Phase II randomized placebo-controlled neoadjuvant trial of nintedanib or placebo with gemcitabine and cisplatin in locally advanced muscle invasive bladder cancer (NEO-BLADE).

Abstract

438 Background: Neo-adjuvant chemotherapy Improves overall survival in patients with MIBC. Nintedanib is an orally available, potent, small molecule, triple kinase inhibitor with the potential to further benefit patient prognosis. Methods: NEO-BLADE was designed as a randomised, placebo controlled phase II study (n=120) to compare the addition of nintedanib (N) (150mg/200mg BD) to a combination of Gemcitabine (G) and Cisplatin (C). The study was powered (80%, alpha=15% [one sided]) to detect an improvement in the histological complete response rate of 20% (OR = 2.37). Results: 120 patients were recruited from 15 sites between 04/Dec/2014 and 03/Sep/2018 (22% Female) with 109 patients evaluable. Complete response (CR) rates ( by ITT) were 22/57 (38.6%) and 25/63 (39.7%) for patients treated with/without N. Pathological CR on ITT was 21/57 (36.8%) and 20/63 (31.74%); For pathological evaluable patients it was 21/41 (51. 22% ) and 20/45 ( 44.44%) respectively. Patients treated with N showed a benefit in terms of PFS and OS with 12 month PFS rates of 89.0% and 74.1% in the Nintedanib and Placebo group respectively. P= 0.038 and HR (CI) 0.479 (0.236, 0.976). OS at 12/24 months N 96.26%/ 88.87% while in Placebo group 82.83%,/69.36%. P=0.022, HR (CI) 0.389 (0.168, 0.902). Toxicity was reported in terms of grade 3 adverse events [12/63 (19%) Placebo, 23/57 (40%) N] and Serious Adverse Events [35/63 (56%) Placebo, 34/57 (53%) N]. In terms of thromboembolic events, this was observed in 16/57 (28%) of patients treated with N and 13/63 (21%) without N (P=0.461). Conclusions: The study failed to reach its primary endpoint in demonstrating an improvement in pathological response rate between N and Placebo when given alongside G and C. The trial met its secondary end point in improvement of progression free survival and over all survival at 12 months and 24 months. Safety data from this placebo -controlled study confirms triplets can be given safely. There are efficacy signals with improvement in PFS and OS and the regimen warrants further investigation in randomised phase III trial. Translational studies to assess bio markers of response are planned. Clinical trial information: 11977.

Bladder cancer: shedding light on the most promising investigational drugs in clinical trials

“…The promising results in early chemoimmunotherapy trials have led to three phase 3 trials testing Nivolumab (ENERGIZE; NCT03661320), Durvalumab (NIAGARA; NCT03732677) Pembrolizumab (KEYNOTE-866; NCT03924856) in cisplatin eligible and one trial testing Pembrolizumab (KEYNOTE-905; NCT03924895) in cisplatin ineligible patients respectively. Similarly, adding Nintedanib, a triple receptor tyrosine kinase inhibitor targeting VEGFR 1-3, FGFR 1-3, and PDGFR α and β to GC showed that while there was no significant difference in pathologic responses, both 12-months and 24-months PFS and OS were significantly improved with addition of angiogenesis inhibition [30].…”

Current Management of Localized Muscle-Invasive Bladder Cancer: A Consensus Guideline from the Genitourinary Medical Oncologists of Canada

“…Combination strategies with targeted therapies are also being investigated. Phase II results have been reported from durvalumab plus olaparib (NEO-DURVARIB trial) and nintedanib, a tyrosine kinase inhibitor, plus GC (NEO-BLADE trial), with pCR rates 50% and 37% respectively [275,276]. The NEO-BLADE trial also reported improved OS over GC alone with HR 0.38, p = 0.018.…”