Panitumumab

Panitumumab is a recombinant, fully human IgG2 monoclonal antibody made in Chinese hamster ovary cells. It binds with high affinity and specificity to the epidermal growth factor receptor (EGFR, also called HER1 or c-ErbB-1), a transmembrane glycoprotein of the type I receptor tyrosine kinase family. EGFR drives cell growth in normal epithelial tissues, including skin and hair follicles, and is expressed on many tumour cells, including those of the colon and rectum.

Mechanism of Action

• Receptor blockade: panitumumab binds the ligand-binding domain of EGFR and competes with the receptor’s natural ligands. It inhibits receptor autophosphorylation induced by all known EGFR ligands, and so the activation of receptor-associated kinases.
• Downstream effects: binding leads to internalisation of the receptor, inhibition of cell growth, induction of apoptosis and lower production of interleukin 8 and vascular endothelial growth factor.
• Role of RAS: KRAS and NRAS are closely related GTP-binding proteins that EGFR signalling activates to promote cell proliferation, survival and new blood vessel growth. Activating RAS mutations are common in human tumours. A mutation of this kind inside a cancer cell can keep these pathways switched on despite EGFR blockade, which explains resistance to EGFR inhibitors and why only wild-type RAS tumours are treated.
• Preclinical activity: in vitro and in animals, panitumumab inhibited the growth and survival of EGFR-expressing tumour cells, with no antitumour effect in xenografts lacking EGFR. Adding it to radiation, chemotherapy or other targeted agents increased antitumour effects in animal studies.
• Skin effects: because EGFR also supports the growth of normal skin and hair follicles, skin reactions are a pharmacological effect of EGFR inhibitors.

Pharmacokinetics

• Non-linear kinetics: after single 1-hour infusions, exposure (AUC) rose more than in proportion to dose, and clearance fell from 30.6 to 4.6 mL/kg/day as the dose increased from 0.75 to 9 mg/kg. Above 2 mg/kg, AUC rises roughly in proportion to dose.
• Steady state: with the recommended 6 mg/kg every 2 weeks as a 1-hour infusion, steady state is reached by the third infusion. Mean (± SD) peak and trough concentrations are 213 ± 59 and 39 ± 14 µg/mL, AUC over the dosing interval is 1,306 ± 374 µg·day/mL, and clearance is 4.9 ± 1.4 mL/kg/day.
• Elimination: the half-life is about 7.5 days (range 3.6 to 10.9 days).
• Special populations: a population analysis found no apparent effect on pharmacokinetics of age (21–88 years), sex, race, hepatic function, renal function, the chemotherapy given, or the intensity of EGFR staining in tumour cells (1+, 2+, 3+). No clinical studies have examined pharmacokinetics in renal or hepatic impairment.

Vectibix is indicated for adults with wild-type RAS metastatic colorectal cancer (mCRC):

• First line: in combination with FOLFOX (infusional fluorouracil, leucovorin and oxaliplatin) or FOLFIRI (fluorouracil, leucovorin and irinotecan).
• Second line: in combination with FOLFIRI, in patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan).
• Monotherapy: after failure of fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens.

Wild-type status of both KRAS and NRAS must be confirmed before treatment starts.

• History of severe or life-threatening hypersensitivity to panitumumab or to any excipient.
• Interstitial pneumonitis or pulmonary fibrosis.
• Combination with oxaliplatin-containing chemotherapy in patients with mutant RAS mCRC, or in whom RAS mCRC status is unknown.

Skin reactions occur in about 94% of patients (analysis of all mCRC trial patients given panitumumab alone or with chemotherapy, n = 2,224). Most are mild to moderate; 23% are severe (grade 3) and under 1% life-threatening (grade 4). Reactions reported in at least 20% of patients were diarrhoea (46%), nausea (39%), vomiting (26%), constipation (23%), abdominal pain (23%), fatigue (35%), pyrexia (21%), decreased appetite (30%), paronychia (20%), rash (47%), dermatitis acneiform (39%), pruritus (36%), erythema (33%) and dry skin (21%).

Very common (≥1/10): conjunctivitis, paronychia; anaemia; hypokalaemia, hypomagnesaemia, decreased appetite; insomnia; dyspnoea, cough; diarrhoea, nausea, vomiting, abdominal pain, stomatitis, constipation; dermatitis acneiform, rash, erythema, pruritus, dry skin, skin fissures, acne, alopecia; back pain; fatigue, pyrexia, asthenia, mucosal inflammation, peripheral oedema; weight loss.

Common (≥1/100 to <1/10): pustular rash, cellulitis, urinary tract infection, folliculitis, localised infection; leucopenia; hypersensitivity; hypocalcaemia, dehydration, hyperglycaemia, hypophosphataemia; anxiety; headache, dizziness; blepharitis, growth of eyelashes, increased lacrimation, ocular hyperaemia, dry eye, eye pruritus, eye irritation; tachycardia; deep vein thrombosis, hypotension, hypertension, flushing; pulmonary embolism, epistaxis; rectal haemorrhage, dry mouth, dyspepsia, aphthous ulcer, cheilitis, gastro-oesophageal reflux disease; skin ulcer, skin exfoliation, exfoliative rash, dermatitis, papular, pruritic, erythematous, generalised, macular and maculo-papular rash, skin lesion, skin toxicity, scab, hypertrichosis, nail breakage, nail disorder, hyperhidrosis, palmar-plantar erythrodysaesthesia syndrome; pain in extremity; chest pain, pain, chills; lower blood magnesium.

Uncommon (≥1/1,000 to <1/100): eye infection, eyelid infection; anaphylactic reaction; ulcerative keratitis, keratitis, eyelid irritation; cyanosis; interstitial lung disease, bronchospasm, nasal dryness; chapped lips, dry lips; toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, angioedema, hirsutism, ingrowing nail, onycholysis; infusion-related reaction.

The SmPC table has no rare or not-known category. Skin necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis and ulcerative keratitis come from post-marketing reports, and their frequency category was estimated from the upper limit of the confidence interval (no more than about 0.13%).

Important serious reactions:

• Skin and soft tissue: after severe skin reactions (including stomatitis), infectious complications such as sepsis, cellulitis, necrotising fasciitis and abscesses needing drainage have occurred, rarely with fatal outcome. The median time to the first skin symptom was 10 days, and the median time to resolution after the last dose was 31 days.
• Infusion-related reactions: about 1% of patients (0.3% severe). Serious reactions, rarely fatal, have been reported after marketing. Hypersensitivity reactions can also occur more than 24 hours after an infusion, including one fatal case of angioedema.
• Diarrhoea: severe (grade 3–4) in 2% of patients on monotherapy and 16% on combination treatment. Acute renal failure has been reported in patients with diarrhoea and dehydration.
• Eyes, lungs and electrolytes: keratitis and ulcerative keratitis that may lead to corneal perforation; interstitial lung disease, fatal and non-fatal; and severe (grade 4) hypomagnesaemia.
• With chemotherapy: hypomagnesaemia, diarrhoea and stomatitis were more frequent than with panitumumab alone, but rarely led to stopping treatment. In elderly patients, serious reactions were more frequent with FOLFIRI (45% versus 32%) or FOLFOX (52% versus 37%) plus panitumumab than with chemotherapy alone; diarrhoea, dehydration and pulmonary embolism were the main ones.

• Irinotecan: panitumumab did not change the pharmacokinetics of irinotecan or its active metabolite SN-38, and irinotecan-containing regimens (IFL or FOLFIRI) had no effect on panitumumab in a cross-study comparison.
• IFL chemotherapy (bolus fluorouracil, leucovorin and irinotecan): do not combine, because of a high incidence of severe diarrhoea.
• Bevacizumab-containing chemotherapy: do not combine. Increased toxicity and deaths were seen, with shorter progression-free survival and more pulmonary embolism, infections (mainly of skin origin), diarrhoea, electrolyte imbalance, nausea, vomiting and dehydration.
• Oxaliplatin-containing chemotherapy: contraindicated in patients with mutant RAS mCRC or unknown RAS status, because progression-free and overall survival were shorter with panitumumab plus FOLFOX in mutant RAS tumours.

Treatment should be supervised by a physician experienced in anti-cancer therapy. Before starting, wild-type RAS status (KRAS and NRAS, exons 2, 3 and 4) must be shown by an experienced laboratory using validated test methods. When Vectibix is used with FOLFOX, the test should preferably be done in a laboratory that takes part in a RAS external quality assurance programme, or wild-type status should be confirmed by a duplicate test.

Recommended Dose

• 6 mg/kg of body weight once every two weeks, as an intravenous infusion through an infusion pump.
• Dilute in sodium chloride 9 mg/mL (0.9%) solution for injection to a final concentration of no more than 10 mg/mL (see SmPC section 6.6).
• Infuse through a low-protein-binding 0.2 or 0.22 µm in-line filter, via a peripheral line or an indwelling catheter. The infusion takes about 60 minutes; if the first infusion is tolerated, later infusions can run over 30 to 60 minutes. Doses above 1,000 mg should be infused over about 90 minutes.
• Flush the line with sodium chloride solution before and after, to avoid mixing with other medicines. Never give it as an intravenous push or bolus.
• In mild or moderate (grade 1 or 2) infusion-related reactions, slow the infusion for that infusion and keep the lower rate for all later infusions.

Dose Modification for Severe Skin Reactions

For skin reactions of grade 3 or higher (severe or life-threatening):

• First occurrence: withhold 1 or 2 doses. If the reaction improves to below grade 3, continue at 100% of the original dose. If it has not recovered, stop treatment.
• Second occurrence: withhold 1 or 2 doses. If it improves, continue at 80% of the original dose; otherwise stop.
• Third occurrence: withhold 1 or 2 doses. If it improves, continue at 60% of the original dose; otherwise stop.
• Fourth occurrence: stop treatment.

Treatment should also be withheld or stopped when skin or soft tissue toxicity comes with severe or life-threatening inflammatory or infectious complications.

Special Populations

• Renal and hepatic impairment: safety and efficacy have not been studied, and no dose recommendation is made.
• Elderly: there are no clinical data to support dose adjustment.
• Children and adolescents: there is no relevant use in the paediatric population for colorectal cancer.

Traceability

Because panitumumab is a biological medicine, the name and batch number of the product given must be recorded clearly.

Wild-Type RAS Status Is Required

Treatment must not start until the tumour is shown to be wild-type for KRAS and NRAS (exons 2, 3 and 4). Panitumumab with oxaliplatin-based chemotherapy is contraindicated in mutant or unknown RAS status.

Skin Reactions and Soft Tissue Toxicity

Skin reactions are a pharmacological effect of EGFR inhibitors and occur in nearly all patients (about 94%). The rash is most common on the face, upper chest and back but can spread to the limbs; paronychia comes with swelling of the nail folds. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported after marketing. Patients with severe skin reactions or soft tissue toxicity should be watched for inflammatory or infectious complications, including cellulitis and necrotising fasciitis, and treated promptly. Management depends on severity and may include a moisturiser, a sunscreen (SPF above 15, UVA and UVB), a topical steroid cream no stronger than 1% hydrocortisone, and/or oral antibiotics such as doxycycline. Patients should wear sunscreen and hats and limit sun exposure, because sunlight can worsen the reactions. They may be advised to apply moisturiser and sunscreen to the face, hands, feet, neck, back and chest every morning, and the topical steroid to the same areas every night.

Infusion-Related Reactions and Late Hypersensitivity

If a severe or life-threatening reaction occurs during an infusion or at any time afterwards (for example bronchospasm, angioedema, hypotension, a need for parenteral treatment, or anaphylaxis), Vectibix must be stopped permanently. Patients should be told that hypersensitivity can appear more than 24 hours after an infusion, and to contact their doctor if symptoms of hypersensitivity develop.

Electrolyte Disturbances

Serum magnesium can fall progressively, leading to severe (grade 4) hypomagnesaemia in some patients. Magnesium, and the accompanying calcium, should be checked before treatment starts and periodically afterwards until 8 weeks after treatment ends, with replacement as appropriate. Other electrolytes, including potassium, should be monitored and replaced in the same way.

Diarrhoea and Acute Renal Failure

Acute renal failure has been seen in patients with severe diarrhoea and dehydration. Patients with severe diarrhoea should be told to consult a healthcare professional urgently.

Pulmonary Complications

Interstitial lung disease, fatal and non-fatal, has been reported, mainly in Japanese patients. If pulmonary symptoms start suddenly or worsen, interrupt Vectibix and investigate promptly; if interstitial lung disease is diagnosed, stop permanently. Patients with interstitial pneumonitis or pulmonary fibrosis were excluded from the studies, and the medicine is contraindicated in them; with a history of these conditions, the benefit must be weighed carefully against the risk.

Eye Reactions

Serious keratitis and ulcerative keratitis, which may lead to corneal perforation, have been reported. Patients with acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmologist. If ulcerative keratitis is confirmed, Vectibix should be interrupted or stopped; if keratitis is diagnosed, the benefits and risks of continuing should be weighed. Use caution in patients with a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens use is also a risk factor.

Combinations to Avoid

Do not combine Vectibix with IFL chemotherapy or with bevacizumab-containing chemotherapy. Combination with oxaliplatin-containing chemotherapy is contraindicated in mutant or unknown RAS status. See Drug Interactions.

Performance Status and Age

In patients with ECOG performance status 2, benefit and risk should be assessed before starting Vectibix with chemotherapy, because a positive benefit-risk balance has not been documented in this group. In elderly patients (65 years or older), safety and efficacy were no different on monotherapy, but more serious reactions were reported with FOLFIRI or FOLFOX than with chemotherapy alone.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no adequate data. Animal studies showed reproductive toxicity, EGFR is implicated in prenatal development, and human IgG crosses the placenta, so Vectibix may cause foetal harm. Women of childbearing potential must use appropriate contraception during treatment and for 2 months after the last dose. If it is used in pregnancy, or pregnancy occurs during treatment, the patient should be told of the risk of pregnancy loss or harm to the foetus.
• Breastfeeding: it is not known whether panitumumab passes into breast milk, but human IgG does. Women should not breastfeed during treatment and for 2 months after the last dose.
• Fertility: in monkeys, reversible effects on the menstrual cycle and reduced female fertility were seen. Panitumumab may affect a woman’s ability to become pregnant.

Sodium

Each mL of concentrate contains 3.45 mg sodium, equivalent to 0.17% of the WHO recommended maximum daily intake of 2 g for an adult.

Effect on Driving

Vectibix may have a minor influence on the ability to drive and use machines. Patients with treatment-related symptoms that affect their vision and/or their ability to concentrate and react should not drive or use machines until the effect subsides.

Store in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the original carton to protect it from light. Vectibix is a cold-chain product: it must be transported and held at 2–8 °C. Storage after dilution is described under Shelf Life.

• Unopened vial: 3 years.
• Diluted solution: Vectibix contains no antimicrobial preservative or bacteriostatic agent, so it should be used immediately after dilution. If it is not, in-use storage times and conditions are the responsibility of the user and should be no longer than 24 hours at 2–8 °C. The diluted solution must not be frozen.

Prescription only (Rx), under restricted medical prescription (Annex II B). Treatment is supervised by a physician experienced in anti-cancer therapy, and only after the tumour’s RAS status has been shown to be wild-type. Vectibix is given as an intravenous infusion in a hospital or clinic, so it is supplied to the hospital or clinic that administers it, as a refrigerated cold-chain product (2–8 °C).