Nintedanib plus best supportive care (BSC) versus placebo plus BSC for the treatment of patients (pts) with colorectal cancer (CRC) refractory to standard therapies: Results of the phase III LUME-colon 1 study

Background

Angiogenesis is critical to CRC tumour growth and metastasis. Nintedanib (N) is a multiple angiokinase signalling pathway inhibitor (including VEGFR, PDGFR and FGFR). N demonstrated similar efficacy to bevacizumab when combined with mFOLFOX6 as 1^st-line therapy in a Phase I/II study. These findings and a manageable safety profile provided the rationale to examine N in refractory CRC. We conducted a global, randomised Phase III study (NCT02149108) to evaluate the efficacy and safety of N in pts with mCRC after failure of standard therapies.

Methods

Eligible pts (aged ≥18 years; ECOG PS 0–1; mCRC adenocarcinoma refractory to standard treatments, including oxaliplatin, irinotecan, fluoropyrimidines, anti-VEGF and anti-EGFR in RAS wt) were randomised 1:1 to receive either N (200 mg bid) + BSC or placebo (P; bid) + BSC. The co-primary endpoints were PFS by central review and OS, evaluated by log-rank test to determine the effect of N independently at the two-sided alpha level of 0.05.

Results

768 mCRC patients (37% pretreated with regorafenib) were randomised to N (n = 386) or P (n = 382). Baseline characteristics were similar between the groups. A statistically significant improvement in PFS was observed (HR [95% CI] 0.58 [0.49, 0.69]; p < 0.0001; median PFS 1.5 months with N vs 1.4 months with P), but no difference in OS (HR [95% CI]: 1.01 [0.86, 1.19]; p = 0.8659; median OS 6.4 months with N vs 6.1 months with P). Disease control by central review was 26% with N vs 11% with P (OR [95% CI]: 2.96 [2.00, 4.4]; p < 0.0001). 14% of patients in the N arm discontinued due to AEs, vs 11% with P. Serious AEs occurred in 39% vs 35% of patients in the N and P arms, respectively. The most frequent ≥Grade 3 AEs (in the N arm, by medical concept) occurring in N vs P patients were liver related investigations (16% vs 8%) and fatigue (9% vs 6%).

Conclusions

N was well tolerated and demonstrated clinical activity, with a significant increase in PFS (HR 0.58). However, improvement in PFS did not translate to an improvement in OS. Additional analyses are ongoing to further interrogate the efficacy findings.

Clinical trial identification

NCT02149108

Legal entity responsible for the study

Boehringer Ingelheim GmbH & Co. KG

Funding

Boehringer Ingelheim GmbH & Co. KG

Disclosure

E. Van Cutsem: Research funding paid to his institute from Amgen; Bayer; Boehringer Ingelheim; Lilly; Merck Serono; Novartis; Roche and Sanofi. T. Yoshino: Research funding from GlaxoSmithKline K.K. and Boehringer Ingelheim. H-J. Lenz: Honoraria and research funding from Boehringer Ingelheim. A. Falcone: Reports grants and personal fees from Amgen, Bayer, Roche, Servier, Lilly, Merck, outside the submitted work. A. Sobrero: Reports personal fees from Roche, Merck, BMS, Sanofi, Bayer, Servier, Amgen, outside the submitted work. F. Ciardiello: Advisory Board Role: Bayer, Boerhinger, Merck Serono, Roche, Lilly, AstraZeneca. Research grants: Roche, Bayer, Merck Serono. J. Hocke, Z. Oum'hamed, S. Vlassak, M. Studeny: Employee of Boehringer Ingelheim. J. Tabernero: Consulting or advisory services for Amgen; Boehringer Ingelheim, Celgene; Chugai Pharma; ImClone Systems; Lilly; Merck KGaA; Millennium Takeda; Novartis; Roche/Genentech; Sanofi and Taiho Pharmaceutical. All other authors have declared no conflicts of interest.