Pertuzumab

Pertuzumab is a recombinant humanised IgG1 monoclonal antibody, made in Chinese hamster ovary cells, that targets the human epidermal growth factor receptor 2 (HER2). HER2 is overexpressed or gene-amplified in about 20% of breast cancers, which generally have a poorer prognosis than HER2-negative disease. Pertuzumab is used with trastuzumab, either as separate infusions (Perjeta) or co-formulated for subcutaneous injection (Phesgo).

Mechanism of Action

• Dimerisation: pertuzumab binds the extracellular dimerisation domain (subdomain II) of HER2 and blocks ligand-dependent pairing of HER2 with other HER family members, including EGFR, HER3 and HER4.
• Signalling: this inhibits ligand-initiated signalling through the MAP kinase and PI3K pathways, which can lead to growth arrest and apoptosis.
• Immune effect: pertuzumab also mediates antibody-dependent cell-mediated cytotoxicity.
• Complementary action: trastuzumab binds a different region of HER2 (subdomain IV) and does not compete with pertuzumab. Pertuzumab alone inhibited the proliferation of human tumour cells, and the combination with trastuzumab significantly augmented antitumour activity in HER2-overexpressing xenograft models.
• Vorhyaluronidase alfa: Phesgo also contains this enzyme, which breaks down hyaluronic acid and so increases the dispersion and absorption of the antibodies after subcutaneous injection.
• Heart: medicines that block HER2 can reduce the left ventricular ejection fraction (LVEF), so cardiac function is assessed before and during treatment.

Pharmacokinetics

• Perjeta, population analysis: the figures below come from 481 patients with advanced malignancies who received 2 to 25 mg/kg every 3 weeks as 30 to 60 minute infusions. Pharmacokinetics were linear within the recommended dose range.
• Absorption: Perjeta is given by intravenous infusion. With an 840 mg loading dose and then 420 mg every 3 weeks, steady state is reached after the first maintenance dose.
• Distribution: in the typical patient the volume of distribution is 3.11 L in the central and 2.46 L in the peripheral compartment.
• Metabolism: not studied directly; antibodies are cleared principally by catabolism into smaller peptides.
• Elimination: median clearance is 0.235 L/day and median half-life is 18 days.
• Special populations: there was no significant difference in pharmacokinetics between patients under 65 years (306) and those aged 65 or over (175), and none by gender or ethnicity (Japanese versus non-Japanese). Baseline albumin and lean body weight influence clearance most, but at the recommended dose neither calls for a dose change. No dedicated renal impairment trial was done; exposure in mild and moderate impairment was similar to normal renal function, and no relationship was seen between creatinine clearance (27 to 244 mL/min) and exposure.
• Subcutaneous (Phesgo): pertuzumab has an absolute bioavailability of about 71% and reaches its median peak (157 µg/mL) after about 3.8 days. Central volume of distribution is 2.77 L, clearance 0.163 L/day and half-life about 24.3 days, and pertuzumab trough levels were non-inferior to the intravenous form. Trastuzumab within Phesgo has a bioavailability of about 77%, peaks after about 3.8 days and has a clearance of 0.111 L/day; at least 95% of patients fall below 1 µg/mL of trastuzumab 7 months after the last dose.

Pertuzumab is used only in HER2-positive disease, defined as a score of 3+ on immunohistochemistry and/or an in situ hybridisation ratio of 2.0 or more, assessed by a validated test in a specialised laboratory.

Perjeta (intravenous infusion; given with trastuzumab and chemotherapy):

• Early breast cancer, neoadjuvant treatment: with trastuzumab and chemotherapy, in adults with HER2-positive, locally advanced, inflammatory or early stage breast cancer at high risk of recurrence.
• Early breast cancer, adjuvant treatment: with trastuzumab and chemotherapy, in adults with HER2-positive early breast cancer at high risk of recurrence.
• Metastatic breast cancer: with trastuzumab and docetaxel, in adults with HER2-positive metastatic or locally recurrent unresectable breast cancer who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease.

Phesgo (subcutaneous fixed-dose combination of pertuzumab and trastuzumab):

• Early breast cancer, neoadjuvant treatment: with chemotherapy, in adults with HER2-positive, locally advanced, inflammatory or early stage breast cancer at high risk of recurrence.
• Early breast cancer, adjuvant treatment: with chemotherapy, in adults with HER2-positive early breast cancer at high risk of recurrence.
• Metastatic breast cancer: with docetaxel, in adults with HER2-positive metastatic or locally recurrent unresectable breast cancer who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease.

Poherdy, a biosimilar of pertuzumab, has its own SmPC.

• Perjeta: hypersensitivity to pertuzumab or to any of the excipients listed in its SmPC.
• Phesgo: hypersensitivity to either active substance (pertuzumab or trastuzumab) or to any of its excipients.

Perjeta has been studied in more than 6,000 patients, mostly alongside other anti-cancer medicines. The frequencies below come from the Perjeta-treated groups of four pivotal trials (CLEOPATRA, NEOSPHERE, TRYPHAENA and APHINITY) and from post-marketing reports. Because pertuzumab was given with trastuzumab and chemotherapy, it is difficult to attribute a reaction to one medicine. The most common reactions (30% or more) were diarrhoea, alopecia, nausea, fatigue, neutropenia and vomiting, and the most common grade 3–4 reactions (10% or more) were neutropenia and febrile neutropenia.

Very common (≥1/10): nasopharyngitis, febrile neutropenia, neutropenia, leucopenia, anaemia, infusion-related reaction, decreased appetite, insomnia, peripheral neuropathy, peripheral sensory neuropathy, headache, dysgeusia, dizziness, paraesthesia, increased lacrimation, hot flush, cough, epistaxis, dyspnoea, diarrhoea, vomiting, stomatitis, nausea, constipation, dyspepsia, abdominal pain, alopecia, rash, nail disorder, pruritus, dry skin, myalgia, arthralgia, pain in extremity, mucosal inflammation, peripheral oedema, pyrexia, fatigue, asthenia.

Common (≥1/100 to <1/10): paronychia, upper respiratory tract infection, hypersensitivity, drug hypersensitivity, left ventricular dysfunction, chills, pain, oedema.

Uncommon (≥1/1,000 to <1/100): anaphylactic reaction, congestive cardiac failure, interstitial lung disease, pleural effusion.

Rare (≥1/10,000 to <1/1,000): cytokine release syndrome, tumour lysis syndrome (reported after marketing).

Febrile neutropenia, infusion-related reaction, hypersensitivity, drug hypersensitivity and anaphylactic reaction have been reported with a fatal outcome. In the metastatic breast cancer trial CLEOPATRA, Perjeta with trastuzumab and docetaxel was compared with placebo plus the same medicines: diarrhoea occurred in 68.4% against 48.7% (grade 3–4: 9.3% against 5.1%), rash in 51.7% against 38.9%, febrile neutropenia in 13.7% against 7.6% (25.8% against 11.3% in Asian patients) and hypersensitivity or anaphylaxis events in 11.3% against 9.3%. Infusion-related reactions occurred in 13.2% of Perjeta-treated patients on the first day, when Perjeta was given alone, and in 18.6% to 25.0% on the first day of Perjeta in the neoadjuvant and adjuvant trials; most were mild or moderate. In the adjuvant trial APHINITY, symptomatic heart failure with an LVEF fall of at least 10 percentage points to below 50% occurred in 0.9% of Perjeta-treated patients against 0.5% with placebo, mostly after anthracyclines. In patients aged 65 or over, decreased appetite, anaemia, weight loss, asthenia, dysgeusia, peripheral neuropathy, hypomagnesaemia and diarrhoea had an incidence at least 5% higher than in younger patients; data above 75 years are limited.

Phesgo has a safety profile generally consistent with intravenous pertuzumab plus trastuzumab, with one additional reaction, injection site reaction (15.3% against 0.4% with the intravenous form; mostly pain or redness and all grade 1 or 2). In the FEDERICA trial alopecia (79% against 73%), myalgia (27% against 20.6%) and dyspnoea (12.1% against 6%) were reported more often with Phesgo. The most common reactions (30% or more) with Phesgo, or with intravenous pertuzumab plus trastuzumab and chemotherapy, were alopecia, diarrhoea, nausea, anaemia, asthenia and arthralgia; the most common serious events (1% or more) were febrile neutropenia, cardiac failure, pyrexia, neutropenia, neutropenic sepsis, decreased neutrophil count and pneumonia. The Phesgo SmPC pools 3,834 patients given pertuzumab with trastuzumab, so its frequencies differ slightly from those above (cardiac failure, for example, is listed there as common).

• Trastuzumab and docetaxel: no pharmacokinetic interaction between pertuzumab and trastuzumab or docetaxel in a sub-study of 37 patients in the CLEOPATRA trial. The population analysis showed no sign of an interaction, and pharmacokinetic data from NEOSPHERE and APHINITY confirmed it.
• Other cytotoxic agents: five studies examined the pharmacokinetics of docetaxel, paclitaxel, gemcitabine, capecitabine, carboplatin and erlotinib given with pertuzumab and found no interaction; the pharmacokinetics of pertuzumab were comparable to those in single-agent studies.
• Anthracyclines: the risk of cardiac toxicity might be expected to be higher with concomitant use of pertuzumab and an anthracycline than with sequential use, so the cardiac risk is weighed against the patient’s medical need before they are combined. Phesgo is given after the whole anthracycline regimen is complete.
• Trastuzumab with other cytotoxic agents (relevant to Phesgo): exposure to paclitaxel and doxorubicin was not altered, but trastuzumab may raise one doxorubicin metabolite (D7D), of unclear significance; capecitabine reached higher concentrations and a longer half-life with trastuzumab, while docetaxel, cisplatin and carboplatin were not affected. These agents did not appear to change trastuzumab pharmacokinetics.

Treatment must be started under the supervision of a physician experienced in giving anti-cancer agents. It must be given by a healthcare professional prepared to manage anaphylaxis, in an environment where full resuscitation facilities are immediately available. The HER2 status of the tumour is confirmed first, on a validated test in a specialised laboratory.

Perjeta (Intravenous Infusion)

• Loading dose: 840 mg as a 60-minute intravenous infusion.
• Maintenance dose: 420 mg every 3 weeks. If the first infusion was well tolerated, later infusions may run over 30 to 60 minutes.
• Observation: 30 to 60 minutes after each infusion, completed before any subsequent infusion of trastuzumab or chemotherapy.
• With trastuzumab: Perjeta and trastuzumab are given one after the other, in any order, and never mixed in the same infusion bag. Trastuzumab follows a 3-weekly schedule, either intravenous (loading dose 8 mg/kg, then 6 mg/kg every 3 weeks) or a fixed subcutaneous injection of 600 mg every 3 weeks irrespective of body weight.
• With a taxane: Perjeta and trastuzumab are given before the taxane. Docetaxel can start at 75 mg/m² and be escalated to 100 mg/m² depending on the regimen and tolerability, or be given at 100 mg/m² every 3 weeks from the start; with a carboplatin-based regimen docetaxel stays at 75 mg/m² with no escalation. In the adjuvant setting the recommended paclitaxel dose is 80 mg/m² once weekly for 12 weekly cycles.
• Method: intravenous infusion only, never as an intravenous push or bolus. Dilution instructions are in sections 6.2 and 6.6 of the SmPC.
• Infusion-related reactions: the infusion can be slowed or interrupted and resumed when symptoms abate. Oxygen, beta agonists, antihistamines, rapid intravenous fluids and antipyretics may help relieve symptoms.
• Duration, metastatic breast cancer: with trastuzumab and docetaxel; Perjeta and trastuzumab may continue until disease progression or unmanageable toxicity even if docetaxel is stopped.
• Duration, early breast cancer: neoadjuvant, 3 to 6 cycles with trastuzumab and chemotherapy; adjuvant, with trastuzumab for a total of one year (up to 18 cycles, or until recurrence or unmanageable toxicity), starting on day 1 of the first taxane-containing cycle and continuing even if chemotherapy stops. With an anthracycline-based regimen, Perjeta and trastuzumab follow completion of the whole anthracycline part.
• Delayed or missed dose: if less than 6 weeks have passed since the last infusion, give 420 mg as soon as possible and return to the planned schedule; if 6 weeks or more, give the 840 mg loading dose again as a 60-minute infusion, then 420 mg every 3 weeks.
• No dose reductions are recommended for Perjeta. If trastuzumab is stopped, Perjeta is stopped too.

Phesgo (Subcutaneous Injection)

Patients on intravenous pertuzumab and trastuzumab can switch to Phesgo. Once pertuzumab-based therapy has been safely established, the physician may decide that a healthcare professional can give Phesgo outside the clinic, for example at home. The vial label is checked to make sure the medicine prepared and given is Phesgo.

• Loading dose: 1,200 mg pertuzumab/600 mg trastuzumab, whatever the body weight, injected over about 8 minutes, with 30 minutes of observation.
• Maintenance dose: 600 mg/600 mg every 3 weeks, injected over about 5 minutes, with 15 minutes of observation. The observation period starts after the injection and ends before any chemotherapy is given.
• Injection site: subcutaneous only, never intravenous. Alternate between the left and right thigh, at least 2.5 cm from the last site, on healthy skin and never where it is red, bruised, tender or hard. Do not split a dose between syringes or sites; other subcutaneous medicines are preferably injected elsewhere.
• Duration: in metastatic disease with docetaxel, until progression or unmanageable toxicity, even if docetaxel is stopped. In early breast cancer, 3 to 6 neoadjuvant cycles with chemotherapy; adjuvant treatment for a total of one year (up to 18 cycles) or until recurrence or unmanageable toxicity, starting on day 1 of the first taxane-containing cycle.
• With chemotherapy: Phesgo is given before a taxane. Docetaxel starts at 75 mg/m² and may be escalated to 100 mg/m², or is given at 100 mg/m² from the start; with carboplatin the dose stays 75 mg/m². Adjuvant paclitaxel is 80 mg/m² weekly for 12 weeks.
• Switching from intravenous therapy: if the last intravenous dose was under 6 weeks ago, give the 600 mg/600 mg maintenance dose and continue every 3 weeks; if 6 weeks or more, give the 1,200 mg/600 mg loading dose first.
• Delayed dose: under 6 weeks since the last injection, give the maintenance dose as soon as possible; 6 weeks or more, repeat the loading dose.

Dose Modifications

• Perjeta, heart: withhold Perjeta and trastuzumab for at least 3 weeks for any signs of congestive heart failure, and stop Perjeta if symptomatic heart failure is confirmed.
  • Metastatic breast cancer (pre-treatment LVEF at least 50%): withhold for at least 3 weeks if LVEF falls below 40%, or to 40–45% with a fall of 10 percentage points or more from baseline; resume once LVEF is above 45%, or 40–45% with a fall of less than 10 points.
  • Early breast cancer (pre-treatment LVEF at least 55%, or 50% after the anthracycline part of chemotherapy): withhold for at least 3 weeks if LVEF falls below 50% with a fall of 10 percentage points or more; resume once LVEF is at least 50%, or less than 10 points below baseline.
  • If LVEF has not improved, or has fallen further at the next assessment, stopping Perjeta and trastuzumab should be strongly considered unless the benefit is judged to outweigh the risk.
• Perjeta, reactions: for a significant infusion-related reaction the infusion is slowed or interrupted, and permanent discontinuation should be considered for severe reactions. Perjeta must be stopped permanently for a grade 4 hypersensitivity reaction (anaphylaxis), bronchospasm or acute respiratory distress syndrome. If diarrhoea does not improve, interruption should be considered, and treatment may be reinstated once it is under control.
• Phesgo: dose reductions are not recommended; treatment can continue through reversible chemotherapy-induced myelosuppression with careful monitoring for neutropenic complications. Phesgo is withheld for at least 3 weeks for signs of heart failure and stopped if symptomatic heart failure is confirmed. It is also withheld for at least 3 weeks if LVEF falls below 40%, or to 40–45% with a fall of 10 points or more, in metastatic disease, and if LVEF falls below 50% with a fall of 10 points or more in early breast cancer. It may resume when LVEF recovers. Treatment is stopped immediately and permanently for a grade 4 hypersensitivity reaction (anaphylaxis), bronchospasm or acute respiratory distress syndrome.

Special Populations

• Elderly: no overall difference in efficacy between patients aged 65 or over and younger patients, and no dose adjustment is needed from 65 years; data above 75 years are limited.
• Renal impairment: no adjustment in mild or moderate impairment; no dose recommendation can be made in severe impairment because pharmacokinetic data are limited.
• Hepatic impairment: safety and efficacy of Perjeta have not been studied, so no specific dose recommendation can be made. Patients with hepatic impairment are unlikely to need a Phesgo dose adjustment.
• Children and adolescents: safety and efficacy under 18 years have not been established, and there is no relevant use in the paediatric population in breast cancer.

Traceability

To improve the traceability of biological medicines, the name and batch number of the product given must be clearly recorded.

Left Ventricular Dysfunction

HER2-blocking medicines, including Perjeta, reduce LVEF. Symptomatic left ventricular systolic dysfunction (congestive heart failure) was more frequent with Perjeta, trastuzumab and chemotherapy than with trastuzumab and chemotherapy. Prior anthracycline treatment or radiotherapy to the chest may raise the risk of LVEF decline, and most symptomatic heart failure in the adjuvant setting followed anthracycline-based chemotherapy.

• Not studied: Perjeta has not been studied with a pre-treatment LVEF below 50%, a history of congestive heart failure, an LVEF decline to below 50% during earlier adjuvant trastuzumab, or conditions that could impair left ventricular function: uncontrolled hypertension, recent myocardial infarction, serious arrhythmia needing treatment, or a cumulative prior anthracycline exposure above 360 mg/m² of doxorubicin or its equivalent. Phesgo has not been studied with a pre-treatment LVEF below 55% in early breast cancer or below 50% in metastatic disease.
• Monitoring: LVEF is assessed before treatment and at regular intervals, for example once during neoadjuvant treatment and every 12 weeks in adjuvant or metastatic treatment.
• Anthracyclines: sequential use of Perjeta with trastuzumab and a taxane was evaluated after the epirubicin or doxorubicin part of anthracycline regimens in APHINITY and BERENICE. Safety data on concurrent use are limited; in TRYPHAENA, Perjeta was given concurrently with epirubicin (FEC) in chemotherapy-naive patients receiving low cumulative doses (up to 300 mg/m²), and cardiac safety was similar to sequential use.

Infusion-Related Reactions

Perjeta has been associated with infusion-related reactions, including events with a fatal outcome. Patients are observed closely during and for 60 minutes after the first infusion, and during and for 30 to 60 minutes after later infusions. If a significant reaction occurs, the infusion is slowed or interrupted and appropriate treatment given; the patient is evaluated and monitored until the signs and symptoms have fully resolved. Permanent discontinuation should be considered for severe reactions, based on the severity of the preceding reaction and the response to treatment.

Hypersensitivity Reactions and Anaphylaxis

Patients are observed closely for hypersensitivity. Severe hypersensitivity, including anaphylaxis and events with a fatal outcome, has been observed with Perjeta. Medicines to treat such reactions and emergency equipment must be available for immediate use, including for any Phesgo administration outside the clinic. Perjeta must be stopped permanently for a grade 4 hypersensitivity reaction (anaphylaxis), bronchospasm or acute respiratory distress syndrome.

Febrile Neutropenia

Patients given Perjeta, trastuzumab and docetaxel have a higher risk of febrile neutropenia than those given placebo, trastuzumab and docetaxel, especially in the first 3 cycles. In CLEOPATRA, nadir neutrophil counts were similar in both groups; the higher rate of febrile neutropenia went with more mucositis and diarrhoea in Perjeta-treated patients, so symptomatic treatment of mucositis and diarrhoea should be considered. No febrile neutropenia was reported after docetaxel was stopped.

Diarrhoea

Perjeta may cause severe diarrhoea, most often during concurrent taxane therapy, and patients over 65 have a higher risk than younger patients. It is treated according to standard practice and guidelines. Early loperamide, fluids and electrolyte replacement should be considered, particularly in elderly patients and in severe or prolonged diarrhoea. Interrupting pertuzumab should be considered if there is no improvement, and treatment may be reinstated once the diarrhoea is under control.

Additional Warnings for Phesgo

• Injection-related reactions: systemic reactions such as fever, chills and headache can occur within 24 hours. Patients are watched during and for 30 minutes after the loading dose and for 15 minutes after the maintenance dose. The injection is slowed or paused if a significant reaction occurs, and permanent discontinuation is considered for severe ones.
• Pulmonary events: severe pulmonary events, occasionally fatal, have been reported with trastuzumab, including interstitial lung disease and acute respiratory distress syndrome. Taxanes, gemcitabine, vinorelbine and radiotherapy are risk factors. Patients with dyspnoea at rest due to advanced malignancy should not be treated.

Pregnancy, Breastfeeding and Fertility

• Contraception: women who could become pregnant should use effective contraception during Perjeta and for 6 months after the last dose of pertuzumab. For Phesgo the period is 7 months after the last dose.
• Pregnancy: data in pregnant women are limited and animal studies showed reproductive toxicity. Perjeta is not recommended during pregnancy, or in women of childbearing potential who are not using contraception. Phesgo is avoided in pregnancy unless the benefit to the mother outweighs the risk, because trastuzumab has caused foetal kidney impairment with oligohydramnios, sometimes with fatal pulmonary hypoplasia; close multidisciplinary monitoring is needed if pregnancy occurs.
• Breastfeeding: human IgG passes into breast milk, and whether the infant could absorb it or be harmed is unknown, so a decision is made to stop breastfeeding or to stop treatment, weighing the benefit of breastfeeding for the child against the benefit of Perjeta for the woman. With Phesgo, breastfeeding is avoided during treatment and for at least 7 months after the last dose.
• Fertility: no specific animal fertility studies were done. Repeat-dose studies in cynomolgus monkeys allowed no definitive conclusion on the male reproductive organs and showed no adverse effects in sexually mature females.

Excipients and Driving

Perjeta contains less than 1 mmol of sodium (23 mg) per dose, so it is essentially sodium-free. It also contains polysorbate 20 (2.8 mg per 14 mL vial), and polysorbates may cause allergic reactions. Phesgo likewise contains less than 1 mmol of sodium (23 mg) per dose and polysorbate 20 (4 mg per 10 mL vial, 6 mg per 15 mL vial). Perjeta has a minor influence on the ability to drive or use machines: dizziness may occur, and patients with infusion-related reactions should not drive or use machines until symptoms abate. The same advice applies to patients given Phesgo who have injection-related reactions or dizziness.

• Perjeta: store the vial in a refrigerator at 2–8 °C, in the outer carton to protect from light. Do not freeze. Each pack holds one 14 mL vial (type I glass, butyl rubber stopper).
• Phesgo: store the vials in a refrigerator at 2–8 °C in the outer carton to protect from light. Do not freeze.
• Cold chain: keep the cold chain unbroken during transport and handling.
• After dilution: see Shelf Life below.

• Unopened vial: Perjeta, 2 years; Phesgo, 18 months.
• Diluted Perjeta solution: chemical and physical in-use stability has been shown for 24 hours at 30 °C and up to 30 days at 2–8 °C protected from light. From a microbiological point of view it should be used immediately; otherwise in-use storage times and conditions are the user’s responsibility and would normally not exceed 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions.
• Phesgo in the syringe: stable for 28 days at 2–8 °C protected from light, and for 24 hours (cumulative time in vial and syringe) at up to 30 °C in diffused daylight. From a microbiological point of view it should be used immediately.

Prescription only (Rx). Perjeta is subject to restricted medical prescription (Annex II B of the marketing authorisation), and treatment is started under the supervision of a physician experienced in the administration of anti-cancer agents. The infusion (Perjeta) and the injection (Phesgo) are given by healthcare professionals, so they are supplied to the hospital or clinic that administers them, under cold-chain conditions (2–8 °C).