High- or low-dose preoperative ipilimumab plus nivolumab in stage III urothelial cancer: the phase 1B NABUCCO trial

Dorp, Jeroen van; Pipinikas, Christodoulos P.; Suelmann, Britt B. M.; Mehra, Niven; Dijk, Nick van; Marsico, Giovanni Antônio; Montfoort, Maurits L. van; Hackinger, Sophie; Braaf, Linde M.; Amarante, Tauanne; Steenis, Charlaine van; McLay, Kirsten; Daletzakis, Antonios; Broek, Daan van den; Kamp, Maaike W. van de; Hendricksen, Kees; Feijter, Jeantine M. de; Boellaard, Thierry N.; Meijer, Richard P.; Heijden, Toine G. van der; Rosenfeld, Nitzan; Jones, Greg; Heijden, Michiel S. van der

doi:10.1038/s41591-022-02199-y

Cited by 34 publications

(25 citation statements)

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“…Other ongoing studies are evaluating the safety and efficacy of combination therapy regimens involving systemic immune checkpoint blockade treatment along with chemotherapy or other targeted agents . A summary of the results reported from the neoadjuvant phase 2 studies is provided in Table 2 …”

Section: Discussion/observationsmentioning

confidence: 99%

Immunotherapy in the Treatment of Localized Genitourinary Cancers

et al. 2023

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ImportanceA true revolution in the management of advanced genitourinary cancers has occurred with the discovery and adoption of immunotherapy (IO). The therapeutic benefits of IO were recently observed not to be solely confined to patients with disseminated disease but also in select patients with localized and locally advanced genitourinary neoplasms.ObservationsKEYNOTE-057 demonstrated the benefit of pembrolizumab monotherapy for treating high-risk nonmuscle invasive bladder cancer unresponsive to bacillus Calmette-Guérin (BCG), resulting in recent US Food and Drug Administration approval. Furthermore, a current phase 3 trial (Checkmate274) demonstrated a disease-free survival benefit with the administration of adjuvant nivolumab vs placebo in muscle-invasive urothelial carcinoma after radical cystectomy. In addition, the recent highly publicized phase 3 KEYNOTE 564 trial demonstrated a recurrence-free survival benefit of adjuvant pembrolizumab in patients with high-risk localized/locally advanced kidney cancer.Conclusions and RelevanceThe adoption and integration of IO in the management of localized genitourinary cancers exhibiting aggressive phenotypes are becoming an emerging therapeutic paradigm. Clinical oncologists and scientists should become familiar with these trials and indications because they are likely to dramatically change our treatment strategies in the months and years to come.

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Section: Discussion/observationsmentioning

confidence: 99%

Immunotherapy in the Treatment of Localized Genitourinary Cancers

et al. 2023

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“…Two recent trials show that combining CTLA-4 and PD-(L)1 inhibitors is a feasible preoperative treatment in MIBC patients, with promising clinical efficacy. Ipilimumab and nivolumab was studied in the NABUCCO trial, in cisplatin-ineligible or cisplatin-refusing patients with locoregionally advanced (cT3-4aN0 or cT1-4aN1-3) urothelial carcinoma [28,29 ▪ ]. Cohort 1 studied the feasibility of the combination as preoperative treatment, with surgical resection within 12 weeks after start of neoadjuvant therapy as the primary endpoint.…”

Section: Combined Immune Checkpoint Inhibitionmentioning

confidence: 99%

Recent developments in perioperative combination therapy in muscle-invasive bladder cancer

Mellema,

van Rhijn,

van der Heijden

2023

Current Opinion in Urology

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Purpose of reviewA summary of recent literature to provide a comprehensive overview of the current state of systemic perioperative treatment combinations for muscle-invasive bladder cancer (MIBC).Recent findingsWe discuss recent developments in standard and experimental treatment modalities. The VESPER trial has shown that six cycles of neoadjuvant dose-dense MVAC are superior to four cycles of gemcitabine/cisplatin (GC), though it is unclear whether the superiority is derived from the specific regimen or number of cycles. Adjuvant cisplatin-based chemotherapy, a subject of longstanding debate, was shown to have comparable overall survival-benefit to neoadjuvant chemotherapy in an updated meta-analysis. Neoadjuvant chemotherapy and anti-PD-(L)1 show encouraging results, but with no comparative studies to standard care, context is lacking. Immunotherapeutic neoadjuvant anti-CTLA-4/PD-(L)1 combinations or combinations of checkpoint inhibitors with antibody-drug-conjugates are in early stages of development and show promising preliminary results.SummarySix cycles of neoadjuvant dose-dense MVAC are superior to four cycles of gemcitabine/cisplatin. Adjuvant cisplatin-based chemotherapy is a viable option for patients with high-risk tumours who did not receive prior neoadjuvant treatment. The added value of anti-PD-(L)1 to chemotherapy still needs to be established. Novel developments in immunotherapy combinations, while promising, are still in an early stage and randomized studies are ongoing.

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“…6 Although single-agent CTLA-4 blockade has been less effective than PD-1/PD-L1 blockade in other solid tumors, response to CTLA-4 blockade may be more dose-dependent raising uncertainties regarding the validity of the therapeutic target versus insufficient dosing in interpretation of prior literature. 7 In the only reported trial to date exploring single-agent CLTA-4 blockade in patients with metastatic urothelial cancer (n = 32), tremelimumab monotherapy (750 mg intravenous every 4 weeks) yielded an objective response rate of 19% according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 8 However, given the timing of when that study was conducted, patients had not received prior PD-1/PD-L1 blockade, which raises the question of whether these classes of immune checkpoint inhibitors are non-cross-resistant in patients with urothelial cancer.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, in castration‐resistant prostate cancer, ipilimumab has shown some promise when used as monotherapy after radiotherapy 6 . Although single‐agent CTLA‐4 blockade has been less effective than PD‐1/PD‐L1 blockade in other solid tumors, response to CTLA‐4 blockade may be more dose‐dependent raising uncertainties regarding the validity of the therapeutic target versus insufficient dosing in interpretation of prior literature 7 …”

Section: Introductionmentioning

confidence: 99%

Phase 2 trial of tremelimumab in patients with metastatic urothelial cancer previously treated with programmed death 1/programmed death ligand 1 blockade

Miller,

Rose,

Maughan

et al. 2024

Cancer

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IntroductionProgrammed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) blockade has changed the landscape of treatment for metastatic urothelial cancer, but single‐agent cytotoxic T‐lymphocyte–associated protein 4 (CTLA‐4) blockade in metastatic urothelial cancer has been underexplored. A prior phase 2 trial of tremelimumab in PD‐1/PD‐L1–blockade naive patients with metastatic urothelial cancer revealed activity comparable to that observed with PD‐1/PD‐L1 blockade raising the hypothesis that these classes of immune checkpoint inhibitors might be non‐cross‐resistant.MethodsThe current phase 2 trial treated patients with PD‐1/PD‐L1 blockade‐resistant metastatic urothelial cancer with single‐agent tremelimumab (750 mg intravenously every 28 days for up to 7 cycles). The primary end point was objective response rate.ResultsTwenty‐six patients were enrolled and 24 patients were evaluable for response. The objective response rate was 8.3%, composed of a total of two partial responses that lasted 10.9 and 24.0 months. Stable disease was observed in another 20.8% of patients, with a median duration of stable disease of 5.4 months. Diarrhea occurred in 15 patients (58%), elevated hepatic transaminases occurred in seven patients (27%), and adrenal insufficiency occurred in two patients (8%); one patient died after experiencing immune‐related hepatitis.ConclusionsHigh dose CTLA‐4 blockade in patients with PD‐1/PD‐L1–resistant metastatic urothelial cancer has modest activity and is associated with treatment‐related toxicity similar to prior reports.

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High- or low-dose preoperative ipilimumab plus nivolumab in stage III urothelial cancer: the phase 1B NABUCCO trial

Cited by 34 publications

References 16 publications

Immunotherapy in the Treatment of Localized Genitourinary Cancers

Immunotherapy in the Treatment of Localized Genitourinary Cancers

Recent developments in perioperative combination therapy in muscle-invasive bladder cancer

Phase 2 trial of tremelimumab in patients with metastatic urothelial cancer previously treated with programmed death 1/programmed death ligand 1 blockade

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