O-141 Combination of gefitinib and methotrexate to treat tubal ectopic pregnancy (GEM3): a multicentre, randomised, double-blind, placebo-controlled trial

Abstract

Abstract Study question Is a combination of parenteral methotrexate and oral gefitinib more effective than methotrexate alone in the treatment of tubal ectopic pregnancy? Summary answer In women with a tubal ectopic pregnancy, adding oral gefitinib to parental methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions. What is known already Current treatment of tubal ectopic pregnancies is with methotrexate or surgery. Methotrexate treatment fails in ∼30% of women and they require rescue surgery. At the time of the design of the trial, it had been shown in preclinical studies that tubal implantation sites express high levels of epidermal growth factor receptor (EGFR) and that gefitinib (an EGFR antagonist) augments methotrexate-induced regression of pregnancy-like tissue. There was also evidence from uncontrolled phase I and II trials that raised the possibility that combination methotrexate and gefitinib could be a more effective medical treatment than methotrexate alone to treat stable ectopic pregnancies. Study design, size, duration Between 2nd November 2016 and 6th October 2021, we performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Eligible participants were women with a tubal ectopic pregnancy deemed suitable for medical management with methotrexate. Inclusion criteria were: aged 18-50 years; pre-treatment serum hCG level of 1000–5000 IU/L; and either a definite diagnosis of tubal ectopic pregnancy or a clinical judgement of ‘probable’ tubal ectopic pregnancy. Participants/materials, setting, methods Participants were administered a single dose of intramuscular methotrexate (50 mg/m2) and randomised (1:1 ratio) to seven days of additional oral gefitinib (250mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. Main results and the role of chance 328 participants were allocated to methotrexate and gefitinib (n = 165) or methotrexate and placebo (n = 163). Three participants in the placebo group withdrew. Surgical intervention occurred in 30% (50/165) of the gefitinib group and in 29% (47/160) of the placebo group (adjusted risk ratio 1.15, 95% confidence interval [CI] 0.85-1.58; adjusted risk difference -0.01, 95% CI -0.10-0.09; p = 0.37). Without surgical intervention, median time to resolution was 28.0 days in the gefitinib group and 28.0 days in the placebo group (subdistribution hazard ratio 1.03, 95% CI 0.75-1.40). Serious adverse events occurred in 3% (5/165) of the gefitinib group and in 4% (6/162) of the placebo group. Diarrhoea and rash were more common in the gefitinib group. Limitations, reasons for caution Limitations of the trial include the fact that we only tested one dose regimen. It is possible gefitinib may be effective if a different protocol were used, such as a longer period of administration. Also, we did not carry out pharmacodynamic studies to determine optimal drug bioavailability. Wider implications of the findings Our results show that the addition of gefitinib to standard medical management with methotrexate to treat tubal ectopic pregnancy is not clinically effective as it does not reduce subsequent surgical intervention and is associated with higher rates of reported symptoms than placebo. Trial registration number ISRCTN67795930