DOI: 10.25934/00005852
title: Infective outcomes in cancer patients treated with subcutaneous versus intravenous trastuzumab and rituximab: an individual patient data meta-analysis 

description: Background: 
Monoclonal antibodies trastuzumab and rituximab were first approved for use as intravenous formulations over two decades ago. These agents, used alone or in combination with cytotoxic chemotherapy, have radically improved survival in patients with HER-2 positive breast cancers and gastric cancers (trastuzumab) and CD20-positive B-cell leukaemias and lymphomas (rituximab). New enabling technology for subcutaneous delivery of monoclonal antibodies and use of fixed dosing schedules offer significant advantages for patient experience and health care resource utilisation.[1, 2] In recent years, drug regulatory authorities across multiple jurisdictions including the United States Food and Drug Administration (US FDA), the Australian Therapeutic Goods Administration (TGA) and the European Medicines Agency (EMA) have approved fixed dose and subcutaneous formulations of trastuzumab and rituximab following evaluation of pharmacokinetic and efficacy data showing non-inferiority to standard intravenous formulations.[3-6] 

Necessity of the research:
Although individual non-inferiority studies have reported slightly higher rates of infection amongst participants receiving subcutaneous treatment,[7] such studies were not powered to show non-inferiority for safety endpoints. It remains unclear how altered pharmacokinetics or novel excipients such as rHuPH20 in the subcutaneous formulation might contribute to infections after injection into the subcutaneous tissue. It is crucial that any safety signals be more thoroughly investigated before wide-scale adoption of this enabling technology into development of novel medicines.

How many patients/ members of the public are potentially affected: 
Findings are directly relevant to all patients treated with subcutaneous formulations of trastuzumab and rituximab, and by extension to patients treated with other subcutaneous monoclonal antibody drug formulations employing similar technologies and co-formulations with recombinant human hyaluronidase enzyme (rHuPH20). Subcutaneous monoclonal antibody drug formulations are being utilised for an increasingly larger proportion patients globally as institutes and clinicians begin to transfer from the original intravenous formulations.  

How the research will add to medical science or patient care
Findings may give confidence or appropriate pause for adoption of subcutaneous dose formulations with/without concern of adverse patient outcomes related to infection or infective complications, may inform further trial or real-world studies to monitor infective risk, or may prompt review of or confidence in excipients for subcutaneous formulations.  

How the research will be conducted:
This is an individual patient data meta-analysis. 

What design and methods you have you chosen and why:
We are seeking to conduct an individual patient data meta-analysis on the basis on safety signals from individual trials, and evidence on increased risk of serious and high-grade infections in a pooled analysis of published trial data conducted by our group (not yet published). Access to individual patient level data to characterise pertinent risk factors and pathogens involved in serious infections will provide greater certainty and validation of findings.  

References:
1.	Davies A, Berge C, Boehnke A et al. Subcutaneous Rituximab for the Treatment of B-Cell Hematologic Malignancies: A Review of the Scientific Rationale and Clinical Development. Adv Ther 2017; 34: 2210-2231.
2.	Bittner B, Richter W, Schmidt J. Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities. BioDrugs 2018; 32: 425-440.
3.	Therapuetic Goods Administration. Australian product information. Herceptin SC (trastuzumab) solution for injection. Revised 07 June 2018. Accessed 23 April 2019. Available: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2015-PI-01512-1.
4.	Food and Drug Administration. FDA Approved Drug Products. Herceptin Hylecta: Biologic Licence Application 761106. Accessed 23 April 2019. Available: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761106.
5.	Food and Drug Administration. FDA Approved Drug Products. Rituxan Hycela: Biologic Licence Application 761064. Accessed 23 April 2019. Available: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761064.
6.	Therapuetic Goods Administration. Australian product information. MabThera SC (rituximab). Revised 03 October 2018. Accessed 23 April 2019. Available: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2014-PI-01953-1.
7.	Ismael G, Hegg R, Muehlbauer S et al. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol 2012; 13: 869-878.