Phase II Study of Bladder-SparIng ChemoradiatioN with MEDI4736 (Durvalumab) in Clinical Stage III, Node PosItive BladdeR CancEr (INSPIRE)

EA8185 represents a joint scientific collaboration between the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and NRG Oncology, with ECOG-ACRIN as the lead group for trial conduct.

By Monika Joshi, MD, MRCP

@MonikaJoshimd

Patients with lymph node positive (LN+), non-metastatic bladder cancer have a better prognosis than those with metastatic disease. However, this patient population has historically been underrepresented in advanced bladder cancer trials and has been ineligible for bladder-sparing trials. Therefore, there are few data defining the optimal way to treat patients with this condition, and consequently there is no standard-of-care treatment.

At the same time, emerging data show this patient population can effectively and safely be treated with chemoradiotherapy (chemoRT) to the pelvis. Given the promise of immunotherapy in metastatic bladder cancer and potential synergy between immunotherapy and radiation, The INSPIRE trial (EA8185) is designed to determine the role of concurrent and adjuvant durvalumab (durva) in this patient population when treated with induction chemotherapy followed by concurrent chemoRT.

This randomized phase II study is enrolling localized bladder cancer patients with stage III (any T, N1-2, M0), pure or mixed urothelial cancer. Patients must have received ≥3 cycles of induction chemotherapy without progression (either before or after registration, prior to randomization).

The four choices of induction chemotherapy include gemcitabine and cisplatin, gemcitabine and carboplatin, gemcitabine, or MVAC chemotherapy. LN+ is defined as radiologic evidence of lymph nodes ≥1.0 cm in short axis, with or without biopsy prior to starting induction chemotherapy.

After completion of induction chemotherapy, patients will be randomized to chemoRT+/- durva using the Simon Pocock minimization method and five stratification factors: induction chemotherapy prior vs. post registration, cisplatin vs. non-cisplatin radiosensitizing regimen, LN size, response to induction chemotherapy, and extent of TURBT (transurethral resection of bladder tumor).

Patients on the chemoRT+durva arm will get radiosensitizing chemotherapy per physician choice with intensity-modulated radiotherapy along with three doses of durva every three weeks for 6.5-8 weeks. Those on the control arm will get chemoRT alone. Patients on the chemoRT+durva arm who have a CR or clinical benefit (defined as ≤T2 in bladder per cystoscopy and biopsy as well as CR/PR/SD in LN by imaging) will get adjuvant durva every 4 weeks for nine doses, while those on the chemoRT arm will undergo observation. Radiosensitizing therapy choices include twice weekly gemcitabine, weekly cisplatin, or 5-FU/mitomycin C.

The primary endpoint is clinical complete response (cCR), defined as no radiologically measurable disease in the LNs and negative cystoscopy and bladder biopsy 8-10 weeks post-chemoRT. Secondary endpoints include overall survival, progression-free survival, bladder-intact event-free survival, rate of toxicity, and salvage cystectomy. A total accrual of 114 patients is needed for the study to meet its primary objective.

Blood and primary tumor tissue pre- and post-chemoRT will be banked in both groups. The study was activated in August 2020 and accrual is ongoing.

INSPIRE is the first prospective study for only LN+ bladder cancer patients. It will define both the short-term and long-term outcomes with bladder-sparing chemoRT and chemoradioimmunotherapy in this patient population, and has the potential to define a new standard treatment strategy for patients with LN+ bladder cancer.

Learn about the INSPIRE trial at ecog-acrin.org

Dr. Joshi (Penn State) is the lead investigator for this trial.