Refining adjuvant treatment in endometrial cancer based on molecular features: the RAINBO clinical trial program

Abstract

Background: The endometrial cancer molecular classification has been integrated into the 2020 World Health Organization (WHO) diagnostic classification and European treatment guidelines, and provides direction towards more effective and less toxic adjuvant treatment strategies for women with endometrial cancer.

Primary objectives: The RAINBO program of clinical trials will investigate four molecular class-directed adjuvant treatment strategies following surgical resection to either increase cure rates through the addition of novel targeted therapies or safely reduce toxicity and improve quality of life through treatment de-escalation.

Study hypothesis: Molecular-directed adjuvant treatment strategies will improve clinical outcomes and reduce toxicity of unwarranted therapies in women with endometrial cancer. The overarching and translational research RAINBO program will advance knowledge of predictive and prognostic (bio)markers that will improve prognostication and treatment allocation.

Trial design: The RAINBO program is a platform of four international clinical trials and an overarching research program. The randomized phase III p53abn-RED trial for women with invasive stage I-III p53abn endometrial cancer compares adjuvant chemoradiation followed by olaparib for 2 years with adjuvant chemoradiation alone. The randomized phase III MMRd-GREEN trial for women with stage II (with lymphovascular space invasion (LVSI)) or stage III mismatch repair-deficient (MMRd) endometrial cancer compares adjuvant radiotherapy with concurrent and adjuvant durvalumab for 1 year to radiotherapy alone. The randomized phase III NSMP-ORANGE trial is a treatment de-escalation trial for women with estrogen receptor positive stage II (with LVSI) or stage III no specific molecular profile (NSMP) endometrial cancer comparing radiotherapy followed by progestin for 2 years to adjuvant chemoradiation. The POLEmut-BLUE trial is a phase II trial in which the safety of de-escalation of adjuvant therapy is investigated for women with stage I-III POLEmut endometrial cancer: no adjuvant therapy for lower-risk disease and no adjuvant therapy or radiotherapy alone for higher-risk disease. The overarching RAINBO program will combine data and tumor material of all participants to perform translational research and evaluate molecular class-based adjuvant therapy in terms of efficacy, toxicity, quality of life, and cost-utility.

Major inclusion/exclusion criteria: Inclusion criteria include a histologically confirmed diagnosis of endometrial cancer treated by hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy or sentinel lymph node biopsy, with no macroscopic residual disease after surgery and no distant metastases, and molecular classification according to the WHO 2020 algorithm.

Primary endpoints: Recurrence-free survival at 3 years in the p53abn-RED, MMRd-GREEN, and NSMP-ORANGE trials and pelvic recurrence at 3 years in the POLEmut-BLUE trial.

Sample size: The p53abn-RED trial will include 554 patients, the MMRd-GREEN trial 316, the NSMP-ORANGE trial 600, and the POLEmut-BLUE trial 145 (120 for lower-risk disease and approximately 25 for higher-risk disease). The overarching research program will pool the four sub-trials resulting in a total sample size of around 1600.

Estimated dates for completing accrual and presenting results: The four clinical trials will have different completion dates; main results are expected from 2028.

Trial registration number: The RAINBO program is registered at clinicaltrials.gov (NCT05255653).

Keywords: endometrial neoplasms.

Conflict of interest statement

Competing interests: J Alexandre reports grants paid to his institution by MSD and Janssen; consulting fees to him by MSD, AstraZeneca, GSK, Eisai, and Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events to him by MSD, AstraZeneca, GSK, Clovis, and Novartis; support for attending meetings and/or travel to him by AstraZeneca and Novartis. SM de Boer reports a research grant paid to her institution by Varian Medical Systems. T Bosse reports research project funding by the Dutch Cancer Society (KWF). DN Church has participated in an advisory board for MSD and has received research funding from HalioDx (on behalf of the TransSCOT consortium). CL Creutzberg reports research grants from the Dutch Cancer Society (KWF) for the conduct of the PORTEC trials and the RAINBO program. JL Ethier reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events by Merck, GSK and AstraZeneca and participation in these companies’ Advisory Boards. JS Frenel reports having personally received consulting fees and support for attending meetings and/or travel by Pfizer, Lilly, Novartis, AstraZeneca, Clovis Oncology, GSK, Gilead, Daiichi Sankyo, and Seagan. Payment or honoraria were personally received for lectures, presentations, speaker bureaus, manuscript writing or educational events from Lilly, Novartis, AstraZeneca, Gilead, Daiichi Sankyo, and Seagen. C Gordon reports being a member of the Canadian Cancer Clinical Trials Group as member of the Patients’ Representatives Committee on a volunteer basis. K Han reports research grants from the Canadian Institutes of Health Research Project Grant and Princess Margaret Hospital Foundation, participating on the Astra Zeneca Cervical Cancer Radiation Oncology Advisory Board (October 2021), and being Endometrial Cancer Working Group Co-Chair of the Canadian Cancer Trials Group. N Horeweg reports research grants paid to her institution from the Dutch Cancer Society (KWF) and an unrestricted research grant by Varian for the RAINBO program and other unrelated research projects. VH Koelzer is principal investigator in a public-private partnership with Roche unrelated to the topic of this manuscript, received research funding from the Image Analysis Group unrelated to the topic of this manuscript, served as an invited speaker on behalf of Indica Labs, and is participant of a patent application co-owned by the Netherlands Cancer Institute (NKI-AVL) and the University of Basel on the assessment of cancer immunotherapy biomarkers by digital pathology. JR Kroep reports having received study drugs and an unrestricted research grant from AstraZeneca for the conduct of the MMRd-GREEN trial, as well as a research grants from the Dutch Cancer Society and WCRF. Consulting fees were paid to the researcher’s institution by AstraZeneca, MSD, GSK, Novartis and Eisai, as well as payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events by MSD and GSK. Participation on a Data Safety Monitoring Board or Advisory Board without payment for the TEIPP trial and the ALISON trial were reported. J McGrane reports having received consulting fees for participation in advisory boards of GSK, MSD and Ipsen and honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events, and for attending meetings and/or travel. A Taylor reports participation in the advisory board of MSD.

© IGCS and ESGO 2022. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.

Figures

Figure 1

Design of the RAINBO program. ER, estrogen receptor status; LVSI, lymphovascular space invasion; MMRd, mismatch repair deficient; NSMP, no specific molecular profile; p53abn, p53 abnormal; POLEmut, DNA polymerase-ε mutated; R, randomization; RAINBO, Refining Adjuvant treatment IN endometrial cancer Based On molecular features.

Figure 2

RAINBO Consortium structure. MMRd, mismatch repair deficient; NSMP, no specific molecular profile; p53abn, p53 abnormal; POLEmut, DNA polymerase-ε mutated; RAINBO, Refining Adjuvant treatment IN endometrial cancer Based On molecular features.

Figure 3

Inclusion algorithm of the RAINBO program. Assessment of the molecular classification must be performed according to the World Health Organization 2020 classification of endometrial cancer. 1POLE status is assessed by DNA sequencing of the POLE gene and at least the five most common (but preferably all) 11 variants as described by Léon-Castillo et al which are considered pathogenic. 2MMR deficiency is assessed by IHC and is defined by loss of one or more of the four MMR proteins (MLH1, PMS2, MSH2 and MSH6). 3 p53 status is assessed by IHC and three abnormal patterns are defined: mutant overexpression, null pattern, and cytoplasmatic expression. DNA sequencing of the entire TP53 gene to detect pathogenic variants is an accepted alternative. 4ER status is assessed by IHC and is considered positive if expression is observed in >10% of the tumor tissue. ER, estrogen receptor; IHC, immunohistochemistry; MMRd, mismatch repair deficient; p53abn, p53 abnormal; POLEmut, DNA polymerase-ε mutant; RAINBO, Refining Adjuvant treatment IN endometrial cancer Based On molecular features.

Figure 4

Sample size of the RAINBO clinical trials and overarching research program. CRT, chemoradiotherapy; ER, estrogen receptor; HT, hormonal therapy; LVSI, lymphovascular space invasion; MI, myometrial invasion; RAINBO, Refining Adjuvant treatment IN endometrial cancer Based On molecular features; RT, radiotherapy; Tx, therapy; tox, toxicity; QoL, quality of life. *Data on POLEmut-BLUE trial participants will be pooled in Group A or B depending on tumor characteristics and received adjuvant treatment strategy.