Nintedanib plus neoadjuvant chemotherapy did not achieve improvement in pathologic complete response in patients with muscle invasive bladder cancer in the phase 2 NEOBLADE study, but the study provided important survival signals.
Adding nintedanib (Ofev) to chemotherapy for the treatment of patients with muscle-invasive bladder cancer did not improve the rate of pathological complete response (pCR), but appeared safe, according to results from the NEOBLADE study (EudraCT, 2012-004895-01).
“Nintedanib is a multikinase inhibitor of the receptor tyrosine kinases PDGF-R, FGFR-1, and VEGFR-2. To our knowledge, this is the first randomized trial to show that intensification of neoadjuvant chemotherapy with the addition of multikinase inhibitors can be safely delivered. The trial did not meet its primary endpoint of pathological complete response,” wrote the study authors led by Syed A. Hussain, MD of NewYork-Presbyterian Medical Group Queens-Fresh Meadows.
For MIBC, neoadjuvant cisplatin-based chemotherapy is the standard-of-care treatment. Although neoadjuvant cisplatin is effective for MIBC with a 5-year overall survival (OS) benefit of 5% along with a 14% reduction in the risk of death, MIBC has a high likeliness of recurrence and metastasis.
With nintedanib, an orally available, potent, small molecule inhibitor with the ability to target the PDGFR, FGFR-1, and VEGFR-2 tyrosine kinases. The agent has demonstrated efficacy and safety in lung cancer, and due to the similarities between lung cancer and bladder cancer like smoking history in the patients and high tumor mutational burden, investigators of NEOBLADE hypothesized that nintedanib would be beneficial for patients with MIBC.
NEOBLADE, parallel-arm, double-blind, randomized, placebo-controlled, phase 2 trial. In the study, oral nintedanib was administered at 150 mg or 200 mg twice daily for 12 weeks in combination with neoadjuvant chemotherapy consisting of gemcitabine 1000 mg/m2 on days 1 and 8 plus IV cisplatin 70 mg/m2 on day 1 of a 3-weekly cycle. In the comparator arm, patients are treated with matching placebo and neoadjuvant chemotherapy.
The primary end point of the study was assessed at the time of cystectomy on day 8 of cycle 3-weekly cycle. The initial hypothesis was that the pCR would be 35% in the control arm with a 20% absolute increase in pCR with the addition of nintedanib in the experimental arm. The study was 78% powered to detect the result with an odds ratio (OR) of 2.27.
Overall, 196 were screened for the study, and 102 were randomly assigned to either treatment arm. The nintedanib arm included 57 patients and the placebo arm included 63. All randomized patients were included in the intention-to-treat population. Baseline characteristics showed that the cohort was largely male including 74% of the nintedanib arm and 83% of the placebo arm. In terms of disease characteristics, patients in the nintedanib arm had a glomerular filtration rate, mL/min of 84.0 (range, 69.0-103.0) compared with 89.0 (range, 73.0-75.0) in the placebo arm. Serum creatinine, μmol/L was 78.0 (range,70.0-89.0) in the nintedanib group vs 82.0 (71.0-102.0) in the placebo arm.
Most patients in both treatment arms had an ECOG performance score of 0 at baseline. Histologic T stage was T2 for 61% of the nintedanib group vs 60% of the placebo group. The least observed histologic T stage in the study was T4, which was only observed in 45 of the nintedanib arm vs 3% of the placebo arm. Most tumors were either poorly differentiated of moderately differentiated at baseline, and most patients were previous smokers.
At a median follow-up of 33.5 months (interquartile range, 14.0-44.0) the pCR was 37% in the ITT patients in the nintedanib arm compared with 32% in the placebo arm (OR, 1.25; 70% CI 0.84-1.87; P =0.28).
In a post-hoc analysis of NEOBLADE, investigators evaluated progression-free survival (PFS) and overall survival (OS), but there was no official evidence of non-proportionality for either outcome. The post-hoc 12-month landmark PFS rate was 82% (95% CI, 71%-92%) with nintedanib vs 71% (95% CI, 58%-83%) with placebo. At 24 months, the post-hoc landmark PFS was 68% (95% CI, 52%-84%) in the nintedanib group compared with 52% (95% CI, 37%-66%) in the placebo arm. The median PFS was not reached in either arm.
In terms of OS, an exploratory post-hoc outcome, the 12-month OS rate was 81% (95% CI, 70%-92%) with nintedanib vs 89% (95% CI, 80-98) in the placebo arm. At 24 months, the OS rate was 60% (95% CI, 30%-89%) in the nintedanib arm compared with 49% (95% CI, 30-68) with placebo. Median OS in the nintedanib group was not reached (95% CI, 54.5 to not reached [NR]) vs 50.6 months (95% CI, 33.5 to not reached) in the placebo group (HR, 0.35; 95% CI 0.13-0.89; P =0.028).
Safety was assessed in the primary analysis. Grade 3 or higher adverse events (AEs) were seen in 93% of the nintedanib arm vs 79% of the placebo arm. The most common grade 3 or higher AEs in the nintedanib vs the placebo arms were thromboembolic events (30% vs 21%) and decreased neutrophil count (39% vs 11%). Serious AEs occurred in 45 patients who were treated with nintedanib vs 43 who received placebo. One patient in the study died due to treatment-related myocardial infarction.
Based on nintedanib’s failure to achieve improvement in pCR among patients with MIBC, cisplatin-based neoadjuvant chemotherapy remains the standard of care for the treatment of this patient population, according to Hussain et al. However, based on the exploratory post-hoc OS findings, further study of neoadjuvant nintedanib in MIBC is warranted with OS as a key end point.
Hussain SA, Lester JF, Jackson T, et al. 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. Lancet Oncol. 2022;23(5):650-658. doi: 10.1016/S1470-2045(22)00158-9