Angiogenesis Inhibitor Has Modest Effect on Progression-Free Survival in Metastatic Colorectal Cancer

November 2016, Vol 7, No 10

Copenhagen, Denmark—Patients with previously treated metastatic colorectal cancer (mCRC) had a small but significant improvement in progression-free survival (PFS) but no overall survival (OS) benefit after receiving the multikinase inhibitor nintedanib (Ofev), according to results from the LUME-Colon 1 clinical trial reported by principal investigator Eric Van Cutsem, MD, Clinical Digestive Oncology, University Hospitals Leuven, Belgium, at the 2016 European Society for Medical Oncology Congress.

The median PFS was 1.5 months with nintedanib versus 1.4 months with placebo. The median OS was 6.4 months with nintedanib versus 6.1 months with placebo. More than twice as many patients who received nintedanib achieved disease control versus patients who received placebo.

Dr Van Cutsem put this modest improvement in PFS into perspective for the broad population of patients with mCRC.

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

The phase 3 LUME-Colon 1 clinical trial, which involved nearly 800 patients with mCRC, reflected the large unmet need for more effective therapy for mCRC. However, Dirk Arnold, MD, Instituto CUF de Oncologia, Lisbon, Portugal, found the outcome underwhelming, especially in light of recent results attained with other agents.

“Having another of those large trials in this specific setting clearly indicates the unmet need. Nintedanib shows good tolerability, but the efficacy results are somewhat disappointing,” said Dr Arnold.

“Nintedanib delays disease progression and increases the rate of stable disease, but these gains are lost when it comes to overall survival,” he added. “This is in contrast to regorafenib [Stivarga] and trifluridine/tipiracil [Lonsurf], both of which showed increases in progression-free survival and overall survival in this line of treatment.”

Study Details

Angiogenesis plays a major role in the progression of CRC. Nintedanib targets multiple tyrosine kinases involved in tumor angiogenesis and associated signaling pathways. A preliminary clinical trial of nintedanib as an add-on therapy to chemotherapy in the front-line setting demonstrated efficacy comparable to bevacizumab (Avastin), said Dr Van Cutsem, which provided the rationale for this study.

Investigators enrolled patients who had received multiple lines of therapy and had disease refractory to standard treatment, anti-VEGF agents, and anti-­EGFR agents. More than one-third (37%) of patients were pretreated with regorafenib. Patients were randomized to nintedanib plus best supportive care or to placebo plus best supportive care.

The co-primary end points were PFS (as evaluated by a central review committee) and OS.

The median PFS was 1.5 months in the nintedanib group versus 1.4 months in the placebo group (P <.0001). No significant difference in survival was found between the 2 groups.

The disease control rate, a secondary end point, was 26% with nintedanib versus 11% with placebo (P <.0001).

Serious adverse events occurred in 39% of patients in the nintedanib group and in 35% of patients in the placebo group. Adverse events led to the discontinuation of therapy in 14% of patients in the nintedanib group and in 11% of patients in the placebo group.

Noting the favorable early findings with nintedanib, Dr Arnold said that more data and analyses are needed to determine “how strong the benefit of nintedanib really is.” Differences in the clinical trial design, patient populations, and a relatively long survival in the placebo arm of the clinical trial may explain differences in outcomes with nintedanib versus regorafenib and trifluridine/tipiracil in similar patients. Alternatively, “it could be that nintedanib simply doesn’t work well enough,” said Dr Arnold.

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