Gefitinib and methotrexate to resolve tubal ectopic pregnancy: the GEM3 RCT

Abstract

Background Tubal ectopic pregnancies can cause significant morbidity or even death. Current treatment is with methotrexate or surgery. However, methotrexate treatment can fail in approximately 30% of women. Gefitinib, an epidermal growth factor receptor inhibitor, may improve the effects of methotrexate. We assessed the efficacy of administering oral gefitinib with methotrexate, versus methotrexate alone, to treat a tubal ectopic pregnancy. Objectives To test the hypothesis a combination of gefitinib with methotrexate can increase resolution of stable tubal ectopic pregnancy without the need for surgery, compared with methotrexate alone. Design A randomised, double-blind, placebo-controlled, multicentre, superiority trial. Setting Fifty UK hospitals. Participants A target of 328 women with a stable, tubal ectopic pregnancy. Intervention Women were randomised to combination of methotrexate and gefitinib or methotrexate and placebo. All participants received a single intramuscular dose of methotrexate 50 mg/m2 and were randomised in a 1:1 ratio of oral gefitinib (250 mg daily for 7 days) or placebo. Main outcome measures The primary outcome was surgical intervention for resolution of ectopic pregnancy. Secondary outcomes were the need for an additional dose of methotrexate, time to resolution of the ectopic pregnancy, number of treatment-associated hospital visits, safety and tolerability, acceptability of treatment and return to menses. Results Between 2 November 2016 and 6 October 2021, 328 women were randomly allocated to methotrexate and gefitinib (n = 165) or methotrexate and placebo (n = 163). Three women 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 0.85 to 1.58; adjusted risk difference −0.01, 95% confidence interval −0.10 to 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% confidence interval 0.75 to 1.40). The need for additional methotrexate doses, number of additional hospital visits, participant acceptability, time to return of menses and serious adverse events were similar in both groups. Diarrhoea and rash were more common in the gefitinib group. Conclusions 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. Limitations We were unable to investigate how different gefitinib doses or modes of delivery would impact on the results. Future work Questions that remain unaddressed relate to the use of methotrexate and gefitinib combination treatment for other extrauterine and uterine ectopic pregnancy, such as caesarean scar pregnancies, or in the management of choriocarcinoma. Trial registration This trial is registered as ISRCTN 67795930 and EudraCT 2015-005013-76. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme and will be published in full in Efficacy and Mechanistic Evaluation; Vol. 10, No. 1. The gefitinib and placebo were supplied by Astra Zeneca. See the NIHR Journals Library website for further project information.