Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study

E Van Cutsem, T Yoshino, H J Lenz, S Lonardi, A Falcone, M L Limón, M Saunders, A Sobrero, Y S Park, R Ferreiro, Y S Hong, J Tomasek, H Taniguchi, F Ciardiello, J Stoehr, Z Oum'Hamed, S Vlassak, M Studeny, G Argiles, E Van Cutsem, T Yoshino, H J Lenz, S Lonardi, A Falcone, M L Limón, M Saunders, A Sobrero, Y S Park, R Ferreiro, Y S Hong, J Tomasek, H Taniguchi, F Ciardiello, J Stoehr, Z Oum'Hamed, S Vlassak, M Studeny, G Argiles

Abstract

Background: Angiogenesis is critical to colorectal cancer (CRC) growth and metastasis. Phase I/II studies have demonstrated the efficacy of nintedanib, a triple angiokinase inhibitor, in patients with metastatic CRC. This global, randomized, phase III study investigated the efficacy and safety of nintedanib in patients with refractory CRC after failure of standard therapies.

Patients and methods: Eligible patients (Eastern Cooperative Oncology Group performance status 0-1, with histologically/cytologically confirmed metastatic/locally advanced CRC adenocarcinoma unamenable to surgery and/or radiotherapy) were randomized 1 : 1 to receive nintedanib (200 mg twice daily) or placebo (twice daily), until disease progression or undue toxicity. Patients were stratified by previous regorafenib, time from onset of metastatic disease to randomization, and region. Co-primary end points were overall survival (OS) and progression-free survival (PFS) by central review. Secondary end points included objective tumor response and disease control by central review.

Results: From October 2014 to January 2016, 768 patients were randomized; 765 were treated (nintedanib n = 384; placebo n = 381). Median follow-up was 13.4 months (interquartile range 11.1-15.7). OS was not improved [median OS 6.4 months with nintedanib versus 6.0 months with placebo; hazard ratio (HR), 1.01; 95% confidence interval (CI), 0.86-1.19; P = 0.8659]. There was a significant but modest increase in PFS with nintedanib versus placebo (median PFS 1.5 versus 1.4 months, respectively; HR 0.58; 95% CI 0.49-0.69; P < 0.0001). There were no complete or partial responses. Adverse events (AEs) occurred in 97% of 384 nintedanib-treated patients and 93% of 381 placebo-treated patients. The most frequent grade ≥3 AEs were liver-related AEs (nintedanib 16%; placebo 8%) and fatigue (nintedanib 9%; placebo 6%).

Conclusions: The study failed to meet both co-primary end points. Nintedanib did not improve OS and was associated with a significant but modest increase in PFS versus placebo. Nintedanib was well tolerated.

Clinicaltrials.gov number: NCT02149108 (LUME-Colon 1).

Figures

Figure 1.
Figure 1.
Patient disposition. Three patients were randomized but not treated in the study, two patients (placebo n =1; nintedanib n=1) due to worsening of underlying disease and one (nintedanib) due to noncompliance with the study protocol. AE, adverse event; PD, progressive disease; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2.
Figure 2.
Overall survival. (A) Kaplan–Meier curves for intention-to-treat population. (B) Subgroup analyses (forest plot). CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; OS, overall survival. *Exploratory analysis.
Figure 2.
Figure 2.
Overall survival. (A) Kaplan–Meier curves for intention-to-treat population. (B) Subgroup analyses (forest plot). CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; OS, overall survival. *Exploratory analysis.
Figure 3.
Figure 3.
PFS by central review. (A) Kaplan–Meier curves for intention-to-treat population. (B) Subgroup analyses (forest plot). CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; PFS, progression-free survival. *Exploratory analysis.
Figure 3.
Figure 3.
PFS by central review. (A) Kaplan–Meier curves for intention-to-treat population. (B) Subgroup analyses (forest plot). CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; PFS, progression-free survival. *Exploratory analysis.

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