PMID- 35933242 OWN - NLM STAT- MEDLINE DCOM- 20221018 LR - 20221130 IS - 1873-7560 (Electronic) IS - 0302-2838 (Linking) VI - 82 IP - 5 DP - 2022 Nov TI - Phase 1 Study of Chemoradiotherapy Combined with Nivolumab +/- Ipilimumab for the Curative Treatment of Muscle-invasive Bladder Cancer. PG - 518-526 LID - S0302-2838(22)02522-2 [pii] LID - 10.1016/j.eururo.2022.07.009 [doi] 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 x 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. CI - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved. FAU - de Ruiter, Ben-Max AU - de Ruiter BM AD - Department of Urology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Cancer Center Amsterdam, Amsterdam, The Netherlands. FAU - van Hattum, Jons W AU - van Hattum JW AD - Department of Urology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Cancer Center Amsterdam, Amsterdam, The Netherlands. FAU - Lipman, Djoeri AU - Lipman D AD - Department of Radiation Oncology, Isala Hospital Zwolle, Zwolle, The Netherlands. FAU - de Reijke, Theo M AU - de Reijke TM AD - Department of Urology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Cancer Center Amsterdam, Amsterdam, The Netherlands. FAU - van Moorselaar, R Jeroen A AU - van Moorselaar RJA AD - Cancer Center Amsterdam, Amsterdam, The Netherlands; Department of Radiotherapy, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. FAU - van Gennep, Erik J AU - van Gennep EJ AD - Department of Urology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands. FAU - Maartje Piet, A H AU - Maartje Piet AH AD - Cancer Center Amsterdam, Amsterdam, The Netherlands; Department of Radiotherapy, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. FAU - Donker, Mila AU - Donker M AD - Department of Radiotherapy, Leiden University Medical Center, Leiden University, Leiden, The Netherlands. FAU - van der Hulle, Tom AU - van der Hulle T AD - Department of Medical Oncology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands. FAU - Voortman, Jens AU - Voortman J AD - Cancer Center Amsterdam, Amsterdam, The Netherlands; Department of Medical Oncology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. FAU - Oddens, Jorg R AU - Oddens JR AD - Department of Urology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Cancer Center Amsterdam, Amsterdam, The Netherlands. FAU - Hulshof, Maarten C C M AU - Hulshof MCCM AD - Cancer Center Amsterdam, Amsterdam, The Netherlands; Department of Radiotherapy, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands. FAU - Bins, Adriaan D AU - Bins AD AD - Cancer Center Amsterdam, Amsterdam, The Netherlands; Department of Medical Oncology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands. Electronic address: a.d.bins@amsterdamumc.nl. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20220803 PL - Switzerland TA - Eur Urol JT - European urology JID - 7512719 RN - 0 (Biomarkers) RN - 0 (Immune Checkpoint Inhibitors) RN - 0 (Ipilimumab) RN - 31YO63LBSN (Nivolumab) RN - 50SG953SK6 (Mitomycin) RN - 6804DJ8Z9U (Capecitabine) SB - IM CIN - Eur Urol. 2022 Nov;82(5):527-528. PMID: 36064477 MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects MH - Biomarkers MH - Capecitabine MH - Chemoradiotherapy/adverse effects MH - Humans MH - Immune Checkpoint Inhibitors/adverse effects MH - Ipilimumab/adverse effects MH - Mitomycin MH - Muscles MH - *Nivolumab/adverse effects MH - *Urinary Bladder Neoplasms/therapy OTO - NOTNLM OT - Bladder cancer OT - Bladder-sparing treatment OT - Chemoradiotherapy OT - Immune checkpoint inhibition EDAT- 2022/08/07 06:00 MHDA- 2022/10/19 06:00 CRDT- 2022/08/06 22:04 PHST- 2022/02/25 00:00 [received] PHST- 2022/06/12 00:00 [revised] PHST- 2022/07/14 00:00 [accepted] PHST- 2022/08/07 06:00 [pubmed] PHST- 2022/10/19 06:00 [medline] PHST- 2022/08/06 22:04 [entrez] AID - S0302-2838(22)02522-2 [pii] AID - 10.1016/j.eururo.2022.07.009 [doi] PST - ppublish SO - Eur Urol. 2022 Nov;82(5):518-526. doi: 10.1016/j.eururo.2022.07.009. Epub 2022 Aug 3.