TY - JOUR
T1 - Phase 1 Study of Chemoradiotherapy Combined with Nivolumab ± Ipilimumab for the Curative Treatment of Muscle-invasive Bladder Cancer
AU - de Ruiter, Ben Max
AU - van Hattum, Jons W.
AU - Lipman, Djoeri
AU - de Reijke, Theo M.
AU - van Moorselaar, R. Jeroen A.
AU - van Gennep, Erik J.
AU - Maartje Piet, A. H.
AU - Donker, Mila
AU - van der Hulle, Tom
AU - Voortman, Jens
AU - Oddens, Jorg R.
AU - Hulshof, Maarten C.C.M.
AU - Bins, Adriaan D.
N1 - Funding Information: Funding/Support and role of the sponsor: The work of Ben-Max de Ruiter and Jons W. van Hattum is funded by the Cure for Cancer Foundation. Ben-Max de Ruiter is cofunded by the Dutch Cancer Society. Funding Information: Financial disclosures: Ben-Max de Ruiter certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Adriaan D. Bins received a research grant from the Dutch Cancer Society (13144/2020-1). Publisher Copyright: © 2022 The Authors
PY - 2022/11
Y1 - 2022/11
N2 - Background: Muscle-invasive bladder cancer (MIBC) has a poor prognosis. Chemoradiotherapy (CRT) in selected patients has comparable results to radical cystectomy. Results of neoadjuvant immune checkpoint inhibitors (ICIs) before radical cystectomy are promising. We hypothesize that ICI concurrent to CRT (iCRT) is safe and may improve treatment outcomes. Objective: To determine the safety of iCRT for MIBC. Design, setting, and participants: This multicenter, phase 1b, open-label, dose-escalation study determined the safety of CRT with three ICI regimens in patients with nonmetastatic (T2-4aN0-1) MIBC. Twenty-six patients received mitomycin C/capecitabine and 20 × 2.75 Gy to the bladder. Tolerability was evaluated in a cohort of up to ten patients. If two or fewer out of the first six patients or three or fewer of ten patients experienced dose-limiting toxicity (DLT), accrual continued in the next cohort. Intervention: Patients received nivolumab 480 mg (NIVO480), nivolumab 3 mg/kg and ipilimumab 1 mg/kg (NIVO3 + IPI1), or nivolumab 1 mg/kg and ipilimumab 3 mg/kg (IPI3 + NIVO1). Outcome measurements and statistical analysis: The primary endpoint was safety. Secondary objectives were response rate, disease-free survival, metastatic-free survival (MFS), and overall survival (OS). Results and limitations: In the NIVO480 cohort, no patients experienced DLT. The NIVO3 + IPI1 2 patients experienced DLT, thrombocytopenia (grade 4), and asystole (grade 5). IPI3 + NIVO1 was discontinued after three out of six patients experienced DLT. Clinically significant adverse events (AEs) of grade ≥3 occurred in zero, three, and five patients in the NIVO480, NIVO3 + IPI1, and IPI3 + NIVO1 groups, respectively. The most common AEs were immune related and gastrointestinal. MFS and OS were 90% at 2 yr for NIVO480 and 90% at 1 yr for NIVO3 + IPI1. Limitations include the absence of a centralized pathology and radiology review, and a lack of biomarker analysis. Conclusions: In this dose-finding study of iCRT, the regimens of nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg have acceptable toxicity. Patient summary: We tested the safety of a new bladder-sparing treatment modality for muscle-invasive bladder cancer patients, combining immune checkpoint inhibitors simultaneously with chemoradiotherapy. We report that two regimens, nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg, are safe and can be used in phase 3 trials.
AB - Background: Muscle-invasive bladder cancer (MIBC) has a poor prognosis. Chemoradiotherapy (CRT) in selected patients has comparable results to radical cystectomy. Results of neoadjuvant immune checkpoint inhibitors (ICIs) before radical cystectomy are promising. We hypothesize that ICI concurrent to CRT (iCRT) is safe and may improve treatment outcomes. Objective: To determine the safety of iCRT for MIBC. Design, setting, and participants: This multicenter, phase 1b, open-label, dose-escalation study determined the safety of CRT with three ICI regimens in patients with nonmetastatic (T2-4aN0-1) MIBC. Twenty-six patients received mitomycin C/capecitabine and 20 × 2.75 Gy to the bladder. Tolerability was evaluated in a cohort of up to ten patients. If two or fewer out of the first six patients or three or fewer of ten patients experienced dose-limiting toxicity (DLT), accrual continued in the next cohort. Intervention: Patients received nivolumab 480 mg (NIVO480), nivolumab 3 mg/kg and ipilimumab 1 mg/kg (NIVO3 + IPI1), or nivolumab 1 mg/kg and ipilimumab 3 mg/kg (IPI3 + NIVO1). Outcome measurements and statistical analysis: The primary endpoint was safety. Secondary objectives were response rate, disease-free survival, metastatic-free survival (MFS), and overall survival (OS). Results and limitations: In the NIVO480 cohort, no patients experienced DLT. The NIVO3 + IPI1 2 patients experienced DLT, thrombocytopenia (grade 4), and asystole (grade 5). IPI3 + NIVO1 was discontinued after three out of six patients experienced DLT. Clinically significant adverse events (AEs) of grade ≥3 occurred in zero, three, and five patients in the NIVO480, NIVO3 + IPI1, and IPI3 + NIVO1 groups, respectively. The most common AEs were immune related and gastrointestinal. MFS and OS were 90% at 2 yr for NIVO480 and 90% at 1 yr for NIVO3 + IPI1. Limitations include the absence of a centralized pathology and radiology review, and a lack of biomarker analysis. Conclusions: In this dose-finding study of iCRT, the regimens of nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg have acceptable toxicity. Patient summary: We tested the safety of a new bladder-sparing treatment modality for muscle-invasive bladder cancer patients, combining immune checkpoint inhibitors simultaneously with chemoradiotherapy. We report that two regimens, nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg, are safe and can be used in phase 3 trials.
KW - Bladder cancer
KW - Bladder-sparing treatment
KW - Chemoradiotherapy
KW - Immune checkpoint inhibition
UR - http://www.scopus.com/inward/record.url?scp=85135592795&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.eururo.2022.07.009
DO - https://doi.org/10.1016/j.eururo.2022.07.009
M3 - Article
C2 - 35933242
SN - 0302-2838
VL - 82
SP - 518
EP - 526
JO - European Urology
JF - European Urology
IS - 5
ER -