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Incidence and severity of anaphylaxis and hypersensitivity in trials of intravenous pertuzumab plus trastuzumab or the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection for HER2-positive breast cancer

Open AccessPublished:November 19, 2022DOI:https://doi.org/10.1016/j.ejca.2022.09.024

      Highlights

      • PH can be administered intravenously or subcutaneously.
      • These are used to treat HER2-positive breast cancer, often combined with chemotherapy.
      • P, H or chemotherapy can cause anaphylaxis/hypersensitivity.
      • Analysis of breast cancer trials showed low incidence of anaphylaxis/hypersensitivity.
      • Discontinuations due to anaphylaxis/hypersensitivity were rare for PH.

      Abstract

      Aim

      To characterise risk of anaphylaxis/hypersensitivity with intravenous pertuzumab plus trastuzumab (PH IV), the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) or concomitant chemotherapy to support potential administration of PH FDC SC by healthcare professionals outside clinics.

      Methods

      A cumulative search for anaphylaxis/hypersensitivity (Roche Standard Adverse Event Group Terms) was performed for all pivotal trials cited in the current EMA P IV/PH FDC SC summaries of product characteristics: MBC: NCT00567190, NCT02402712; EBC: NCT01358877, NCT00545688, NCT00976989, NCT02132949, NCT03493854 and NCT03674112. Occurrence, incidence and severity of events were analysed and a time–trend analysis (by cycle) was performed.

      Results

      This analysis includes 4772 patients who received PH IV and/or PH FDC SC. Incidence of all-grade (grade ≥3) anaphylaxis/hypersensitivity events: 3–11% (≤2%) for PH IV MBC trials; 1–13% (0–3%) for PH IV EBC trials; and 2–3% (<1%; not related to PH FDC SC) for PH FDC SC EBC trials. Discontinuations due to anaphylaxis/hypersensitivity were rare for PH IV (generally <1% except two arms of TRYPHAENA: 1% and 3%); no discontinuations of PH FDC SC have been recorded so far. Time–trend analysis showed that most events were reported during the first 6–8 cycles with concurrent chemotherapy, with a decrease in later cycles (except MetaPHER).

      Conclusion

      PH IV and PH FDC SC were well tolerated, with few grade ≥3 anaphylaxis/hypersensitivity events reported with PH IV and no grade ≥3 related events with PH FDC SC. Most events occurred during chemotherapy.

      Keywords

      1. Introduction

      Pertuzumab–trastuzumab (PH) is standard of care in first line HER2-positive metastatic breast cancer (MBC) and high-risk HER2-positive early breast cancer (EBC) [
      National Comprehensive Cancer Network (NCCN)
      NCCN clinical practice guidelines in Oncology (NCCN Guidelines®): breast cancer.
      ,
      • Cardoso F.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rubio I.T.
      • et al.
      Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,
      • Gennari A.
      • André F.
      • Barrios C.H.
      • Cortés J.
      • de Azambuja E.
      • DeMichele A.
      • et al.
      ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer.
      ,
      • Burstein H.J.
      • Curigliano G.
      • Thürlimann B.
      • Weber W.P.
      • Poortmans P.
      • Regan M.M.
      • et al.
      Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.
      ]. PH can be administered intravenously (PH IV) or as a fixed-dose combination for subcutaneous injection (PH FDC SC), which is approved for the same indications as PH IV [,
      • Hoffmann-La Roche Ltd F.
      European Commission approves Roche's Phesgo (fixed-dose combination of Perjeta and Herceptin for subcutaneous injection) for people with HER2-positive breast cancer.
      ].
      PH IV and PH FDC SC are usually given with chemotherapy for the first 3–8 treatment cycles, all of which can trigger anaphylaxis/hypersensitivity [
      Roche Registration Ltd
      PERJETA® (pertuzumab). Summary of product characteristics.
      ,
      Genentech Inc
      PERJETA® (pertuzumab).
      ,
      Roche Registration Ltd
      Herceptin® (trastuzumab). Summary of product characteristics.
      ,
      ,
      • Registration GmbH Roche
      PHESGO® (pertuzumab and trastuzumab). Summary of Product Characteristics.
      ,
      Genentech Inc
      PHESGO (pertuzumab, trastuzumab, and hyaluronidase-zzxf).
      ]. These events are often a concern with monoclonal antibodies [
      Roche Registration Ltd
      PERJETA® (pertuzumab). Summary of product characteristics.
      ,
      Genentech Inc
      PERJETA® (pertuzumab).
      ]. Anaphylaxis is an acute, potentially fatal systemic allergic reaction with varied mechanisms and clinical presentations. The most common symptoms are cutaneous reactions, including urticaria, angio-oedema, erythema and pruritus [
      • Fischer D.
      • Vander Leek T.K.
      • Ellis A.K.
      • Kim H.
      ]. Anaphylactic reactions typically begin within 15 min of exposure to the allergen. Symptoms range from mild to severe/life-threatening; each person usually has the same symptoms each time. Like other allergic reactions, an anaphylactic reaction does not usually occur after first exposure to the antigen but may occur after a later exposure to the allergen []. Events that trigger anaphylaxis are anaphylactic (immunoglobulin E immunologically mediated) or anaphylactoid (non-immunoglobulin mediated), although usually multiple pathways are involved [
      • Brown A.F.
      Anaphylactic shock: mechanisms and treatment.
      ]. Hypersensitivity is broadly defined as ‘objectively reproducible symptoms or signs, initiated by exposure to a defined stimulus at a dose tolerated by normal subjects, and may be caused by immunologic (allergic) and non-immunologic mechanisms’ [
      • Johansson S.G.
      • Hourihane J.O.
      • Bousquet J.
      • Bruijnzeel-Koomen C.
      • Dreborg S.
      • Haahtela T.
      • et al.
      A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force.
      ]. Drug-induced hypersensitivity reactions can encompass a spectrum of immunologically mediated hypersensitivity reactions with varying mechanisms and clinical presentations, accounting for ∼5–10% of all adverse drug reactions [
      • Warrington R.
      • Silviu-Dan F.
      • Wong T.
      Drug allergy.
      ]. Factors associated with increased risk of allergic reaction include age (higher in young/middle-aged adults vs. infants or the elderly), sex (higher in females), genetic polymorphisms in the human leucocyte antigen region, certain viral infections (e.g. HIV, herpes, Epstein–Barr virus-related mononucleosis) and drug-related factors (e.g. frequency of exposure [more frequent results in higher risk], route of administration [higher with topical vs. parenteral or oral], molecular weight [high molecular weight compounds and/or hapten-forming drugs are more immunogenic]) [
      • Warrington R.
      • Silviu-Dan F.
      • Wong T.
      Drug allergy.
      ,
      • Mirakian R.
      • Ewan P.
      • Durham S.
      • Youlten L.
      • Dugué P.
      • Friedmann P.
      • et al.
      BSACI guidelines for the management of drug allergy.
      ].
      In the US, once concomitant chemotherapy has been completed, PH FDC SC has the potential to be administered by healthcare professionals (HCPs) in patients’ homes []. Therefore, there is a need to provide a broader characterisation of the anaphylaxis/hypersensitivity with PH-based regimens and supportive guidance, particularly for those who would like to opt for PH FDC SC home administration.
      This exploratory analysis was performed to assess the occurrence, incidence and severity of anaphylaxis/hypersensitivity events with PH IV or PH FDC SC in pivotal clinical trials in HER2-positive BC. A time–trend analysis (by cycle) was also carried out.

      2. Materials and methods

      2.1 Studies

      A cumulative search for anaphylaxis/hypersensitivity events (Roche Standard Adverse Event [AE] Group Terms and Medical Dictionary for Regulatory Activities [MedDRA] v22.1; see preferred terms in Appendix 1) from 11/9/2001 (date of authorization to conduct a clinical trial in any country) to 31/12/2019 (cut-off date) was conducted for patients treated with PH IV or PH FDC SC across pivotal trials in HER2-positive BC (Table 1).
      Table 1Overview of clinical trials included in the analysis.
      Doses of HER2-targeted therapy: P: 840 mg loading dose; 420 mg maintenance; H: 8 mg/kg loading; 6 mg/kg maintenance.
      Patients (n)ChemotherapyAnti-HER2 therapy
      MBCCLEOPATRA (Phase III; NCT00567190) [
      • Baselga J.
      • Cortés J.
      • Kim S.B.
      • Im S.A.
      • Hegg R.
      • Im Y.H.
      • et al.
      Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.
      ]
      •  Placebo + H + D
      397≥6 cycles

      (median 8 cycles)
      Administered until disease progression
      •  PH IV + D
      407
      MetaPHER (Phase IIIb; NCT02402712) [
      • Kümmel S.
      • Tondini C.A.
      • Abraham J.
      • Nowecki Z.
      • Itrych B.
      • Hitre E.
      • et al.
      Subcutaneous trastuzumab with pertuzumab and docetaxel in HER2-positive metastatic breast cancer: Final analysis of MetaPHER, a phase IIIb single-arm safety study.
      ]
      •  H SC + P IV + D
      412≥6 cycles

      (median 8 cycles)
      Administered until disease progression
      EBCAPHINITY (Adjuvant, phase III; NCT01358877) [
      • von Minckwitz G.
      • Procter M.
      • de Azambuja E.
      • Zardavas D.
      • Benyunes M.
      • Viale G.
      • et al.
      Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.
      ]
      •  PH IV + chemo
      23646–8 cycles18 cycles
      •  Placebo + H IV + chemo
      2405
      NeoSphere (Neoadjuvant, phase II; NCT00545688) [
      • Gianni L.
      • Pienkowski T.
      • Im Y.H.
      • Roman L.
      • Tseng L.M.
      • Liu M.C.
      • et al.
      Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.
      ]
      •  Arm A (H IV + D)
      1073–7 cycles13–17 cycles
      In NeoSphere and TRYPHAENA, PH IV was administered during neoadjuvant treatment. After surgery, patients received adjuvant H only.
      •  Arm B (PH IV + D)
      107
      •  Arm C (PH IV)
      108
      •  Arm D (P IV + D)
      94
      TRYPHAENA (Neoadjuvant, phase II; NCT00976989) [
      • Schneeweiss A.
      • Chia S.
      • Hickish T.
      • Harvey V.
      • Eniu A.
      • Hegg R.
      • et al.
      Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).
      ]
      •  Arm A (FEC + PH IV → PH IV + D)
      726 cycles18 cycles
      In NeoSphere and TRYPHAENA, PH IV was administered during neoadjuvant treatment. After surgery, patients received adjuvant H only.
      •  Arm B (FEC→ PH IV + D)
      75
      •  Arm C (PH IV + C + D)
      76
      BERENICE (Neoadjuvant, phase II; NCT02132949) [
      • Swain S.M.
      • Ewer M.S.
      • Viale G.
      • Delaloge S.
      • Ferrero J.M.
      • Verrill M.
      • et al.
      Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study.
      ]
      8 cycles17 cycles
      •  Cohort A (ddAC + PH IV + T)
      199
      •  Cohort B (FEC + PH IV + D)
      198
      EBCFeDeriCa (Neoadjuvant, phase III; NCT03493854) [
      • Tan A.R.
      • Im S.-A.
      • Mattar A.
      • Colomer R.
      • Stroyakovskii D.
      • Nowecki Z.
      • et al.
      Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study.
      ]
      •  PH IV + chemo
      2528 cycles18 cycles
      •  PH FDC SC + chemo
      248
      PHranceSCa (Adjuvant, phase II; NCT03674112) [
      • O'Shaughnessy J.
      • Sousa S.
      • Cruz J.
      • Fallowfield L.
      • Auvinen P.
      • Pulido C.
      • et al.
      Preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer (PHranceSCa): a randomised, open-label phase II study.
      ]
      •  PH IV → PH FDC SC crossover
      80Physician discretion
      In PHranceSCa, chemotherapy was administered in the neoadjuvant setting, before trial enrolment. Most patients (90.6%) received ≥4 cycles of neoadjuvant PH IV.
      6 cycles
      •  PH FDC SC →PH IV crossover
      806 cycles
      •  PH IV continuation
      21To complete 18 cycles
      Eighteen cycles of HER2 therapy in PHranceSCa includes those administered during the neoadjuvant period, before study enrolment.
      •  PH FDC SC continuation
      137To complete 18 cycles
      Eighteen cycles of HER2 therapy in PHranceSCa includes those administered during the neoadjuvant period, before study enrolment.
      Chemo, chemotherapy; D, docetaxel; ddAC, dose-dense doxorubicin plus cyclophosphamide; EBC, early breast cancer; FEC, fluorouracil, epirubicin and cyclophosphamide; H IV, intravenous trastuzumab; H SC, subcutaneous trastuzumab; MBC, metastatic breast cancer; PH FDC SC, fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection; PH IV, intravenous pertuzumab plus trastuzumab; P IV, intravenous pertuzumab; T, paclitaxel.
      a Doses of HER2-targeted therapy: P: 840 mg loading dose; 420 mg maintenance; H: 8 mg/kg loading; 6 mg/kg maintenance.
      b In NeoSphere and TRYPHAENA, PH IV was administered during neoadjuvant treatment. After surgery, patients received adjuvant H only.
      c In PHranceSCa, chemotherapy was administered in the neoadjuvant setting, before trial enrolment. Most patients (90.6%) received ≥4 cycles of neoadjuvant PH IV.
      d Eighteen cycles of HER2 therapy in PHranceSCa includes those administered during the neoadjuvant period, before study enrolment.

      2.2 Databases

      Searches were performed on the European database of suspected adverse drug reaction reports with the substance ‘pertuzumab’ and the product ‘Phesgo’, and on the U.S. Food and Drug Administration (FDA) AE Reporting System with the terms ‘pertuzumab’, ‘perjeta’, ‘pertuzumab∖trastuzumab’, ‘hyaluronidase-zzxf∖pertuzumab∖trastuzumab’ and ‘Phesgo’ on 9/6/2022 [
      US Food and Drug Administration (FDA)
      FDA adverse events reporting System (FAERS) public Dashboard.
      ,
      European Medicines Agency (EMA)
      EudraVigilance - European database of suspected adverse drug reaction reports.
      ]. These databases include publicly available data submitted to the European Medicines Agency (EMA) and FDA by drug manufacturers, HCPs and consumers. The top three most prevalent events from the preferred terms list (Appendix 1) are reported.

      2.3 Treatment

      2.3.1 Clinical trials

      Study drugs were administered per protocol guidance. In MBC, PH was administered with docetaxel (D) until disease progression or unmanageable toxicity [
      Roche Registration Ltd
      PERJETA® (pertuzumab). Summary of product characteristics.
      ]. PH was continued if D was discontinued. Unlike CLEOPATRA, in MetaPHER the combination of endocrine therapy with PH after chemotherapy was allowed at investigator's discretion [
      • Kümmel S.
      • Tondini C.A.
      • Abraham J.
      • Nowecki Z.
      • Itrych B.
      • Hitre E.
      • et al.
      Subcutaneous trastuzumab with pertuzumab and docetaxel in HER2-positive metastatic breast cancer: Final analysis of MetaPHER, a phase IIIb single-arm safety study.
      ] per clinical practice and international guidelines [
      National Comprehensive Cancer Network (NCCN)
      NCCN clinical practice guidelines in Oncology (NCCN Guidelines®): breast cancer.
      ,
      • Gennari A.
      • André F.
      • Barrios C.H.
      • Cortés J.
      • de Azambuja E.
      • DeMichele A.
      • et al.
      ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer.
      ].
      In EBC, patients received PH for 3–6 cycles in the neoadjuvant setting with chemotherapy. In the adjuvant setting, PH was administered for a total of 1 year (maximum 18 cycles or until disease recurrence, or unmanageable toxicity; whichever occurred first), as part of a complete regimen for EBC, including standard anthracycline- and/or taxane-based chemotherapy. In BERENICE, FeDeriCa and PHranceSCa, patients received PH across the neoadjuvant and adjuvant settings to complete 1 year (maximum 18 cycles).
      For PH IV, the initial P dose (840 mg) was administered as a 60-min IV infusion, followed once every 3 weeks (q3w) by 420 mg over 30–60 min [
      Roche Registration Ltd
      PERJETA® (pertuzumab). Summary of product characteristics.
      ,
      Genentech Inc
      PERJETA® (pertuzumab).
      ]. An observation period (30–60 min) was recommended after each P infusion prior to subsequent H infusions. The initial H IV dose (8 mg/kg body weight) was administered as an IV infusion over approximately 90 min, followed by an observation period of up to 360 min in the EU [
      Roche Registration Ltd
      Herceptin® (trastuzumab). Summary of product characteristics.
      ,
      ]. This was followed q3w by 6 mg/kg body weight over 30 min with up to 120 min of observation in the EU. H SC was given as a 600 mg fixed dose over 2–5 min q3w. Observation times were 30 min for loading doses and 15 min for maintenance doses [
      Electronic Medicines Compendium (EMA)
      Herceptin 600 mg solution for injection in vial SmPC.
      ]. For PH FDC SC, the loading dose was 1200 mg P and 600 mg H in 15 ml of solution in a single-dose vial [
      • Registration GmbH Roche
      PHESGO® (pertuzumab and trastuzumab). Summary of Product Characteristics.
      ,
      Genentech Inc
      PHESGO (pertuzumab, trastuzumab, and hyaluronidase-zzxf).
      ]. The maintenance dose was 600 mg P and 600 mg H in 10 ml of solution in a single-dose vial. Observation times were up to 30 min for loading doses and 15 min for maintenance doses [
      • Registration GmbH Roche
      PHESGO® (pertuzumab and trastuzumab). Summary of Product Characteristics.
      ,
      Genentech Inc
      PHESGO (pertuzumab, trastuzumab, and hyaluronidase-zzxf).
      ].

      2.3.2 Clinical practice

      For the European database of suspected adverse drug reaction reports and the FDA AE Reporting System, it was assumed that P, H and PH FDC SC were used in line with prescribing information [
      Roche Registration Ltd
      PERJETA® (pertuzumab). Summary of product characteristics.
      ,
      Genentech Inc
      PERJETA® (pertuzumab).
      ] and international guidelines [
      National Comprehensive Cancer Network (NCCN)
      NCCN clinical practice guidelines in Oncology (NCCN Guidelines®): breast cancer.
      ,
      • Cardoso F.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rubio I.T.
      • et al.
      Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,
      • Gennari A.
      • André F.
      • Barrios C.H.
      • Cortés J.
      • de Azambuja E.
      • DeMichele A.
      • et al.
      ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer.
      ,
      • Burstein H.J.
      • Curigliano G.
      • Thürlimann B.
      • Weber W.P.
      • Poortmans P.
      • Regan M.M.
      • et al.
      Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.
      ,
      Genentech Inc
      PERJETA® (pertuzumab).
      ].

      3. Results

      3.1 Patients

      This analysis includes 4772 patients from the safety populations of eight pivotal Roche-sponsored trials. Baseline demographics and disease characteristics in the intention-to-treat populations have been published [
      • Baselga J.
      • Cortés J.
      • Kim S.B.
      • Im S.A.
      • Hegg R.
      • Im Y.H.
      • et al.
      Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.
      ,
      • Kümmel S.
      • Tondini C.A.
      • Abraham J.
      • Nowecki Z.
      • Itrych B.
      • Hitre E.
      • et al.
      Subcutaneous trastuzumab with pertuzumab and docetaxel in HER2-positive metastatic breast cancer: Final analysis of MetaPHER, a phase IIIb single-arm safety study.
      ,
      • von Minckwitz G.
      • Procter M.
      • de Azambuja E.
      • Zardavas D.
      • Benyunes M.
      • Viale G.
      • et al.
      Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.
      ,
      • Gianni L.
      • Pienkowski T.
      • Im Y.H.
      • Roman L.
      • Tseng L.M.
      • Liu M.C.
      • et al.
      Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.
      ,
      • Schneeweiss A.
      • Chia S.
      • Hickish T.
      • Harvey V.
      • Eniu A.
      • Hegg R.
      • et al.
      Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).
      ,
      • Swain S.M.
      • Ewer M.S.
      • Viale G.
      • Delaloge S.
      • Ferrero J.M.
      • Verrill M.
      • et al.
      Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study.
      ,
      • Tan A.R.
      • Im S.-A.
      • Mattar A.
      • Colomer R.
      • Stroyakovskii D.
      • Nowecki Z.
      • et al.
      Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study.
      ,
      • O'Shaughnessy J.
      • Sousa S.
      • Cruz J.
      • Fallowfield L.
      • Auvinen P.
      • Pulido C.
      • et al.
      Preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer (PHranceSCa): a randomised, open-label phase II study.
      ].

      3.2 Incidence, severity and timing of anaphylaxis/hypersensitivity events

      Incidence of all-grade and grade ≥3 anaphylaxis/hypersensitivity events are shown in Table 2.
      Table 2Incidence and severity of anaphylaxis/hypersensitivity events in pivotal clinical trials of PH IV and PH FDC SC.
      Patients (n)Incidence of anaphylaxis/hypersensitivity,

      patients, n (%)
      P
      Discontinuation of PH IV or PH FDC SC.
      discontinuation rate due to anaphylaxis/hypersensitivity events, patients, n (%)
      All gradesGrade ≥3
      PH IV clinical trials
      MBCCLEOPATRA (NCT00567190) [
      • Baselga J.
      • Cortés J.
      • Kim S.B.
      • Im S.A.
      • Hegg R.
      • Im Y.H.
      • et al.
      Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.
      ]
      •  Placebo + H + D
      39736 (9.1)10 (2.5)N/A
      No PH IV or PH FDC SC were administered in these arms so there is no P discontinuation rate.
      •  PH IV + D
      40744 (10.8)8 (2.0)4 (1.0)
      MetaPHER (NCT02402712) [
      • Kümmel S.
      • Tondini C.A.
      • Abraham J.
      • Nowecki Z.
      • Itrych B.
      • Hitre E.
      • et al.
      Subcutaneous trastuzumab with pertuzumab and docetaxel in HER2-positive metastatic breast cancer: Final analysis of MetaPHER, a phase IIIb single-arm safety study.
      ]
      •  H SC + P IV + D
      41214 (3.4)1 (0.2)1 (0.2)
      EBCAPHINITY (NCT01358877) [
      • von Minckwitz G.
      • Procter M.
      • de Azambuja E.
      • Zardavas D.
      • Benyunes M.
      • Viale G.
      • et al.
      Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.
      ]
      •  PH IV + chemo
      2364116 (4.9)18 (0.8)6 (0.3)
      •  Placebo + H IV + chemo
      240586 (3.6)17 (0.7)N/A
      No PH IV or PH FDC SC were administered in these arms so there is no P discontinuation rate.
      NeoSphere
      Data reported for the neoadjuvant period only.
      (NCT00545688) [
      • Gianni L.
      • Pienkowski T.
      • Im Y.H.
      • Roman L.
      • Tseng L.M.
      • Liu M.C.
      • et al.
      Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.
      ]
      •  Arm A (H IV + D)
      1072 (1.9)0N/A
      No PH IV or PH FDC SC were administered in these arms so there is no P discontinuation rate.
      •  Arm B (PH IV + D)
      1076 (5.6)1 (0.9)1 (0.9)
      •  Arm C (PH IV)
      1086 (5.6)2 (1.9)1 (0.9)
      •  Arm D (P IV + D)
      946 (6.4)00
      TRYPHAENA
      Data reported for the neoadjuvant period only.
      (NCT00976989) [
      • Schneeweiss A.
      • Chia S.
      • Hickish T.
      • Harvey V.
      • Eniu A.
      • Hegg R.
      • et al.
      Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).
      ]
      •  Arm A (FEC + PH IV → PH IV + D)
      727 (9.7)2 (2.8)1 (1.4)
      •  Arm B (FEC→ PH IV + D)
      751 (1.3)00
      •  Arm C (PH IV + C + D)
      7610 (13.2)2 (2.6)2 (2.6)
      BERENICE
      Data reported for the neoadjuvant period only.
      (NCT02132949) [
      • Swain S.M.
      • Ewer M.S.
      • Viale G.
      • Delaloge S.
      • Ferrero J.M.
      • Verrill M.
      • et al.
      Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study.
      ]
      •  Cohort A (ddAC + PH IV + T)
      1997 (3.5)00
      •  Cohort B (FEC + PH IV + D)
      1985 (2.5)2 (1.0)0
      PH FDC SC clinical trials
      EBCFeDeriCa
      Data reported for the neoadjuvant period only.
      (NCT03493854) [
      • Tan A.R.
      • Im S.-A.
      • Mattar A.
      • Colomer R.
      • Stroyakovskii D.
      • Nowecki Z.
      • et al.
      Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study.
      ]
      •  PH IV + chemo
      2525 (2.0)1 (0.4)1 (0.4)
      •  PH FDC SC + chemo
      2484 (1.6)00
      PHranceSCa (NCT03674112) [
      • O'Shaughnessy J.
      • Sousa S.
      • Cruz J.
      • Fallowfield L.
      • Auvinen P.
      • Pulido C.
      • et al.
      Preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer (PHranceSCa): a randomised, open-label phase II study.
      ]
      •  PH IV crossover
      160000
      •  PH FDC SC crossover
      1603 (1.9)00
      •  PH IV continuation
      21000
      •  PH FDC SC continuation
      1372 (1.5)00
      Chemo, chemotherapy; D, docetaxel; ddAC, dose-dense doxorubicin plus cyclophosphamide; EBC, early breast cancer; FEC, fluorouracil, epirubicin and cyclophosphamide; H IV, intravenous trastuzumab; H SC, subcutaneous trastuzumab; MBC, metastatic breast cancer; N/A, not applicable; PH FDC SC, fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection; PH IV, intravenous pertuzumab plus trastuzumab; P IV, intravenous pertuzumab; T, paclitaxel.
      a Discontinuation of PH IV or PH FDC SC.
      b No PH IV or PH FDC SC were administered in these arms so there is no P discontinuation rate.
      c Data reported for the neoadjuvant period only.

      3.3 MBC

      3.3.1 CLEOPATRA

      The proportion of patients experiencing anaphylaxis/hypersensitivity AEs was balanced between arms. No fatal events were reported. In the PH IV arm, the outcome was ‘recovered/resolved with sequelae’ for one event (hypersensitivity) and ‘recovered/resolved’ for remaining events. 4/407 patients (1.0%) in the PH IV arm discontinued treatment due to an anaphylaxis/hypersensitivity event. These were deemed to be study medication-related; three patients received treatment (Appendix 2). Incidence of all-grade and grade ≥3 anaphylaxis/hypersensitivity events in CLEOPATRA was highest during the initial cycles when patients were receiving D, then decreased in later cycles (Fig. 1a). The vast majority of grade ≥3 events occurred during the chemotherapy phase; only one grade 3 hypersensitivity event (which led to drug discontinuation) occurred later, in cycle 18.
      Fig. 1
      Fig. 1Incidence of anaphylaxis/hypersensitivity events during HER2-targeted therapy by cycle.*
      Similar figures have not been included for NeoSphere and TRYPHAENA as patients received H only after surgery.
      * Graphs represent number of anaphylaxis/hypersensitivity events observed.
      D, docetaxel; ddAC, dose-dense doxorubicin plus cyclophosphamide; FEC, fluorouracil, epirubicin and cyclophosphamide; H, trastuzumab; pac, paclitaxel; PH IV, intravenous pertuzumab and trastuzumab; PH FDC SC, fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection.
      Fig. 1
      Fig. 1Incidence of anaphylaxis/hypersensitivity events during HER2-targeted therapy by cycle.*
      Similar figures have not been included for NeoSphere and TRYPHAENA as patients received H only after surgery.
      * Graphs represent number of anaphylaxis/hypersensitivity events observed.
      D, docetaxel; ddAC, dose-dense doxorubicin plus cyclophosphamide; FEC, fluorouracil, epirubicin and cyclophosphamide; H, trastuzumab; pac, paclitaxel; PH IV, intravenous pertuzumab and trastuzumab; PH FDC SC, fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection.

      3.3.2 MetaPHER

      One patient (0.2%) discontinued treatment due to an anaphylaxis/hypersensitivity event: grade 3 anaphylaxis during cycle 2 when the patient was receiving D (Fig. 1b). This was deemed to be P-related (Appendix 2) and the patient received treatment. No fatal events anaphylaxis/hypersensitivity events were reported. All events recovered/resolved.

      3.4 Adjuvant EBC

      3.4.1 APHINITY

      6/2364 patients (0.3%) in the P IV arm discontinued treatment due to an anaphylaxis/hypersensitivity event. Of those, four experienced events that were deemed to be anti-HER2 therapy-related (Appendix 2). No fatal events were reported. All anaphylaxis/hypersensitivity events reported in the P IV arm recovered/resolved. Incidence of all-grade and grade ≥3 events was highest during the initial cycles and decreased in later cycles (Fig. 1c). The vast majority of grade ≥3 events occurred during the chemotherapy phase.

      3.4.2 PHranceSCa

      Four patients experienced anaphylaxis/hypersensitivity events that were reported as injection-related reactions. All were non-serious, grade 1 or 2 in intensity and subsequently resolved. Among these, three events occurred during PH FDC SC treatment during the crossover period that were PH FDC SC-related. No patients discontinued treatment due to anaphylaxis/hypersensitivity during crossover; the continuation period is ongoing [
      • O'Shaughnessy J.
      • Sousa S.
      • Cruz J.
      • Fallowfield L.
      • Auvinen P.
      • Pulido C.
      • et al.
      Preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer (PHranceSCa): a randomised, open-label phase II study.
      ].

      3.5 Neoadjuvant EBC

      3.5.1 NeoSphere

      All anaphylaxis/hypersensitivity events were reported as ‘drug hypersensitivity’, with the exception of one grade 2 anaphylaxis event (Arm D), following which the D dosage was modified. This event resolved on the same day, without sequelae. In Arms B and D, the majority of hypersensitivity reactions were specifically attributed to D, whereas in Arm C the majority were attributed to P IV. The reported events occurred in up to three cycles across the four arms and the outcome was reported as ‘recovered-no sequelae’ for all. One patient (0.9%) in each of Arm B (n = 107) and Arm C (n = 108) discontinued treatment due to drug hypersensitivity. Only one of the events leading to discontinuation was deemed to be anti-HER2 therapy-related (Appendix 2).

      3.5.2 TRYPHAENA

      All but two anaphylaxis/hypersensitivity events were reported as ‘drug hypersensitivity’. The outcome was ‘resolved-no sequelae’ for all. 1/72 in Arm A (1.4%) and 2/76 in Arm C (2.6%) had grade ≥3 events (drug hypersensitivity), which led to study treatment discontinuation. One of these events was deemed to be D-related; all patients who discontinued received treatment for the hypersensitivity event (Appendix 2). One patient experienced a grade 1 circulatory collapse, which was unrelated to study treatment and resolved without sequelae. Three out of the four grade ≥3 events were reported at cycle 1; the remaining event, at cycle 5 when patients were receiving chemotherapy.

      3.5.3 BERENICE

      During neoadjuvant treatment, the incidence of anaphylaxis/hypersensitivity events was low in both cohorts. Two grade ≥3 events occurred during the neoadjuvant period in Cohort B: hypersensitivity and anaphylactic reaction. The PH IV dose was not altered in response to the events for these two patients and the outcome was reported as recovered. No patients discontinued P due to anaphylaxis/hypersensitivity (Appendix 2). Most events occurred during the neoadjuvant phase, where the first four cycles of HER2-targeted therapy were given in combination with chemotherapy.

      3.5.4 FeDeriCa

      Anaphylaxis/hypersensitivity events occurred with low and comparable incidence across treatment arms. All events related to HER2-targeted therapy were grade 1 (two patients in the PH IV arm and three in the PH FDC SC arm) or grade 2 (one patient per arm). One grade 3 event (in the PH IV arm) was considered related to concomitant levofloxacin. Most events occurred during the neoadjuvant phase, where the first four cycles of HER2-targeted therapy were given in combination with chemotherapy (Fig. 1e). One patient (0.4%) in the PH IV arm discontinued treatment due to anaphylaxis/hypersensitivity (grade 2 paclitaxel-related, infusion-related reaction [Appendix 2]); none discontinued in the PH FDC SC arm.

      3.6 Databases

      The European database of suspected adverse drug reaction reports had 8170 instances for the substance ‘pertuzumab’ and 68 for the product ‘Phesgo’. For ‘pertuzumab’, 197 were hypersensitivity reactions (2.4%), 93 were anaphylactic reactions (1.1%) and 57 were anaphylactic shock (0.7%). For ‘Phesgo’, two were anaphylactic reactions (2.9%), one was hypersensitivity (1.5%) and one was drug hypersensitivity (1.5%). The FDA AE Reporting System had 14,221 instances reported for the search terms ‘pertuzumab’, ‘perjeta’, ‘pertuzumab∖trastuzumab’, ‘hyaluronidase-zzxf∖pertuzumab∖trastuzumab’ and ‘Phesgo’. Of those, 190 were hypersensitivity reactions (1.3%), 102 were anaphylactic reactions (0.7%) and 45 were anaphylactic shock (0.3%).

      4. Discussion

      To our knowledge, this is the first analysis to report the incidence and severity of anaphylaxis/hypersensitivity events involving P-containing regimens in. HER2-positive BC. The incidence of grade ≥3 anaphylaxis/hypersensitivity events was generally low in the Roche-sponsored PH IV and PH FDC SC clinical trials assessed here (0.2–2.0% for MBC studies, 0–0.8% in the adjuvant EBC setting and 0–2.8% in the neoadjuvant EBC setting), and no fatal events were reported.
      Time–trend analysis for PH IV and PH FDC SC studies in MBC and EBC showed that the majority of all-grade and grade ≥3 anaphylaxis/hypersensitivity events occurred during the first 6–8 cycles of treatment, when PH IV or PH FDC SC were administered with chemotherapy. The relatedness could not be determined due to the limited information collected with respect to timing; however, the reported events may well be attributable to the chemotherapy given. The incidence of all-grade and grade ≥3 anaphylaxis/hypersensitivity events in MetaPHER (P IV + H SC) was lower than in the PH IV studies, and the time–trend relationship was less obvious; cross-study comparisons should be made with caution due to possible differences in study populations, treatments and AE reporting requirements.
      Within the PH FDC SC studies, only one grade 3 event was reported; this was considered related to a concomitant medication in FeDeriCa (levofloxacin). Discontinuations due to anaphylaxis/hypersensitivity were rare for PH IV (generally ≤1% except for one arm in TRYPHAENA, which was 3%) and PH FDC SC (<1%; notably, this case was related to paclitaxel in FeDeriCa). One limitation of this analysis is that not all events leading to discontinuation were attributed to a specific study treatment so we cannot fully ascertain how many were related to P.
      The European database of suspected adverse drug reaction reports and FDA AE Reporting System have some limitations, including the potential for submission of incomplete, inaccurate, untimely, unverified information. No link between the medicine and the observed effect(s) is confirmed, and incidence or prevalence of an event cannot be determined due to possible under reporting. However, it is interesting to note the similarly low incidences of anaphylaxis/hypersensitivity reported in clinical use.
      The risk of anaphylaxis/hypersensitivity should be considered when assessing patients’ eligibility to be treated at home with PH FDC SC. Risk factors such as patient age, concomitant diseases and concurrent medications should also be taken into account [
      • Warrington R.
      • Silviu-Dan F.
      • Wong T.
      Drug allergy.
      ,
      • Mirakian R.
      • Ewan P.
      • Durham S.
      • Youlten L.
      • Dugué P.
      • Friedmann P.
      • et al.
      BSACI guidelines for the management of drug allergy.
      ]. An ongoing expanded access single-arm study is assessing the feasibility of home administration of PH FDC SC after completing concurrent chemotherapy during the COVID-19 pandemic [
      ClinicalTrials.gov
      An expanded access study to provide at home subcutaneous administration of pertuzumab and trastuzumab fixed-dose combination (PH FDC SC) for patients with HER2-positive breast cancer during the COVID-19 pandemic.
      ,
      • Dang C.T.
      • Tolaney S.M.
      • Riaz F.
      • Tan A.R.
      • Tkaczuk K.H.R.
      • Yu A.F.
      • et al.
      Preliminary analysis of an expanded access study of the fixed-dose combination of pertuzumab (P) and trastuzumab (H) for subcutaneous injection (PH FDC SC) for at-home administration (admin) in patients (pts) with HER2-positive (HER2+) breast cancer (BC) during the COVID-19 pandemic.
      ]. Data for 114 patients were available at a preliminary analysis: no new AEs emerged during home administration and two patients (2.7%) experienced hypersensitivity events (both grade 1).
      The overall risk of anaphylaxis or hypersensitivity during PH IV or PH FDC SC treatment is very low. Patients should be closely monitored during and after PH IV infusions and PH FDC SC injections. If a significant infusion- or injection-related reaction occurs, it is recommended that treatment should be slowed down or paused and that appropriate medical therapies should be administered. Patients should be carefully monitored until complete resolution of symptoms. Permanent discontinuation of PH IV or PH FDC SC in patients who experience anaphylaxis or severe infusion- or injection-related reactions is recommended [
      Genentech Inc
      PERJETA® (pertuzumab).
      ,
      Genentech Inc
      PHESGO (pertuzumab, trastuzumab, and hyaluronidase-zzxf).
      ].

      5. Conclusion

      Analysis of pivotal clinical trials in HER2-positive EBC and MBC showed that PH IV and PH FDC SC were well tolerated, with few grade ≥3 anaphylaxis/hypersensitivity events reported with PH IV and no grade ≥3-related events with PH FDC SC. The majority of the anaphylaxis/hypersensitivity events were grade 1 and 2 and occurred within the first 6–8 cycles when PH IV or PH FDC SC were given with chemotherapy. The incidence rate of grade ≥3 events after the chemotherapy cycles was very low. The presented data provide additional evidence to support the administration of PH FDC SC by HCPs outside a hospital setting.

      Disclosure of prior presentation

      The current analysis was presented at the ESMO virtual congress 2021 (Swain SM et al., abstract number 138P).
      • The individual studies have been presented either fully or in part:
        • CLEOPATRA:
          • Primary analysis (NEJM 2012; PMID 22149875)
          • Interim overall survival analysis (Lancet Oncol 2013; PMID 23602601)
          • Final overall survival analysis (NEJM 2015; PMID 25693012)
          • End-of-study analysis (Lancet Oncol 2020; PMID 32171426)
        • MetaPHER:
          • First interim analysis (SABCS 2016; P4-21-42)
          • Second interim analysis (ESMO 2018; 323P)
          • Final analysis (Breast Cancer Res Treat 2021; PMID: 33748921)
        • APHINITY
          • Primary analysis (NEJM 2017; PMID 28581356)
          • Six-year follow-up analysis (J Clin Oncol 2021; PMID 33539215)
        • NeoSphere
          • Primary analysis (Lancet Oncol 2012; PMID 22153890)
          • Five-year analysis (Lancet Oncol 2016; PMID 27179402)
        • TRYPHAENA
          • Primary analysis (Ann Oncol 2013; PMID 23704196)
          • Five-year analysis (Eur J Cancer 2018; PMID: 29223479)
        • BERENICE
          • Primary analysis (Ann Oncol 2018; PMID 29253081)
          • Interim analysis of safety (SABCS 2017; P5-20-04)
          • Final analysis (Cancers 2022; PMID 35681574)
        • FeDeriCa
          • Primary analysis (Lancet Oncol 2021; PMID: 33357420)
          • Adjuvant safety analysis (ESMO Breast Cancer 2021; 46P)
        • PHranceSCa
          • Primary analysis (Eur J Cancer 2021; PMID: 34147014)

      Data sharing

      Qualified researchers may request access to individual patient-level data through the clinical study data request platform: https://vivli.org/. Further details of Roche's criteria for eligible studies are available here: https://vivli.org/members/ourmembers/. For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here: https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm.

      Author contributions

      Conceptualisation: CA, SH, ER, LG, SK, AS, HL, HM, SMS, JOS, CTD.
      Investigation: CA, SH, ER, LG, SK, SL, AS, HL, HM, SMS, ART, KY, JOS, CTD.
      Methodology: HL, HM.
      Software: HM.
      Supervision: CA.
      Roles/Writing - original draft: SMS.
      Writing - review & editing: All authors.

      Role of the funding source

      F. Hoffmann-La Roche Ltd funded the studies and the analysis, provided study drugs and was involved in the study design, protocol development, regulatory and ethics approvals, safety monitoring and reporting, data management and data analysis and interpretation of the studies included. The sponsor funded third-party writing assistance, provided by Alison McGonagle, PhD.

      Conflict of interest statement

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
      SMS reports honoraria (self) and advisory/consultancy roles for AstraZeneca, Daiichi Sankyo, F. Hoffmann-La Roche Ltd/Genentech, Inc., Exact Sciences (Genomic Health), Molecular Templates, Silverback Therapeutics, Lilly, Natera, Athenex, Beijing Medical Foundation, Merck and Inivata; institutional research funding from F. Hoffmann-La Roche Ltd/Genentech, Inc. and Kailos Genetics; and travel/accommodation/expenses from F. Hoffmann-La Roche Ltd/Genentech, Inc. and Daiichi Sankyo. ART reports institutional research funding from F. Hoffmann-La Roche Ltd/Genentech, Inc., Merck, Pfizer and Tesaro; advisory role for AbbVie, Athenex, Celgene, Eisai, G1 Therapeutics, Genentech, Inc., Immunomedics, Merck and Novartis. LG reports advisory/consultancy roles for ADC Therapeutics, Amgen, AstraZeneca, Celgene, Eli Lilly, F. Hoffmann-La Roche Ltd, Forty Seven, G1 Therapeutics, Genentech, Inc., Genomic Health, Menarini Ricerche, Metis Precision Medicine, MSD, Novartis, Odonate Therapeutics, Oncolytics Biotech, Onkaido Therapeutics, Pfizer, Revolution Medicines, Sandoz, Seattle Genetics, Synthon, Synaffix and Taiho Pharmaceutical; institutional research funding from Pfizer, Revolution Medicines and Zymeworks; pending patent (self) with F. Hoffmann-La Roche Ltd. SK reports advisory role for Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Exact Science, F. Hoffmann-La Roche Ltd, Genomic Health, Lilly, MSD, Novartis, Pfizer, pfm medical, Seattle Genetics and Somatex; non-financial relationship with Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Lilly and Sonoscape. CTD reports honoraria (self) from Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech, Inc., Lilly and Puma Biotechnology. AS reports institutional research funding from AbbVie, Celgene and F. Hoffmann-La Roche Ltd; expert testimony for AstraZeneca and F. Hoffmann-La Roche Ltd; travel expenses from Celgene, F. Hoffmann-La Roche Ltd and Pfizer; honoraria (self) from AstraZeneca, Celgene, F. Hoffmann-La Roche Ltd, Lilly, MSD, Novartis, Pfizer, Seattle Genetics and Tesaro. JOS reports advisory role for AbbVie, Agendia, Amgen, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Eisai, F. Hoffmann-La Roche Ltd, Genentech, Inc., Immunomedics, Ipsen, Lilly, Merck, Novartis, Odonate Therapeutics, Pfizer, Prime Oncology, Puma Biotechnology and Seattle Genetics. HL reports full-time/part-time employment and stocks/shares (self) with Genentech, Inc. CA reports full-time employment at F. Hoffmann-La Roche Ltd and stocks/shares (self) with F. Hoffmann-La Roche Ltd. SH reports full-time/part-time employment and stocks/shares (self) with F. Hoffmann-La Roche Ltd; patent (self) with F. Hoffmann-La Roche Ltd. HM reports full-time/part-time employment with F. Hoffmann-La Roche Ltd. KY reports full-time/part-time employment with F. Hoffmann-La Roche Ltd. ER reports full-time/part-time employment with F. Hoffmann-La Roche Ltd; and stocks/shares (self) with F. Hoffmann-La Roche Ltd and Genentech, Inc. SL reports consulting/advisory board roles (self) for AbbVie, Amgen, AstraZeneca, Beyer, BMS, Celgene, Daiichi Sankyo, Eirgenix, GSK, Gilead, F. Hoffmann-La Roche Ltd, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Puma, PriME/Medscape, Sanofi and Seagen; honoraria (self) from AstraZeneca, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Novartis, Pfizer, Pierre Fabre, PriME/Medscape and Samsung; funded research (self) from Abbvie, AstraZeneca, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Gilead, Novartis and Pfizer; royalties/patents (self), numbers EP14153692.0, EP21152186.9, EP15702464.7, EP19808852.8, and with VM Scope GmbH; employment (self) from GBG Forschungs GmbH; and non-financial medical writing support from Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Gilead, Novartis, Pfizer, Puma and Seagen. All authors received research support via third-party writing assistance, furnished by Alison McGonagle, PhD, of Health Interactions, provided by F. Hoffmann-La Roche Ltd.

      Acknowledgements

      We would like to acknowledge all patients and investigators participating in these trials. Support for third-party writing assistance for this manuscript, furnished by Alison McGonagle, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

      Appendix 1.

      Tabled 1Preferred terms included in the analysis
      Administration site hypersensitivity
      Allergic reaction to excipient
      Anaphylactic reaction
      Anaphylactic shock
      Anaphylactic transfusion reaction
      Anaphylactoid reaction
      Anaphylactoid shock
      Application site hypersensitivity
      Catheter site hypersensitivity
      Challenge site reaction
      Circulatory collapse
      Dialysis membrane reaction
      Documented hypersensitivity to administered product
      Drug hypersensitivity
      Human seminal plasma hypersensitivity
      Hypersensitivity
      Hypersensitivity myocarditis
      Hypersensitivity vasculitis
      Hypotensive crisis
      Implant site hypersensitivity
      Infusion related hypersensitivity reaction
      Infusion site hypersensitivity
      Infusion site recall reaction
      Injection related reaction
      Injection site hypersensitivity
      Instillation site hypersensitivity
      Kounis syndrome
      Medical device site hypersensitivity
      Nutritional supplement allergy
      Reaction to excipient
      Shock
      Shock symptom
      Stoma site hypersensitivity
      Type I hypersensitivity
      Type II hypersensitivity
      Type IV hypersensitivity reaction
      Vaccination site hypersensitivity

      Appendix 2.

      Tabled 1Summary of related study treatments and treatments administered for anaphylaxis/hypersensitivity events leading to discontinuation in pivotal clinical trials of PH IV and PH FDC SC.
      TrialAnaphylaxis/hypersensitivity event leading to discontinuation (grade)Study treatment that event was related toTreatment for anaphylaxis/hypersensitivity event
      CLEOPATRAHypersensitivity (2)Study medication
      Exact study treatment not specified.
      Chlorphenamine
      Hypersensitivity (3)P and D
      • Hydrocortisone (for both P and D)
      • Nimodipine, ipratropium bromide, fenoterol, furosemide and diphenhydramine (for reaction to D)
      Hypersensitivity (3)Study medication
      The event occurred days after study drug administration, so it is not clear which of the three drugs was most likely to be the cause.
      No treatment was given
      Anaphylactic reaction (4)P and HEpinephrine, diphenhydramine, oxygen therapy and dexamethasone
      MetaPHERAnaphylactic reaction (3)PClemastine, hydrocortisone and epinephrine
      APHINITYHypersensitivity (3)DHydrocortisone, chlorphenamine and IV fluids
      Hypersensitivity (1)P and HParacetamol (same day as event); betamethasone (11 days after event)
      Hypersensitivity (1)DMethylprednisolone and dexchlorpheniramine
      Hypersensitivity (3)P and HPrednisolone, clemastine, pethidine, metoclopramide and ranitidine
      Hypersensitivity (2)P and HNo treatment was given
      Hypersensitivity
      Grade 2 allergic reaction during cycle 2, after completion of P infusion. Grade 2 allergic reaction during P infusion on cycle 3. At cycle 4, patient received pre-medication with dexamethasone and dexchlorpheniramine before P infusion. After P and H infusions, patient presented with a grade 2 allergic reaction.
      P
      • Cycle 2 event: dexchlorpheniramine, methylprednisolone and sodium chloride infusion
      • Cycle 3 event: saline solution, loxoprofen and teprenone
      • Cycle 4 event: no treatment was given
      NeoSphereHypersensitivity (3)DRanitidine, chlorphenamine and hydrocortisone
      Hypersensitivity (3)P and/or H
      Investigator assessed the event as also being related to pre-existing disease (hypertension) and related to new illness stress related to infusion reaction.
      Dose of P was discarded. Nitroglycerine, hydrocortisone, diphenhydramine and pethidine
      TRYPHAENAHypersensitivity (4)Study medicationaSalbutamol, hydrocortisone and chlorphenamine
      Hypersensitivity (4)PPrednisolone hemisuccinate, oxygen, nifedipine and clemastine
      Hypersensitivity
      Grade not specified.
      DDocetaxel infusion stopped. Chlorphenamine, hydrocortisone and oxygen
      BERENICEAnaphylactic reaction (4)DDocetaxel permanently discontinued. Hydrocortisone
      FeDeriCaIRR (2)TPrednisolone
      D, docetaxel; H, trastuzumab; IRR, infusion-related reaction; IV, intravenous; P, pertuzumab; T, paclitaxel.
      a Exact study treatment not specified.
      b The event occurred days after study drug administration, so it is not clear which of the three drugs was most likely to be the cause.
      c Grade 2 allergic reaction during cycle 2, after completion of P infusion. Grade 2 allergic reaction during P infusion on cycle 3. At cycle 4, patient received pre-medication with dexamethasone and dexchlorpheniramine before P infusion. After P and H infusions, patient presented with a grade 2 allergic reaction.
      d Investigator assessed the event as also being related to pre-existing disease (hypertension) and related to new illness stress related to infusion reaction.
      e Grade not specified.

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