Subcutaneous trastuzumab with pertuzumab and docetaxel in HER2-positive metastatic breast cancer: Final analysis of MetaPHER, a phase IIIb single-arm safety study.

PURPOSE: Intravenous trastuzumab, pertuzumab, and docetaxel are first-line standard of care for patients with HER2-positive metastatic breast cancer (mBC). MetaPHER is the first study assessing the safety and tolerability of subcutaneous trastuzumab plus intravenous pertuzumab and chemotherapy in a global patient population with HER2-positive mBC. METHODS: In this open-label, single-arm, multicenter, phase 3b study, eligible patients were ≥ 18 years old with histologically/cytologically confirmed previously untreated HER2-positive mBC. All received ≥ 1 subcutaneous trastuzumab 600 mg fixed dose plus intravenous pertuzumab (loading dose: 840 mg/kg; maintenance: 420 mg/kg) and docetaxel (≥ 6 cycles; initial dose 75 mg/m2) every 3 weeks. The primary objective was safety and tolerability; secondary objectives included efficacy. RESULTS: At clinical cutoff, 276 patients had completed the study; median duration of follow-up was 27 months. The most common any-grade adverse events were diarrhea, alopecia, and asthenia; the most common grade ≥ 3 events were neutropenia, febrile neutropenia, and hypertension. There were no cardiac deaths and mean left ventricular ejection fraction was stable over time. Median investigator-assessed progression-free survival was 18.7 months; objective response rate was 75.6%. CONCLUSIONS: Safety and efficacy with subcutaneous trastuzumab plus intravenous pertuzumab and docetaxel in mBC are consistent with historical evidence of intravenous trastuzumab with this combination. Findings further support subcutaneous administration not affecting safety/efficacy profiles of trastuzumab in HER2-positive BC with increased flexibility in patient care. A fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection has recently been approved for the treatment of HER2-positive early/mBC, further addressing the increasing relevance of and need for patient-centric treatment strategies. TRIAL REGISTRATION: NCT02402712.

Safety and tolerability of subcutaneous trastuzumab at home administration, results of the phase IIIb open-label BELIS study in HER2-positive early breast cancer.

PURPOSE: The subcutaneous (SC) administration of trastuzumab is highly preferred by patients. At home, administration of trastuzumab SC might further improve patient benefit. The aims of the BELIS study are to evaluate the safety and tolerability of trastuzumab SC when administered at home by a healthcare professional (HCP) and to evaluate patient-reported outcomes for treatment experience of at home cancer therapy. METHODS: This open-label phase IIIb study enrolled HER2-positive early breast cancer patients in Belgium and Israel who completed the first six cycles of trastuzumab IV (neo)adjuvant therapy. The study consisted of three consecutive treatment periods: three cycles of trastuzumab IV and SC each at the hospital and six cycles of trastuzumab SC at home. RESULTS: Between November 2013 and December 2014, 23 centres enrolled 102 patients in the intent-to-treat population of which 101 patients entered the safety population. No new safety signals were detected with as expected, more mild administration site events with trastuzumab SC when compared to IV treatment. All patients agreed that they had benefit from at home administration to a large (18/81; 22%) or very large (63/81; 78%) extent. All HCPs (21/21) agreed that SC is the quickest method from start of preparation to finish of administration and that less resource use is needed. CONCLUSION: The results of the BELIS study support that trastuzumab SC can be safely administered at home by a HCP and all patients considered this setting as beneficial. HCPs consider the SC formulation as the quickest method to administer trastuzumab. TRIAL REGISTRATION: EudraCT Identifier: 2013-000123-13. ClinicalTrials.gov Identifier: NCT01926886.

Phase III study to evaluate patient's preference of subcutaneous versus intravenous trastuzumab in HER2-positive metastatic breast cancer patients: Results from the ChangHER study (GEICAM/2012-07).

OBJECTIVE: We compared patients' preferences for intravenous (IV-t) versus subcutaneous (SC-t) trastuzumab administration. METHODS: Phase III, open-label, multicentre study in HER2-positive metastatic breast cancer. Patients were receiving IV-t for at least 4 months without progression. Randomisation was 1:1 to administer 2 cycles of SC-t with vial followed by 2 cycles with single injection device (SID) or the reverse sequence (600mg SC-t every 3 weeks for 4 cycles). PRIMARY OBJECTIVE: patients' preference for IV-t versus SC-t; secondary objectives: patients' preference for vial versus SID, healthcare professional (HCP) preference and safety. RESULTS: We randomised 166 patients in 26 sites. Median number of previous lines of chemotherapy and/or endocrine therapy was 1 (1-7). Median duration of prior IV-t was 1.8 years (0.3-14). Of the159 patients completing the questionnaires, 86.2% preferred SC-t, 6.9% preferred IV-t, and 6.9% had no preference. Patients preferred SID (59.2%) over vial (26.3%). Most (87.2%) HCP preferred SC-t of whom 51.3% and 28.2% preferred SID and vial respectively. Related adverse events included G1-2 injection site reactions in 18 patients (10.8%), G1 pain in 8 (4.8%), G1-2 allergic reaction in 2 (1.2%), one G3 heart failure and 1 G2 ejection fraction decrease. CONCLUSIONS: SC-t is preferred with no safety impact.

Neoadjuvant Trastuzumab and Pertuzumab in Combination with Standard Chemotherapy for HER2-Positive Early Breast Cancer: Real-World Practice in Cuba.

PURPOSE: Dual HER2 blockade chemotherapy is the standard of care for localized HER2+ breast cancer (BC). However, despite the efficacy of neoadjuvant therapy, relapses occurring in around 10% of patients highlight the need to improve its clinical approach. Therefore, this study aimed to evaluate the effectiveness/safety of neoadjuvant therapy with subcutaneous (SC) trastuzumab- pertuzumab chemotherapy (real world) to extend the evidence, which comes mainly from clinical trials (selected population; intravenous [IV] trastuzumab). MATERIALS AND METHODS: A prospective, longitudinal, observational study in a Cuban hospital. POPULATION: women aged ≥18 years with histologically confirmed HER2+ early-stage BC (2017-2021) eligible for neoadjuvant treatment (IV pertuzumab, SC trastuzumab, taxane-based chemotherapy). The aim was to determine the pathological complete response (pCR) rate to this scheme, its safety, and the impact of patient's characteristics on the outcomes. RESULTS: Eighty-seven women were included: n=29 (DPT [docetaxel-IV pertuzumab- SC trastuzumab 600 mg; 4 cycles]); n=58 (ddAC-DPT [dose-dense anthracycline-based scheme+DPT]; 8 cycles). The median age was 57 years (range 30-83), ECOG 0: 97%. Time from diagnosis to treatment (median) was 28 days. The overall pCR rate was 62.1% (55.2%, DPT; 66.5%, ddAC-DPT; p =0.351); HR+, 47.7% vs. HR-, 76.7% (p=0.006). There were no statistically significant differences based on nodal status, stage, or Ki-67 levels. Overall, 94.2% of patients experienced ≥1 adverse event related to treatment, all of them grade 1-3 and more common with ddAC-DPT. The main cause of treatment delays (n=19; ddAC-DPT, 16; DPT, 3) was treatment-related toxicities. CONCLUSION: Neoadjuvant trastuzumab (SC) and pertuzumab plus chemotherapy for HER2+ early-stage BC showed benefits in a real-life setting, with an acceptable safety profile.

Trastuzumab and thyroid dysfunction: An association to be aware of.

The incidence of autoimmune thyroid disorders is higher among women with breast cancer (BC) than in other solid malignancies, while it has not a prognostic impact. Trastuzumab (T) is a humanized monoclonal antibody approved for human epidermal growth factor receptor 2 (HER2)-positive BC in the neoadjuvant, adjuvant, and metastatic scenarios. Since 2014, subcutaneous (SC) T has been employed with the same efficacy as the intravenous formulation together with an easier way of administration. To date, autoimmune thyroiditis has been linked rarely to the use of intravenous T, and no cases have been related to the SC presentation. We report two cases of HER2-positive early BC patients who developed hypothyroidism during maintenance therapy with SC T that required levothyroxine supplementation. SC T includes recombinant human hyaluronidase to facilitate tissue penetration of the drug. This enzyme may alter the thyroid gland stroma and facilitate the development of thyroid disorders. Thyroid function tests are recommended in patients on SC T.

Neo-adjuvant and/or Adjuvant Subcutaneous Trastuzumab (Herceptin®) in Patients With Early HER2-positive Breast Cancer: Real World Data from a German Observational Study - (NIS HerSCin).

BACKGROUND/AIM: Subcutaneous Herceptin (HER SC) has been shown to be equally effective and safe compared to intravenous Herceptin (HER i.v.) application in early HER2-positive breast cancer (HER2+ BC). However, real-world data from the subcutaneous application are currently limited. PATIENTS AND METHODS: Based on a non-interventional study (NIS), data from routine clinical use of HER SC have been gathered between 2013 and 2018 in 135 hospitals and open-care practices throughout Germany. RESULTS: A total of 265 patients were recruited in the neo-adjuvant and 605 patients in the adjuvant setting. Primary effectiveness endpoint in the neoadjuvant treatment setting was pathological complete response rate, which was achieved in 41.5%. Primary endpoint in the adjuvant setting was disease free survival rate after 2 years (94.9%). Safety results from the study were comparable to the well-known safety profile of HER i.v. including preferred terms, incidence, severity, including cardiac events. No new safety signals were detected. CONCLUSION: Effectiveness and safety of HER SC were comparable to data from HER i.v. in early HER2+ BC.

Subcutaneous Trastuzumab Combined with Pertuzumab and Docetaxel as First-line Treatment of Advanced HER2-positive Breast Cancer.

BACKGROUND/AIM: Subcutaneous (s.c.) trastuzumab was introduced in the (neo)adjuvant setting, based on the non-inferiority results and patient preference. In the advanced setting, preliminary safety data have only been reported. We conducted an observational study of s.c. trastuzumab in combination with i.v. pertuzumab and docetaxel in the first-line setting of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. PATIENTS AND METHODS: In this single-institution study, patients received 600 mg s.c. trastuzumab in combination with 840 mg pertuzumab for the first cycle and 420 mg for the following cycles, and 75-100 mg/m2 docetaxel, followed by maintenance with s.c. trastuzumab and pertuzumab until disease progression or unacceptable toxicity. Endpoints were efficacy and safety. RESULTS: Forty patients were enrolled. The median number of cycles with docetaxel was six, while the median number of maintenance cycles was 21. With a median follow-up of 37 months, median progression-free survival and overall survival were 24 and 35 months. CONCLUSION: Subcutaneous trastuzumab in combination with pertuzumab and docetaxel is well tolerated and effective in HER2-positive advanced breast cancer.

Safety profile of subcutaneous trastuzumab for the treatment of patients with HER2-positive early or locally advanced breast cancer: primary analysis of the SCHEARLY study.

BACKGROUND: Subcutaneous trastuzumab (H SC) is a valuable alternative to the intravenous formulation. This study assessed H SC safety and tolerability in human epidermal growth factor receptor 2 (HER2)+ early/locally advanced breast cancer (EBC/LABC). METHODS: SCHEARLY is a prospective, two-cohort, non-randomised, multicentre Italian trial included in the umbrella study UmbHER1, planning a 1-year treatment with H SC 600 mg in HER2+ EBC/LABC. Patients were sequentially assigned to cohort A (N = 121) and B (N = 119) to receive H SC via a handheld syringe and a single-use injection device, respectively. Adjuvant or neoadjuvant treatment included anthracycline-containing regimens followed by H SC plus taxanes and then alone for 18 cycles totally. RESULTS: Two hundred forty patients were enrolled (adjuvant therapy: 81.7%; neoadjuvant therapy: 18.3%), and 201 completed the treatment (early discontinuation was mainly due to intercurrent adverse events [AEs], 7.5%). Overall, the two cohorts displayed similar safety profiles. From H SC start, the rate of treatment-related AEs in the safety population (N = 228) was 3.9% for grade ≥3 AEs; 0.9% for serious AEs (one pleuropericarditis and one anaphylactic shock, both resolved) and 14.5% for cardiac AEs, the most common being the decreased left ventricular ejection fraction (7.9%; mean reduction from the screening to the follow-up visit was 2.9%). No cases of congestive heart failure occurred. The rate of systemic administration-related reactions and local injection site reactions was 68.0% and 21.9%, respectively, mostly of grade 1-2. CONCLUSIONS: H SC 600 mg confirmed to be a safe and tolerable option as adjuvant/neoadjuvant therapy in patients with HER2+ EBC and LABC. CLINICALTRIALS. GOV IDENTIFIER: NCT01940497.

Real-World Data on Health-Related Quality of Life Assessment in Patients With Breast Cancer Receiving Subcutaneous Trastuzumab.

PURPOSE: Trastuzumab, a humanized anti-human epidermal growth factor receptor 2 (anti-HER2) antibody delivered intravenously, has revolutionized the treatment of patients with breast cancer overexpressing HER2 protein. Recently, a newer subcutaneous formulation was shown to have comparable efficacy to the initial intravenous trastuzumab. In this study, we aimed to evaluate the impact of subcutaneous trastuzumab on the health-related quality of life (HRQoL) of patients diagnosed with early or metastatic HER2-overexpressing breast cancer. METHODS: Patients were provided with the EORTC QLQ-C30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30) and the BR-23 questionnaires. The scoring of questionnaires and patient's sociodemographic and clinicopathologic characteristics were recorded and analyzed by descriptive and correlation statistics employing t test and 2-way analysis of variance. RESULTS: A total of 163 patients agreed to participate in the study. About 90 of 163 patients (55.21%) received subcutaneous trastuzumab and 21 patients intravenous trastuzumab (12.88%). A control group of 52 HER2+ patients received chemotherapy without trastuzumab (31.90%). Patients receiving subcutaneous trastuzumab were older and of more advanced disease stage compared with those receiving chemotherapy (58.5 vs 51 years, 39.8% vs 28.8% advanced disease). In univariate analysis, subcutaneous trastuzumab was associated with less nausea and vomiting (P = .002) but worse cognitive function (P = .013) and dyspnea (P = .042). Patients who have received >8 cycles of subcutaneous trastuzumab reported less diarrhea (P = .049) and systemic therapy side effects (P = .015). Multivariate analysis showed that patients without comorbidity receiving subcutaneous trastuzumab had less treatment side effects, less upset by hair loss, and higher emotional functioning. Of note, mastectomy and subcutaneous trastuzumab were associated with improved role functioning (P = .021). In metastatic disease, no negative impact of subcutaneous trastuzumab on HRQoL was found. CONCLUSIONS: The administration of subcutaneous trastuzumab improved certain symptoms and did not adversely affect most of the assessed functional scales. Particularly, in the metastatic setting, subcutaneous trastuzumab had no negative impact on HRQoL.

Resource utilization and cost saving analysis of subcutaneous versus intravenous trastuzumab in early breast cancer patients.

We conducted an economic evaluation of intravenous (IV) vs subcutaneous (SC) trastuzumab for the treatment of patients with early breast cancer (EBC). Data of patients receiving adjuvant IV trastuzumab at our institute in 2014 were used to study three different treatment scenarios: 1) IV trastuzumab, 2) SC trastuzumab, and 3) IV trastuzumab during chemotherapy followed by SC trastuzumab. Our cohort included 114 patients with a median weight of 63.75 kg. Scenario 2 was the most time-saving treatment, with 71.7% reduction in preparation time and 89.3% reduction in chair time compared to scenario 1. Considering full costs, the mean costs per patient/year were € 14,233 ± 8,698 for scenario 1, € 14,272 ± 8,312 for scenario 2, and € 14,535 ± 8,646 for scenario 3 (p = 0.959). When mean body weight was > 65.2 kg, the mean cost was lower in scenario 2 than in scenario 1. Scenario 2 proved a valuable time-saving and cost-saving option. A shift from IV to SC trastuzumab should be considered, especially in capacity-constrained oncology departments.

Trastuzumab for patients with HER2 positive breast cancer: delivery, duration and combination therapies.

With the exception of endocrine therapy, no other systemic treatment of patients with breast cancer has reached such a magnitude of beneficial effect as trastuzumab. This targeted agent (monoclonal antibody) is associated with a significant improvement in both disease-free (DFS) and overall survival (OS) in women with HER-2 positive breast cancer when given in combination with or in sequence to adjuvant chemotherapy. This has been confirmed in a recent Cochrane meta-analysis of randomized controlled trials (RCTs), including 6 adjuvant and 2 neoadjuvant studies (NSABP B-31, NCCTG N9831, BCIRG 006, HERA, FinHer, PACS-04, Buzdar and NOAH), with data collection until February 2010. Overall, mortality is reduced by one-third and the risk of relapse by 40%. Concerns regarding cardiac dysfunction are declining, with reports indicating its reversibility in most instances, however truly long term cardiac evaluation is still lacking. Hence, the benefit of trastuzumab could be challenged by cardiac toxicity, in lower-risk patients [T1a,b node-negative (N0) tumors] or those with increased cardiovascular risk (older women and patients with previous significant heart disease/suboptimal left ventricular ejection fraction [LVEF (<55%)], all of whom were largely excluded from the aforementioned adjuvant RCTs. These patient subgroups might warrant a specific approach, such as anti-HER2 treatment combined with just a taxane (avoiding anthracyclines) or with endocrine therapy. Reasonably large phase II trials aimed at exploring these more individualized regimens are underway in the US. The optimal duration of trastuzumab therapy remains unknown since the selection of the one year duration in the pivotal trials was arbitrary. The HERA trial showed that prolonging trastuzumab administration to two years does not confer additional advantage over one year. The PHARE trial compared 6 versus 12 months of trastuzumab and failed to show non-inferiority of the shorter treatment administration. At the present time, one year of adjuvant trastuzumab remains the standard-of-care until results from SOLD, Short-HER and PERSEPHONE consolidate or negate this finding. The route of trastuzumab administration has also been recently challenged. A subcutaneous formulation is being evaluated in several studies. The HannaH phase III trial compared the subcutaneous (SC) to the intravenous (IV) formulation of trastuzumab. The former was proven non-inferior to the latter, although the incidence of serious adverse events was slightly higher in the SC arm. The authors concluded that SC trastuzumab, administered at a fixed dose of 600mg over 5min, is a valid alternative option, with the potential for human and economic savings in clinical practice.