment combined with chemotherapy and bevacizumab is associated with an unfavourable benefit-to-risk profile irrespective of tumour KRAS mutational status.This medicinal product has been authorised under a conditional approval scheme. This means that further evidence on this medicinal product is awaited, in particular data are required to confirm the effect of monotherapy in patients with wild-type KRAS tumours which is currently supported by a retrospective analysis. Studies investigating this effect are currently ongoing. The European Medicines Agency (EMA) will review new information on this medicinal product at least every year and this SPC will be updated as necessary.
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with Vectibix in all subsets of the paediatric population in colorectal cancer (see section 4.2 for information on paediatric use).
Medicinal product shelf life3 years.
In-use shelf lifeVectibix does not contain any antimicrobial preservative or bacteriostatic agent. The product should be used immediately after dilution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should be no longer than 24 hours at 2°C to 8°C.The diluted solution must not be frozen.
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