Nintedanib falls short in bladder cancer trial

In the phase II NEOBLADE* trial, the addition of the multikinase** inhibitor nintedanib to neoadjuvant chemotherapy (CT) consisting of gemcitabine and cisplatin failed to improve pathological complete response (pCR) and progression-free survival (PFS) in individuals with locally advanced muscle-invasive bladder cancer (MIBC).

Despite CT and radical treatment, MIBC is tied to high incidences of recurrence and metastatic disease, hence the need to optimize cisplatin-based CT, the researchers said. “[N]intedanib has emerged as a potential candidate with a favourable efficacy and toxicity profile, rendering it suitable for combination with neoadjuvant CT.”

“[However, our] study did not meet its primary endpoint of improvement in pCR. Therefore, cisplatin-based neoadjuvant CT remains the standard of care for the treatment of MIBC,” they continued.

A total of 120 patients (median age 68.5 years, 78 percent male, 61 percent with T2 disease) were randomized 1:1 to receive either oral nintedanib 150 mg (for patients with glomerular filtration rate [GFR] 40–60 mL/min) or 200 mg BID for 12 weeks or placebo on top of usual neoadjuvant CT***. [Lancet Oncol 2022;23:650-658]

After a median follow-up of 33.5 months, in the intention-to-treat (ITT) population, similar fractions of nintedanib and placebo recipients achieved pCR^# (37 percent vs 32 percent; odds ratio [OR] 1.25; p=0.28). This effect was mirrored in the modified ITT cohort (51 percent vs 44 percent; OR, 1.31; p=0.74) and among those who underwent cystectomy (47 percent vs 46 percent; OR, 1.00; p=0.94).

At the time of analysis, median PFS was not reached (NR) in either arm (hazard ratio [HR], 0.53; p=0.058).

The percentage of participants reporting grade ≥3 toxicities was greater in the nintedanib vs the placebo arm (93 percent vs 79 percent), with the most common being thromboembolic events (30 percent vs 21 percent) and reduced neutrophil count (39 percent vs 11 percent). While the overall venous thromboembolism rate was higher in this study compared with that seen in another trial evaluating patients with metastatic disease, these rates were not increased by VEGF^## inhibition. [J Clin Oncol 2021;39:2486-2496]

Potential OS benefit?

Though an exploratory endpoint, overall survival (OS) was numerically higher with nintedanib vs placebo across all timepoints evaluated (96 percent vs 81 percent [12 months], 89 percent vs 69 percent [24 months], and 60 percent vs 49 percent [60 months]). Median OS was NR in the nintedanib arm as opposed to 50.6 months in the placebo arm at the time of analysis (HR, 0.45; p=0.038).

“[The OS improvement] might have been driven by nintedanib rather than by choice of radical treatment,” the researchers noted. This should however be interpreted with caution as the study was not powered for this analysis.

More established endpoints better

Although the study suggested that combining nintedanib with CT may be safe for MIBC in the neoadjuvant setting, the regimen did not improve pCR and PFS was similar between arms.

Also, the primary endpoint is not validated in this setting. “With hindsight, more established endpoints such as PFS and OS would have been preferable,” the researchers pointed out. “[Moreover,] in patients opting for bladder preservation, the absence of evaluable tissue in some patients resulted in the incomplete assessment of the primary endpoint of pCR.”

“[W]e would avoid the use of pCR as primary endpoint in future novel combination neoadjuvant studies that permit radical radiotherapy and would instead focus on OS and relapse-free survival outcomes,” they said, calling for further evaluation to ascertain the OS benefit.