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Addition of nintedanib or placebo to neoadjuvant gemcitabine and cisplatin in locally advanced muscle-invasive bladder cancer (NEOBLADE): a double-blind, randomised, phase 2 trial

  • Syed A Hussain,
  • Jason F Lester,
  • Richard Jackson,
  • Matthew Gornall,
  • Muneeb Qureshi,
  • Anthony Elliott,
  • Simon J Crabb,
  • Robert A Huddart,
  • Naveen Vasudev,
  • Alison J Birtle,
  • Jane Worlding,
  • Nicholas D James,
  • Omi Parikh,
  • Maria Vilarino-Varela,
  • Roberto Alonzi,
  • Mark D Linch,
  • Irbaz B Riaz,
  • James W F Catto,
  • Thomas Powles,
  • Robert J Jones


Recurrence is common after neoadjuvant chemotherapy and radical treatment for muscle-invasive bladder cancer. We investigated the effect of adding nintedanib to neoadjuvant chemotherapy on response and survival in muscle-invasive bladder cancer.


NEOBLADE was a parallel-arm, double-blind, randomised, placebo-controlled, phase 2 trial of neoadjuvant gemcitabine and cisplatin chemotherapy with nintedanib or placebo in locally advanced muscle-invasive bladder cancer. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0–1, were recruited from 15 hospitals in the UK. Patients were randomly assigned (1:1) to nintedanib or placebo using permuted blocks with random block sizes of two or four, stratified by centre and glomerular filtration rate. Treatments were allocated using an interactive web-based system, and patients and investigators were masked to treatment allocation throughout the study. Patients received oral nintedanib (150 mg or 200 mg twice daily for 12 weeks) or placebo, in addition to usual neoadjuvant chemotherapy with intravenous gemcitabine 1000 mg/m2 on days 1 and 8 and intravenous cisplatin 70 mg/m2 on day 1 of a 3-weekly cycle. The primary endpoint was pathological complete response rate, assessed at cystectomy or at day 8 of cyclde 3 (plus or minus 7 days) if cystectomy did not occur. Primary analyses were done in the intention-to-treat population. The trial is registered with EudraCT, 2012-004895-01, and ISRCTN, 56349930, and has completed planned recruitment.


Between Dec 4, 2014, and Sept 3, 2018, 120 patients were recruited and were randomly allocated to receive nintedanib (n=57) or placebo (n=63). The median follow-up for the study was 33·5 months (IQR 14·0–44·0). Pathological complete response in the intention-to-treat population was reached in 21 (37%) of 57 patients in the nintedanib group and 20 (32%) of 63 in the placebo group (odds ratio [OR] 1·25, 70% CI 0·84–1·87; p=0·28). Grade 3 or worse toxicities were observed in 53 (93%) of 57 participants who received nintedanib and 50 (79%) of 63 patients in the placebo group (OR 1·65, 95% CI 0·74–3·65; p=0·24). The most common grade 3 or worse adverse events were thromboembolic events (17 [30%] of 57 patients in the nintedanib group vs 13 [21%] of 63 patients in the placebo group [OR 1·63, 95% CI 0·71–3·76; p=0·29]) and decreased neutrophil count (22 [39%] in the nintedanib group vs seven [11%] in the placebo group [5·03, 1·95–13·00; p=0·0006]). 45 treatment-related serious adverse events occurred in the nintedanib group and 43 occurred in the placebo group. One treatment-related death occurred in the placebo group, which was due to myocardial infarction.


The addition of nintedanib to chemotherapy was safe but did not improve the rate of pathological complete response in muscle-invasive bladder cancer.


Boehringer Ingelheim.

by Dr. Laura Mertens

For muscle-invasive bladder cancer (MIBC), neoadjuvant cisplatin-based chemotherapy, before radical cystectomy, leads to a 5-year overall survival (OS) benefit of 5-8%. Nevertheless, MIBC has high likeliness of recurrence and metastases. For this reason, improving neoadjuvant systemic therapies for MIBC is a priority. 

Hussain and colleagues reported the NEOBLADE study, a double-blind, randomised, placebo-controlled phase 2 trial, in which standard-of-care neoadjuvant chemotherapy (four cycles of gemcitabine-cisplatin + placebo) is compared with an “intensified” scheme, with the addition of a multikinase inhibitor, nintedanib (oral, 150-200 mg twice daily for 12 weeks). The primary end point of the study was pathological complete response (pCR) at radical cystectomy or (in case of organ preservation) at cystoscopy, transurethral resection and CT (performed after three courses), in an intention-to-treat analysis. The study was designed to detect an absolute increase in pCR of 20%.

A total of 120 patients with locally advanced (cT2-4N0M0) urothelial carcinoma of the bladder was included and randomly assigned in 15 UK hospitals during approximately four years. Fifty-seven patients received nintedanib versus 63 placebo. Interestingly, patients with a GFR higher than 60 mL/min as well as GFR 40-60 mL/min were included in the study; the latter receiving split-dose cisplatin and nintedanib 150 mg. Both patients and investigators remained masked for the treatment allocation.  After neoadjuvant chemotherapy, radical cystectomy (including pelvic lymph node dissection) as well as organ-preservation treatments were permitted as consolidating therapy. 

Ultimately, 102 of 120 patients (85%) received potentially curative treatment (86% in the nintedanib group vs 84% in the placebo group); in a total of 86 patients, tissue was available for pathological evaluation. Two points in baseline data have to underlined: 1) the relatively low clinical disease stage (61% cT2) and 2) that in the nintedanib arm, organ preservation was relatively more common (47% vs. 32% placebo).

Regarding the primary end point: the pCR rate in intention-to-treat analysis (n=120) was 37% in the nintedanib group vs 20% in the placebo group (OR: 1.25, 70% confidence interval (CI) 0.84 – 1.87, P=0.28). When taking into account only the 86 patients in whom tissue was available, pCR rates were also not statistically significantly different (nintedanib: 51% vs placebo: 44% (OR: 1.31, 70% CI 0.84 – 2.06, P=0.74)).

The secondary end point of this study was progression free survival (PFS). Median follow up was 33.5 months. In both (intention-to-treat) groups, median PFS was not reached. Two-year PFS in the nintedanib group was 79% (95% CI, 60 – 90) vs 57% (95 CI, 43 – 71) in the placebo group. A post-hoc analysis of overall survival (OS) showed a survival benefit for adding nintedanib (median OS in the placebo group: 50.6 months (95% CI, 33.5 – not reached) vs was not reached in the nintedanib group (HR: 0.45, 95% CI, 0.21 – 0.98, P=0.038)). However, the study was not powered for this end point, so this result should be interpreted with caution. Regarding toxicity, grade III or more toxicity was reported in 92% of patients in the nintedanib group vs 79% in the placebo group (OR: 1.65, 95% CI, 0.74 – 3.65, P=0.24).

All in all, within the context of this double-blind placebo-controlled  trial, the addition of nintedanib to neoadjuvant gemcitabine-cisplatin, did not meet its primary end point; a significant improvement in pCR. Secondly, no significant improvement in PFS was observed. Therefore, cisplatin-based neoadjuvant chemotherapy remains the standard-of-care for the treatment of MIBC. In a broader sense, the NEOBLADE study adds to the debate about optimal end points for neoadjuvant trials, particularly in view of (the emerging tendency) for organ preservation for MIBC.