Clin Transl Oncol DOI 10.1007/s12094-014-1181-y

EDUCATIONAL SERIES



RED SERIES

NEW TRENDS IN CLINICAL ONCOLOGY

Subcutaneous trastuzumab: drug development and current position P. Martı´n Martorell • B. Bermejo de las Heras J. A. Pe´rez-Fidalgo • M. Huerta Alvaro • M. Martı´n • J. Albanell • A. Lluch Herna´ndez



Received: 20 December 2013 / Accepted: 28 March 2014 Ó Federacio´n de Sociedades Espan˜olas de Oncologı´a (FESEO) 2014

Abstract HER2-positive breast cancer, accounting for 15 % of the total breast cancer patient population, carries in itself a bad prognosis, which has now become much better after the advent of anti-HER2 drugs. HER2-targeted therapy has significantly improved disease free- and overall survival in HER2-positive breast cancer, and has rendered better disease control both in the early and advanced disease setting. Trastuzumab treatment duration is often prolonged and poses significant time and resource challenges both on the treatment institutions and on the patient. The recent development of a subcutaneous formulation has meant a significant advance in this respect. We review the drug development of the compound and the current evidence on its use. Keywords Trastuzumab  Breast cancer  HER2  Subcutaneous

P. Martı´n Martorell (&)  B. Bermejo de las Heras  J. A. Pe´rez-Fidalgo  M. Huerta Alvaro  A. Lluch Herna´ndez Hematology and Medical Oncology Department, Hospital Clı´nico Universitario de Valencia, Avda. Blasco Iba´n˜ez 17, 46010 Valencia, Spain e-mail: [email protected] M. Martı´n Medical Oncology Department, Instituto de Investigacio´n Sanitaria Gregorio Maran˜o´n, Complutente University, Madrid, Dr. Esquerdo 46, 28029 Madrid, Spain J. Albanell Medical Oncology Department, Hospital del Mar (Hospital del Mar Research Institute), Parc de Salut Mar, Pompeu Fabra University, Passeig Maritim 25-29, 08003 Barcelona, Spain

Introduction HER2-positive breast cancer accounts for approximately 15 % of malignant breast tumors, which confers them a more aggressive behavior and a worse prognosis. However, anti-HER2 therapy associated to chemotherapy has been able to reduce the risk of relapse between 30 and 55 % in several studies in early disease, as well as to diminish the risk of disease progression in the advanced setting. The phase III randomized study HERA, a registering study including 5,102 patients, aiming to determine the efficacy and safety parameters of trastuzumab treatment in the early breast cancer setting alongside antracycline-based adjuvant chemotherapy, achieved a clinically and statistically significant increase in disease-free survival (DFS; hazard ratio 0.64, CI 95 % 0.54–0.76; p \ 0.0001) and overall survival (OS; hazard ratio 0.66, CI 95 % 0.47–0.91; p \ 0.0115) after 1 year of treatment [1]. This very favorable effect remained patent after 8 years of follow up [2]. The NSABP B-31 and NCCTG N9831 studies also showed very similar results in terms of DFS and OS, which also remained statistically significant after 10 years of follow up [3, 4]. The BCIRG006 trial confirmed these results with different adjuvant chemotherapy regimens, thus adding to the robustness of the available data [5], as did two meta-analyses [6, 7]. Similarly, other studies have shown the importance of trastuzumab treatment in the neoadjuvant setting. This clear benefit of adjuvant trastuzumab applies to all patient subpopulations, irrespective of age, hormonal receptor status, and classical pathological parameters. In the advanced disease setting, trastuzumab has also become the cornerstone of HER2-positive disease therapy. The pivotal study by Slamon et al. [8] demonstrated a clear and significant 49 % reduction in the relative risk of

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disease progression (hazard ratio 0.51, CI 95 % 0.41–0.63) and 20 % decrease in the relative risk of death (hazard ratio 0.80, CI 95 % 0.64–1.00) in comparison to chemotherapy alone. This has been shown to apply not only to antracycline-and taxane-based chemotherapy, but also to other chemotherapy regimens, whether intravenous or oral, as well as hormonal treatments [9–11]. However, the current duration of adjuvant trastuzumab therapy is prolonged, and poses a considerable weight on time and economic resources, both of the health institution and the patient. Also in the advanced disease setting is this duration prolonged through sequential chemotherapy regimens. Although initially developed as a weekly administration schedule, with a 4 mg/kg loading dose, and subsequent 2 mg/kg weekly maintenance dose, soon the need arose for a more convenient dosing schedule for trastuzumab, which would easily combine with the most frequent three weekly chemotherapy regimens. A phase II study established similar average exposure between both dosing regimens, with similar efficacy and tolerability parameters, despite an expected higher Cmax and lower Ctrough of the three weekly scheme [12]. The current three weekly regimen requires nonetheless an 8 mg/kg loading dose to be administered in 90 min, and a maintenance dose of 6 mg/kg to be administered in 30 min. The phase III HERA (1 versus 2 years) and PHARE (6 months versus 1 year) trials have established 1 year of trastuzumab treatment as the optimum duration in the early breast cancer setting [2, 13]. If we take into account the human and economic resources consumed by such an efficacious therapy in HER2-positive breast cancer, it becomes easily understandable that the development of a subcutaneous (SC) formulation would be so appealing.

Subcutaneous administration route The main obstacle to the subcutaneous drug administration route is the volume restriction. The subcutaneous space is made up of a matrix of glycosaminoglycans such as hyaluronan, and structural glycoproteins such as collagen fibers, which limit the volume to be injected to \1 ml. Hyaluronan has an approximate half life of 15–20 h, and thus becomes a good modifiable factor. Hyaluronidase, an enzyme which hydrolyzes and degrades hyaluronan, has been used for over 60 years, and its recombinant form, rHuPH20, is FDA approved for subcutaneous drug injection. rHuPH20 causes a temporary and partial degradation of the subcutaneous space which allows for a greater SC infusion, and which is restored after a few hours thanks to its short half life.

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Preclinical and clinical development of subcutaneous trastuzumab A phase I/Ib was designed to compare intravenous and subcutaneous trastuzumab administration. This study was carried out in healthy male volunteers and HER2-positive breast cancer patients in the adjuvant setting, thus eliminating the possible confusing pharmacokinetic factor due to tumor burden [14]. The main objective was to select the subcutaneous trastuzumab dose resulting in a comparable bioavailability with respect to the intravenous formulation through the time–serum concentration curve (AUC). Secondary objectives were tolerability and toxicity. In part 1, healthy male volunteers received a single dose of trastuzumab 6 mg/kg intravenous (IV; cohort 1) or two different doses of SC trastuzumab, 6 mg/kg (cohort 3) or 10 mg/kg (cohort 4), at an injection rate comfortable to the patient. After pharmacokinetic analysis of these cohorts, a 8 mg/kg subcutaneous dose was determined as most probably achieving an equivalent dose to the standard 6 mg/kg IV, after which a fifth cohort with this dose was set up in healthy male volunteers. Part 2 of the study confirmed this as the most adequate dose in breast cancer patients. Intravenous pharmacokinetics between both groups of patients were very similar, thus permitting the extrapolation of subcutaneous administration data of healthy volunteers to breast cancer patients (Table 1). Healthy volunteers were between 18 and 43 years old, and had a body mass index (BMI) ranging between 19.2 and 27.6 mg/m2, while the BMI of breast cancer patients ranged between 17.3 and 48.3 mg/m2. AUC in patients receiving 8 mg/kg SC was comparable to the AUC of the 6 mg/kg IV cohort. Cmax of the subcutaneous formulation was lower, as expected. Ctrough in day 22 was similar to the 6 mg/kg i.v. dose. Bioavailability in healthy volunteers at the 6, 8 and 10 mg/kg dose, respectively was 84, 91 and 93 %. For the breast cancer patients this was 87 and 99 % for the 8 and 12 mg/kg, respectively. Most adverse events were mild (71 % in part 1, and 73 % in part 2). No serious adverse events were reported resulting in dose withholding or modifications. Most adverse events in the SC group were due to local inflammatory reaction, and edema or local discomfort at the injection site. The PK data from this phase I/Ib trial allowed for the confirmatory phase III HannaH trial (NTC00950300) where patients with HER2-positive breast cancer were treated in the (neo)adjuvant setting [15]. This 1:1 randomized trial aimed to establish the equivalence between the standard intravenous administration and the 600 mg subcutaneous dose, in terms of pharmacokinetic (PK) data and efficacy parameters. The main objectives were to obtain Ctrough levels prior to cycle 8 before surgery and

Phase I/Ib open label

Phase III (neo)adjuvant, open label, randomized

Phase II

Adjuvant, open label, randomized, crossover

Phase III

Adjuvant, open label, nonrandomized (ongoing)

Phase III

Advanced disease, open label, randomized (ongoing)

NCT00800436

HannaH trial (NTC00950300)

PrefHer trial

(NTC 01401166)

SafeHer trial

(NTC01566721)

ChangHer trial

(NTC01875367)

Continuation with preference modality

Arm B: 6 mg/kg IV trastuzumab (2 cycles) and crossover to 600 mg SC trastuzumab single injection device

Arm A: 600 mg SC trastuzumab single injection device (2 cycles) and crossover to 6 mg/kg IV trastuzumab (2 cycles)

600 mg SC trastuzumab assisted administration/600 mg SC trastuzumab self administered via hand-held device

Arm B: 6 mg/kg IV trastuzumab (4 cycles), after which crossover to 600 mg SC trastuzumab

Arm A: 600 mg SC trastuzumab hand held device (4 cycles) after which crossover to 6 mg/kg IV trastuzumab

600 mg SC trastuzumab/6 mg/kg IV trastuzumab ? T (4) followed by FEC-75 (4) (adjuvant completion to 1 year)

SC: 8 and 12 mg/kg—breast cancer patients

Part 2: dose confirmation

SC: 6, 8 and 10 mg/kg healthy male volunteers

IV: 6 mg/kg—healthy male volunteers and breast cancer patients

Part 1: dose finding

Treatment

Estim. 160

Estim. 2,500

248

596

Incidence of adverse events

Incidence of adverse events

Proportion of patients indicating preference for one or the other administration method

Ctrough non inferiority values in the SC arm pCR rates in breast

Part 1: identification of SC trastuzumab dose

24 healthy male patients 42 breast cancer patients

Primary objective

N

patient satisfaction

Overall survival

Disease free survival

Patient satisfaction

Overall survival

Disease free survival

Time saving

Health care professional preference

Inmunogenicity

Event free survival

Tolerability

Safety

Tolerability

Toxicity

Time to response

PK profile Response rate

Safety and tolerability

Other objectives

SC subcutaneous, IV intravenous, Ctrough serum trough concentrations, pCR pathologic complete response rate, T docetaxel 75 mg/m2, FEC-75 5-fluorouracil 500 mg/m2, epirrubicin 75 mg/m2, cyclophosphamide 500 mg/m2

Study design

Study

Table 1 Summary of subcutaneous trastuzumab trials

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pathologic complete response rates (pCR, defined as absence of infiltrating component in the breast) with the subcutaneous formulation which would be comparable to the IV dosing. Secondary objectives were pharmacokinetic profiling, pathologic complete response both in the breast and axilla (tpCR), response rate, time to response, eventfree survival, overall survival safety and tolerance, as well as immunogenicity data. It was pre-specified that the SC dose should reach Ctrough levels which would be higher or equivalent to the 8 mg/kg IV dose in order to consider omitting a SC loading dose. Patients in the control arm received neoadjuvant trastuzumab and chemotherapy (4 cycles of docetaxel 75 mg/ m2 followed by 4 cycles of FEC-75) followed by surgery. Trastuzumab was continued until completion of 1 year of treatment, according to current standards. Local radiotherapy and hormonal treatment were applied according to the local practice. The experimental arm received the same treatment, but with a 600 mg SC dose of trastuzumab every 3 weeks diluted in 10,000 U rHuPH20 in 5 ml. Subcutanous trastuzumab administration was carried out by the nursing team using a hand-held syringe (Fig. 1; Table 1). Five hundred and ninety-six patients were treated, with similar patient characteristics between both arms. The dose intensity in the intravenous trastuzumab arm was 135.9 mg/week (range 87.0–234.6) and 195.9 mg/week (range 152.2–211.9) in the subcutaneous arm. The relative dose intensity was over 96 % in both groups. Non-inferiority was demonstrated in the SC arm with respect to the Ctrough pre-surgery. The geometric mean ratio Ctrough trastuzumab SC/Ctrough trastuzumab IV was 1.33 (90 % CI 1.24–1.44), thus greater than the pre-specified non-inferiority margin. 98.7 % of the patients in the IV arm reached a Ctrough [ 20 lg/ml versus 97 % in the SC arm, therefore demonstrating the potential to omit the loading dose in the SC formulation. Subcutanous trastuzumab was also non-inferior to the intravenous formulation with respect to pCR: 45.4 % in the SC arm, and 40.7 % in the IV group, with a 4.7 % difference between arms (95 % CI -4.9 to 13.4 %), well Fig. 1 Design of the HannaH trial [15]

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underneath the -12.5 % pre-specified non-inferiority value. Total complete pathologic response (tpCR) both in the breast and axilla was also similar between both arms. No differences were found between arms after adjusting for basal patient characteristics. Other secondary endpoints (PK profile, response rate, time to response, toxicity and tolerability, and immunogenicity data) were comparable between both arms. Event free survival and overall survival data remain immature. Adverse event occurrence was similar between the SC and IV formulation (52 % in both arms) although the incidence of infections was greater in the SC arm, despite no differences in hematological toxicity. There were four fatal adverse events (three in the SC arm and one in the IV group) all during the neoadjuvant phase, two being reported by the investigator as drug related, and three occurring in obese patients. A multiple logistic regression analysis did not reveal any correlation between serum trastuzumab exposure and body weight on the adverse event rate. In conclusion, the HannaH study established the equivalence between the current intravenous trastuzumab formulation and the 600 mg SC dose, both in terms of PK parameters, as well as efficacy data. The toxicity profile seems similar. The SC loading dose can be omitted.

PrefHerence Several trials address the patient and health team preference for the SC versus the IV administration. The PrefHer trial (NTC01401166), randomized 248 breast cancer patients in the adjuvant setting 1:1 to receive 600 mg handheld administration of subcutaneous trastuzumab every 3 weeks by the nursing team for four cycles (arm A, 124 patients), after which they were switched to receive the intravenous formulation. Arm B patients (N = 124) received first four cycles of IV trastuzumab, followed by the SC dose (Fig. 2; Table 1). Two telephone interviews were carried out, one before patient randomization, and one after eight cycles of treatment [16].

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Fig. 2 Design of the PrefHer trial [16] Fig. 3 Design of the ChangHer trial

Trastuzumab SC x 2

HER2 positive MBC without IV trastuzumab progression for at least 4 months

Trastuzumab IV x 2

Arm A R

IV x 1

Arm B

Patients allowed to continue with the formulation of their choice

Trastuzumab IV x 2 Trastuzumab SC x 2

Most patients (91.5 %) showed a preference for the SC formulation (95 % CI 87.2–94.7 %, p \ 0.0001), 6.8 % for IV trastuzumab (95 % CI 3.9–10.8 %), and 1.7 % showed no preference. The main reasons for preferring the SC administration route were time reduction in the administration, as well as less discomfort. Similarly, 73.8 % of the health professionals involved preferred the SC route (95 % CI 64.2–82.0 %), while 24.3 % showed no preference. We await results of the SafeHer study (NTC01566721), another large randomized trial involving approximately 2,500 early breast cancer patients, which will analyze the safety and tolerance profile of the SC administration between the hand-held syringe or self administration using a single-use injection device, as well as the ongoing ChangHer phase III study, a similar trial aiming to randomize approximately 160 patients in the metastatic setting (Fig. 3; Table 1).

Cost efficacy analysis An analysis carried out in the United Kingdom in parallel to the PrefHer study, Time & Motion, established a favorable cost efficacy profile for the subcutaneous single-use trastuzumab injection device compared to the intravenous administration [17]. The SC administration route mounted to a potential saving of £2,014 for each administration year in an early breast cancer patient. This was mainly attributable to lower administration costs, although there was also some contribution of the preparation time and consumables involved. Although

this study only analyzed costs derived from drug administration, and not due to adverse effects of the drug, the data from the phase I/Ib study and the HannaH study do not suggest expected differences derived from toxicity. Another observational prospective international Time & Motion study confirmed these results [18]. The reduction in trastuzumab administration time ranged between 58 and 81 % across the different countries. A reduction in the drug’s preparation time and health staff resources was observed.

Conclusions Almost 15 % of breast cancer is HER2 positive, and trastuzumab has long shown to be very beneficious in the treatment of these patients, both in the early- and in the advanced setting of the disease. However, the need for an intravenous administration, and the prolonged treatment in many cases, has, posed a great demand on the health care resources and patient’s time, which have encouraged the search for alternative routes of administration. Subcutaneous trastuzumab at a fixed dose of 600 mg has shown to be equivalent to the current three weekly intravenous dose, both in terms of PK parameters, as well as efficacy and safety data. It has also demonstrated to be the preferred administration route both by patients and health care staff. And last, but not least, cost-efficacy analyses are favorable to the SC formulation. All these data taken together, and given the robustness of the HannaH trial,

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make further trials of the subcutaneous trastuzumab formulation largely unnecessary. It is predictable that the progressive development of the single-use self administered device will derive in further cost and time reduction in such a widespread therapy. Conflict of interest

The authors declare no conflict of interest.

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Subcutaneous trastuzumab: drug development and current position.

HER2-positive breast cancer, accounting for 15 % of the total breast cancer patient population, carries in itself a bad prognosis, which has now becom...
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