Lead Investigator: Marliese Alexander, Peter MacCallum Cancer Centre
Title of Proposal Research: Infective outcomes in cancer patients treated with subcutaneous versus intravenous trastuzumab and rituximab: an individual patient data meta-analysis
Vivli Data Request: 5852
Funding Source: None
Potential Conflicts of Interest: None
Summary of the Proposed Research:
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. 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.
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.
Statistical Analysis Plan:
Measures of treatment effect: Relative risk (RR) Unit of analysis: Individual patient data
Statistical analysis: The proportion of patients with infection among subcutaneous patients, the proportion of patients with VTE among intravenous patients, and the relative risk for the difference between subcutaneous and intravenous patients along with 95% confidence intervals (CI) will be estimated from a logistic regression model with a random effect for study.
Planned adjustment: Age, sex, weight/BSA, stage, chemotherapy regimen, cycles of trastuzumab/rituximab
Meta-analysis methods: The random effects model was selected as the most accurate statistical method due to variation in cohort size and number of events as well as clinical heterogeneity. The fixed effects model, giving each study equal weighting, was considered inappropriate however results will be reported for the purpose of sensitivity analysis.
Power: From six identified studies, we will include 3049 patients including 1965 rituximab and 1084 trastuzumab. *If seventh study not currently on CSDR (NCT00930514) is able to be included, this will increase to 3330 overall, 2246 rituximab and 1084 trastuzumab
Overall: Given expected 10-20% incidence grade 3-5 infective adverse event with intravenous rituximab or trastuzumab, to detect increase to 15-25% with subcutaneous drug formulation, for 5% type 1 error rate and 80% power, we require 1368-2230 patients.
Rituximab: Given expected 15-20% incidence grade 3-5 infective adverse event with intravenous rituximab, to detect increase to 20-25% with subcutaneous drug formulation, for 5% type 1 error rate and 80% power, we require 1788-2230 patients (Kelsey method).
Trastuzumab: Given expected 5-10% incidence grade 3-5 infective adverse event with intravenous trastuzumab, to detect increase to 10-15% with subcutaneous drug formulation, for 5% type 1 error rate and 80% power, we require 874-1368 patients (Kelsey method).
Sensitivity analyses: Fixed-effects model (c.f random effects primary analysis), exclusion of studies using cross-over study design (potential residual effects of prior treatment arm).
Subgroup analyses: Monoclonal antibody (trastuzumab or rituximab), prior or concomitant immunosuppressive therapy (trastuzumab/rituximab alone and trastuzumab/rituximab in combination with other chemotherapeutic agents), cancer diagnosis.
Missing data: Patients with missing data will be excluded from the relevant analysis.
Requested Studies:
A Two-Stage Phase III, International, Multi-Center, Randomized, Controlled, Open-Label Study to Investigate the Pharmacokinetics, Efficacy and Safety of Rituximab SC in Combination With CHOP or CVP Versus Rituximab IV in Combination With CHOP or CVP in Patients With Previously Untreated Follicular Lymphoma Followed by Maintenance Treatment With Either Rituximab SC or Rituximab IV
Sponsor: Roche
Sponsor ID: BO22334
NCT ID: NCT01200758
An Adaptive, Comparative, Randomized, Parallel-group, Multi Center, Phase Ib Study of Subcutaneous (SC) Rituximab Versus Intravenous (IV) Rituximab Both in Combination With Chemotherapy (Fludarabine and Cyclophosphamide), in Patients With Previously Untreated CLL
Sponsor: Roche
Sponsor ID: BO25341
NCT ID: NCT01292603
A Comparative, Randomized, Parallel-group, Multi-center, Phase IIIB Study to Investigate the Efficacy of Subcutaneous (SC) Rituximab Versus Intravenous (IV) Rituximab Both in Combination With CHOP (R-CHOP) in Previously Untreated Patients With CD20-positive Diffuse Large B-cell Lymphoma (DLBCL)
Sponsor: Roche
Sponsor ID: MO28107
NCT ID: NCT01649856
A Randomized, Open-label, Mutli-centre Study to Evaluate Patient Preference With Subcutaneous Administration of Rituximab Versus Intravenous Rituximab in Previously Untreated Patients With CD20+ Diffuse Large B-cell Lymphoma or CD20+ Follicular Non-Hodgkin’s Lymphoma Grades 1, 2, OR 3A
Sponsor: Roche
Sponsor ID: MO28457
NCT ID: NCT01724021
A Phase III, Randomized Open-Label Study to Compare the Pharmacokinetics, Efficacy, and Safety of Subcutaneous (SC) Trastuzumab With Intravenous (IV) Trastuzumab Administered in Women With HER2-Positive Early Breast Cancer (EBC)
Sponsor: Roche
Sponsor ID: BO22227
NCT ID: NCT00950300
A Randomized, Multi-Center Cross-Over Study to Evaluate Patient Preference and Health Care Professional (HCP) Satisfaction With Subcutaneous (SC) Administration of Trastuzumab in HER2-Positive Early Breast Cancer (EBC) (PrefHER)
Sponsor: Roche
Sponsor ID: MO22982
NCT ID: NCT01401166
Public Disclosures:
Alexander M, Jachno K, Phillips KA, Seymour JF, Slavin MA, Cheung A, Shen V, Maarouf D, Wolfe R, Lingaratnam S. Infective complications in cancer patients treated with subcutaneous versus intravenous trastuzumab and rituximab: An individual patient data meta-analysis. Journal of Oncology Pharmacy Practice. 2023 Jun 16. doi: 10.1177/10781552231180875