RAINBO NSMP-ORANGE - Refining Adjuvant treatment IN endometrial cancer Based On molecular features (RAINBO) No Specific Molecular Profile (NSMP)-ORANGE trial

Research summary

BACKGROUND Endometrial cancer is the most common gynaecological cancer. The cornerstone of treatment is surgery with adjuvant therapy for women at increased risk of recurrence based on clinico-pathological features. This is imprecise and clinicians and patients must balance the risks of poor survival outcomes with treatment-related toxicity. A new molecular classification system identifies four groups with different prognostic profiles: p53-abnormal (p53abn),POLE-mutant (POLEmut),mismatch repair-deficient (MMRd) and no specific molecular profile (NSMP). The PORTEC-3 trial showed that adjuvant chemoradiotherapy is beneficial for high-risk endometrial cancer patients overall but when stratified by molecular group,only p53abn tumours showed a clear benefit,POLEmut and MMRd tumours showed no benefit,and the benefit for NSMP tumours was uncertain. AIMS NSMP-ORANGE aims to investigate whether adjuvant radiotherapy with maintenance progestin tablets is as effective as chemoradiotherapy,whilst reducing toxicity and thus improving quality of life,in patients with high-risk NSMP endometrial cancer. METHODS NSMP-ORANGE is an international,multicentre,randomised phase III non-inferiority trial coordinated by the UCL & CRUK Cancer Trials Centre. Molecular profiling will use immunohistochemistry (p53,MMR and estrogen receptor (ER) expression) and POLE next generation sequencing on diagnostic biopsies. Eligible women will have completely resected stage II with substantial lymphovascular space invasion or stage III ER+ NSMP tumours. Participants will be randomised 1:1 to chemoradiotherapy (standard care) or radiotherapy followed by 2 years of oral progestin. Follow up will record survival events,toxicity and quality of life in a uniform manner to enable pooling for the overarching RAINBO programme. Assuming a 3-year recurrence-free survival (RFS) rate of 82.5%,a non-inferiority margin of 7.5% will exclude a RFS rate below 75%. 600 patients,recruited over 5 years with 3 years of additional follow-up,are required to observe 153 events,for 80% power at the one-sided 5% significance level after allowing for 5% dropout. Approximately 300 UK patients will be recruited from 25-30 participating centres and 300 from international sites (funded separately),including the Netherlands,France and Canada,who are leading the MMRd-GREEN,p53abn-RED and POLEmut-BLUE RAINBO trials respectively. Clinically-annotated tumour blocks will be prospectively collected and biobanked in Leiden for trial-specific and overarching translational research programmes. TIMELINES One year to set up and obtain approvals; five years to recruit; three years follow up; and one year to analyse and publish our findings. NSMP-ORANGE will take 10 years to complete.

Principal Investigator

Dr Sally Trent

Contact us

Email: latephaseoncology@ouh.nhs.uk

IRAS number

1007892