EA8185: Phase 2 study of bladder-sparing chemoradiation (chemoRT) with durvalumab in clinical stage III, node-positive urothelial carcinoma (INSPIRE), an ECOG-ACRIN/NRG collaboration.
Authors: Joshi Monika , Kim Se Eun , Solanki Abhishek A , Miyamoto David Tomoaki , Degraff David , Zou Jennifer Wei , Meeks Joshua J , Mitin Timur , Collins Sean P. , Trabulsi Edouard John , Hahn Noah M. , Efstathiou Jason A. , Carducci Michael Anthony 
Published: June 2022

TPS4617 Background: Patients [pts] withlymph node positive (LN+), non-metastatic bladder cancer (BC) have a better prognosis than those with metastatic (M1) disease. However, this population is under-represented in advanced bladder trials and ineligible for bladder-sparing trials. Therefore, there have been no larger prospective trials establishing the standard of care in LN+ BC. Given the promise of immunotherapy in advanced BC and potential synergy between immunotherapy and radiation, INSPIRE was designed to determine the role of concurrent and adjuvant durvalumab (durva) in this patient population when treated with induction chemotherapy (IC) followed by concurrent chemoRT. Methods: This is a randomized phase II study that is enrolling BC pts with stage III [N1-3 M0], pure or mixed urothelial cancer. Pts must have received ≥3 cycles of IC [either before or after registration, prior to randomization] without progression. LN+ is defined as radiologically LN ≥1.0 cm in short axis, with or without biopsy prior to IC. As long as pts do not progress on induction chemotherapy, they will be randomized to chemoRT+/- durva using 5 stratification factors (Simon Pocock minimization method) a) IC prior vs. post registration b) cisplatin vs non-cisplatin regimen during RT c) LN size d) response to IC e) extent of TURBT. Pts on the chemoRT+durva arm will get chemotherapy per physician choice + IMRT + 3 x doses of Q3wk durva for 6.5-8 wks, whereas those on the control arm will get chemoRT alone. The primary end point is clinical complete response [CR], defined as no radiologically measurable disease in the LNs and negative cystoscopy and bladder biopsy 8-10 weeks post-chemoRT +/- durva. Pts on the chemoRT + durva arm who have a CR or clinical benefit ( > T0 and ≤T2 in bladder per cystoscopy, biopsy + CR/PR/SD in LN by imaging) will get adjuvant Q4wk durva for 9 doses, while those on the chemoRT arm will undergo observation. Secondary end points include OS, PFS, bladder-intact event-free survival, rate of toxicity and salvage cystectomy. This study is designed to detect an improvement of 25% in clinical CR between both arms (37.5% to 62.5%). A total accrual of 114 pts (in order to enroll 92 evaluable pts) will provide 81% power to detect this difference using a Fisher’s exact test (assuming 10% drop out + anticipating that 20% chemotherapy-naïve pts will progress post IC). We are banking blood and primary tumor tissue pre- and post-chemoRT in both groups. The study was activated in August 2020 and accrual is ongoing. We expanded eligibility to include N3 in 9/2021. INSPIRE is the first prospective study designed for only LN+ BC and will define both short-term and long-term outcomes for bladder sparing in this patient population and has the potential to define a new treatment strategy for stage III BC. Clinical trial information: NCT04216290.