Nintedanib Produces Opposing Survival Results in Colorectal Cancer

In a phase 3 trial, nintedanib improved progression-free survival in metastatic colorectal cancer patients, but did not improve overall survival.

The LUME-colon 1 study was the first phase 3 trial of nintedanib in patients suffering from metastatic colorectal cancer who are refractory to all available treatments, including chemotherapy and biological therapies.

“Colorectal cancer is a frequent disease and a large proportion of patients have metastases,” said lead study author Eric Van Cutsem. “Many patients progress to several different lines of treatment and then stop responding. There is a need to find new therapies for this big group of patients.”

For the trial, researchers enrolled 768 patients randomized 1:1 to receive nintedanib or placebo, and all patients received best supportive care. To be eligible for the study, participants had to be in good general condition, defined as performance status 0 and 1, and have a good organ function.

The co-primary endpoints were progression-free survival and overall survival. The results of the study showed that nintedanib significantly improved median progression-free survival compared with placebo (1.5 versus 1.4 months, HR: 0.58, 95% CI 0.49-0.69, p<0.0001).

No difference in overall survival was seen between the 2 groups. Compared with placebo (11%), disease control was improved with nintedanib (26%).

Serious adverse events occurred in 39% of patients in the nintedanib arm, and 35% in the placebo arm. Fourteen percent of patients in the nintedanib group discontinued treatment due to adverse events, compared with 11% in the placebo group.

“Nintedanib was well tolerated and gave a significant increase in progression-free survival which means that tumors stopped growing more frequently inpatients taking the drug,” Van Cutsem said. “But patients receiving nintedanib did not live longer, which was disappointing.”

Although it remains unclear precisely why patients in the placebo arm survived longer than expected, researchers believe that treatments taken after the trial that stopped their tumor from growing may have contributed to the findings.

“After the trial finished, patients were followed until death and these subsequent treatments may have diluted the effect of nintedanib, leading to a loss in potential survival benefit,” Van Cutsem said.

He noted that more research is currently being done in molecular markers and subtypes of colorectal cancer to see who may benefit from nintedanib after all other therapies have failed.

“Having another of those large trials in this specific setting clearly indicates the unmet need,” said researcher Dirk Arnold. “Nintedanib shows good tolerability but the efficacy results are somehow disappointing. Nintedanib delays disease progression and increases the rate of stable disease but these gains are lost when it comes to overall survival. This is in contrast to regorafenib and trifluridine/tipiracil which both showed increases in both progression-free survival and overall survival in this line of treatment.”

Arnold believes this disparity may be because more patients who progressed in the LUME-colon 1 trial received salvage treatments than in the earlier trials.

“The relatively long overall survival also of patient with placebo in the current trial supports this hypothesis,” Arnold said. “Also by contrast to the other trials, quite a lot of patients already underwent treatment for this late-line situation before. Another possibility could be that nintedanib simply doesn’t work well enough, since both regorafenib and trifluridine/tipiracil also had somewhat larger effects on progression-free survival.”

The authors noted that more research needs to be done to explain the findings and understand how strong the benefit of nintedanib actually is.