Nuevas vías de administración de Trastuzumab MIQUEL ÀNGEL SEGUÍ PALMER

Nuevas vías de administración de Trastuzumab MIQUEL ÀNGEL SEGUÍ PALMER

Trastuzumab, a humanized monoclonal antibody against the extracellular domain of the HER2 receptor, is the standard-of-care treatment for patients with early and advanced HER-2 positive breast cancer Rituximab and trastuzumab were the first monoclonal antibodies (mabs) approved for the treatment of cancer. In oncology, mabs are typically administered by intravenous (IV) infusion; however, this administration route faces some challenges

Challenges of Intravenous administration of mabs The need for trained personnel, dedicated infusion facilities, dose calculation, aseptic preparation of required infusion volumes, and extended post-infusion observation. Long infusion times and slow workflow for medical staff. Potential difficulties with IV catheter placements. Risk of infusion-related reactions and complications (e.g. relevant thromboembolic events, infections), leading to hospitalisation and additional costs. Costs associated with the placement of permanent IV lines.

Revenues of IV versus SC-administered anti-tnf-alpha treatments (2001 2006)

Subcutaneous (SC) administration can potentially overcome many of these challenges. Although administration-associated reactions (AARs) may occur with SC administration, they are likely to be less severe than IV-associated infusion-related reactions, given the more gradual absorption of the SC formulation. SC formulations may be more convenient for patients, offering potential improvements in quality of life and treatment adherence. In oncology, SC administration of mabs has been shown to reduce administration times and health-care costs relative to IV infusion.

However, the biggest challenge with SC formulations has been the ability to deliver the required volume of drug to patients. The extracellular matrix, which maintains tissue architecture and controls diffusion/molecule flow, limits drug volumes to 1 2 ml, with volumes >2ml causing tissue distortion and pain. The extracellular matrix is composed of a structural network of fibrous proteins (collagen and elastin)embedded within a hydrated viscoelastic gel, composed of glycosaminoglycans that are complex linear polysaccharides characterized by repeating disaccharide structures of an N-substituted hexosamine and an uronic acid, including hyaluronan (hyaluronic acid9, chondroitin sulfate, dermatan sulfate, heparin sulfate, heparin and keratin sulfate.

Development of a SC Formulation of Trastuzumab These hurdles have been overcome by concentrating IV formulations 12-fold and adding recombinant human hyaluronidase (rhuph20). By hydrolysing hyaluronan, rhuph20 reversibly opens the interstitial space in SC tissue and allows the installation of >2 3 ml.

Administration site before and immediately after infusion without and with rhuph20

Clinical trials of subcutaneous trastuzumab in patients with HER2+ early stage breast cancer

Comparison of SC and IV Administration of Trastuzumab. Phase I/Ib Trial A subcutaneous trastuzumab dose of 8 mg/kg was found to result in exposure comparable with the intravenous trastuzumab dose of 6 mg/kg. The subcutaneous formulation was well tolerated. Wynne C et al. J Clin Pharmacol. 2013;53(2):192-201

Development of a Fixed-Dose Subcutaneous Formulation of Trastuzumab The fixed dose of subcutaneous trastuzumab given every 3 weeks was determined by pharmacokinetic modelling of data from the phase I. 600-mg trastuzumab s.c. dose, administered thriceweekly (Q3W) without a loading dose, would provide C trough (predose Cycle 8) and area under the time concentration curve (AUC 0 21 days, Cycle 7) at least as high as Q3W i.v. administration. Hourcade-Potelleret F et al. CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e87

HannaH Trial Fixed Dose for Trastuzumab SC Comparable Efficacy Expected Based on PK Profiles

HannaH Trial Randomized Open-Label Phase III Non-Inferiority Study to Compare the PK, Efficacy and Safety of Trastuzumab SC and IV in HER2-Positive EBC

Baseline patient demographic and tumour characteristics Ismael G, et al. Lancet Oncol. 2012;13(9);869-878

HannaH Trial: Efficacy Results Ismael G, et al. Lancet Oncol. 2012;13(9);869-878

HannaH Trial: Safety and Tolerability Ismael G, et al. Lancet Oncol. 2012;13(9);869-878

HannaH Trial: Anti-Drug Antibodies (ADAs) Ismael G, et al. Lancet Oncol. 2012;13(9);869-878

HannaH Trial Demonstrated the noninferiority of the fixed-dose SC trastuzumab formulation vs the IV formulation by meeting the co-primary endpoints of noninferior serum trough concentration and pathologic complete response (pcr) with neo)adjuvant SC trastuzumab via manual injection compared to IV The overall safety profile of the fixed-dose SC trastuzumab formulation was comparable to that of IV trastuzumab, and consistent with the known safety profile of trastuzumab in early breast cancer

PrefHer Trial To investigate benefits of the trastuzumab SC formulation, the international, multicenter, openlabel, randomized, two-cohort, two-arm PrefHer study was designed to assess patients preferences for trastuzumab SC or IV in the adjuvant breast cancer setting.

PrefHer Trial 1. Pivot X, et al. Lancet Oncol. 2013;14(10):962-970. 2. Pivot X, et al. Cancer Res. 2013;73(24 Suppl): Abstract P4-12-11.

Cohort 1: Trastuzumab SC administered via SID Patient Preferences High preference for trastuzumab SC was maintained, irrespective of whether patients were de novo or non-de novo trastuzumab IV prior to study enrolment. Pivot X, et al. Lancet Oncol. 2013;14(10):962-70

Cohort 1: Trastuzumab SC administered via SID Primary Reasons for Patients Preferences Pivot X, et al. Lancet Oncol. 2013;14(10):962-70

Cohort 1: Trastuzumab SC administered via SID Strength of Patients Preferences Pivot X, et al. Lancet Oncol. 2013;14(10):962-70

Cohort 1: Trastuzumab SC administered via SID Healthcare Professional (HCP) Satisfaction Pivot X, et al. Lancet Oncol. 2013;14(10):962-70

Cohort 2: Trastuzumab SC administered via SC hand-held syringe Patients Preferences Pivot X, et al. Cancer Res. 2013;73(24 Suppl): Abstract P4-12-11

Cohort 2: Trastuzumab SC administered via SC hand-held syringe Strength of Patients Preferences Pivot X, et al. Cancer Res. 2013;73(24 Suppl): Abstract P4-12-11

Cohort 2: Trastuzumab SC administered via SC hand-held syringe Healthcare Professional (HCP) Satisfaction Pivot X, et al. Cancer Res. 2013;73(24 Suppl): Abstract P4-12-11

Patients in the PrefHer study had a very strong preference for SC over IV trastuzumab, mainly because it saved them time and caused them less pain/discomfort/side effects than IV administration. Confirmed advantages of SC trastuzumab administration include: - Improved patient convenience - Reduced use of hospital resources and the time of healthcare professionals There was a high level of healthcare professional satisfaction with SC trastuzumab. The overall safety profile of 4 cycles of trastuzumab SC and 4 cycles of trastuzumab IV observed during the crossover period in the PrefHer study was consistent with the known safety profile of trastuzumabin early breast cancer. Safety data did not raise any safety concerns thus far.

SafeHer Trial Design

Patient time associated with IV and SC trastuzumab formulations Lopez-Vivanco G et al. 19th Congress of the European Association of Hospital Pharmacists. 26-28 March 2014,

Conclusions For patients receiving treatment over prolonged periods, SC administration offers significant benefits over IV administration and is considered convenient. SC formulations of trastuzumab can potentially improve convenience and quality of life for patients and provide cost savings to health-care systems. Patient preference and safety results from PrefHer, combined with efficacy, pharmacokinetic, and safety results from HannaH, suggest that a fixed dose of 600 mg trastuzumab SC every 3 weeks, for about 5 min, is a validated, well tolerated, and preferred option for the treatment of HER2-positive breast cancer