RE-ARM – a multicentre phase II randomised controlled trial of radiotherapy plus atezolizumab in metastatic urothelial carcinoma – investigating the abscopal effect


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Robert Huddart1, Hannah Gribble1, Rebecca Lewis1, Solomon Brown1, Eleanor Cheadle2, Ananya Choudhury2, Simon Crabb3, Charlotte Emery1, Jo Haviland1, Timothy Illidge2, Mark Linch4, Henry Scowcroft5, Aslam Sohaib6, Isabel Syndikus7, Richard Walshaw2, Anna Wilkins1, Alan Melcher1, Emma Hall1
1Institute of Cancer Research (ICR), 2University of Manchester, 3University of Southampton, 4University College London (UCL), 5No affiliation, 6Royal Marsden NHS Foundation Trust, 7Clatterbridge Cancer Centre NHS Foundation Trust

Abstract

Background

Urothelial carcinoma is relatively common, affecting around 10,000 people in the UK each year. The PD-L1 inhibitor atezolizumab  is one of few available treatment options available for patients with metastatic urothelial carcinoma and has been demonstrated to induce durable responses in 15%-20% of patients, with late responses or disease stabilisation in around the same proportion of patients, despite initial progression.

The RE-ARM trial (CRUKE/19/009, ISRCTN12606219) will investigate whether these late responses can be boosted by the addition of palliative radiotherapy, with the aim of augmenting the immune response.

Method

RE-ARM is an adaptive 2-arm randomised group-sequential trial, seeking to include 102 patients with metastatic urothelial carcinoma receiving a minimum of 3 and maximum of 6 atezolizumab cycles as routine care, with an overall best response of stable disease. Participants will be randomised (1:1) between continuing atezolizumab alone or atezolizumab plus radiotherapy. In both groups, 1200mg intravenous atezolizumab will be given three weekly until loss of clinical benefit or unmanageable toxicity. For those receiving radiotherapy 20Gy in 5 fractions will be given to the primary site or a metastatic lesion over 1 week.

Participants will be followed up 3-weekly whilst on treatment, with CT CAP for RECIST v1.1 and iRECIST assessment every nine weeks. Serial research blood samples and routinely obtained diagnostic tissue will be collected to assess molecular and pathological changes in response to atezolizumab +/- radiotherapy.

The primary endpoint is objective response according to RECIST v1.1 nine weeks after start of study atezolizumab. Secondary endpoints include objective response according to iRECIST, toxicity, time to progression, overall survival and patient reported quality of life. Translational studies of the anti-tumour immune response will also be performed.

An interim analysis to assess response rate will be conducted when 23 patients per group have completed the nine week assessment.

The trial is due to open in summer 2021 and will be conducted at twenty NHS Trusts in the UK.

Results


Conclusion


Impact statement

Results will contribute to the international evidence base regarding the abscopal effect and should provide further treatment options for this group of patients if addition of radiotherapy to atezolizumab improves response rates.