2024TiP - NETOS: A personalized approach of neoadjuvant therapy, including INCB099280 monotherapy and bladder preservation, for muscle-invasive urothelial bladder carcinoma (MIBC) with ctDNA monitoring

Background

MIBC is a systemic disease as >40% of patients (pts) ultimately develop recurrence after radical cystectomy (RC). There are increasing concerns by the pts related to the need to undergo RC whenever they achieve a clinical complete response (cCR) with TURBT and systemic therapy. INCB099280 is a potent, orally bioavailable, selective, small molecule that targets PD-L1 that is being developed for the treatment of advanced malignant diseases. A phase 1, dose-escalation and expansion study is ongoing in pts with select advanced solid tumors (NCT04242199; Prenen et al. ESMO-IO 2023). Our hypothesis is that INCB099280 can be offered in selected pts as an induction and maintenance therapy instead of RC in pts who achieve a cCR.

Trial design

Pts should have a predominant urotelial carcinoma (UC) histology, have a clinical stage T2-T4N0M0 MIBC, be ineligible for or refuse to receive cisplatin-based chemotherapy. The study will also select pts with a circulating tumor DNA (ctDNA)-positive test (Signatera ctDNA assay) and pts will be staged with pelvic MRI. Pts will receive 12 weeks of INCB099280 at the dose of 400 mg twice daily (BID), continuously. Pts who will achieve a cCR (i.e., no evidence of residual disease at reTURBT, clearance of ctDNA and evidence of no residual detectable disease at cross-sectional imaging) will receive additional INCB099280 400 mg BID for 12 months. Pts with evidence of high grade or infiltrating residual disease will be discontinued from the study. Those with a Ta/T1-low grade disease will be managed according to physician’s preference: they may be eligible to continue within the study protocol and receive maintenance INCB099280 400 mg BID for 12 months. The primary endpoint is the proportion of cCR and the study is planned according to A'Hern one-stage binomial design, with H0 ≤5% and H1 ≥20%, 5% one-sided Alpha, 80% power and 10% drop-out rate. The overall sample size Will be of 30 pts. Secondary endpoints will include safety (CTCAE v.5.0), event-free survival, bladder-intact overall survival (OS) and OS (EUCT number: 2024-511029-73-00).

Clinical trial identification

EUCT 2024-511029-73-00.

Editorial acknowledgement

Legal entity responsible for the study

IRCCS Ospedale San Raffaele.

Funding

Incyte.

Disclosure

A. Necchi: Financial Interests, Institutional, Research Grant: Merck, AstraZeneca, Ipsen, BMS, Gilead; Financial Interests, Personal, Steering Committee Member: Roche, Janssen, Bayer, Astellas, AstraZeneca, Merck, Clovis Oncology; Financial Interests, Coordinating PI: Incyte; Financial Interests, Local PI: Pfizer; Non-Financial Interests, Leadership Role: Global society of Rare Genitourinary Tumors (GSRGT). All other authors have declared no conflicts of interest.