ESMO 2016 Press Release: Nintedanib Improves Progression-free Survival but not Overall Survival in Phase III Trial of Metastatic Colorectal Cancer

LUGANO-COPENHAGEN – Nintedanib improves progression-free survival but not overall survival in patients with metastatic colorectal cancer who are not responding to standard therapies, according to results of the phase III LUME-colon 1 trial presented at the ESMO 2016 Congress in Copenhagen.

“Colorectal cancer is a frequent disease and a large proportion of patients have metastases,” said lead author Professor Eric Van Cutsem, head of Clinical Digestive Oncology at University Hospitals Leuven, Belgium. “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.”

Nintedanib is a multiple tyrosine kinase inhibitor with anti-angiogenic activity. LUME-colon 1 was the first phase III trial of nintedanib in patients with metastatic colorectal cancer refractory to all available treatments including chemotherapy and biological therapies. Patients had to be in good general condition (defined as performance status 0 and 1) and have good organ function.

The trial included 768 patients who were randomised 1:1 to nintedanib or placebo. All patients received best supportive care. The co-primary endpoints were progression-free survival and overall survival.

Nintedanib significantly improved median progression-free survival compared to placebo (1.5 vs 1.4 months, hazard ratio 0.58, 95% confidence interval [CI] 0.49–0.69, p<0.0001). There was no difference in overall survival between the two groups.

Disease control was improved with nintedanib compared to placebo (26% vs 11%, odds ratio 2.96, 95% CI 2.00–4.4, p<0.0001). Serious adverse events occurred in 39% of patients taking nintedanib and 35% on placebo. Some 14% of patients in the nintedanib group discontinued treatment due to adverse events, compared to 11% in the placebo group.

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

“The reason why patients on placebo survived longer than expected is not completely clear, but treatments taken after the trial that stopped their tumour from growing may have contributed to this finding,” continued Van Cutsem. “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.”

He concluded: “We are conducting additional analyses in molecular markers and subtypes of colorectal cancer to see if there is a group of patients who benefit from nintedanib after other therapies have failed.”

Commenting on the findings, Dr. Dirk Arnold, Instituto CUF de Oncologia, Lisbon, Portugal, said: “Having another of those large trials in this specific setting clearly indicates the unmet need. 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,” continued Arnold. “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.”

“The disparity could be because more patients who progressed in the LUME-colon 1 trial received salvage treaments than in the earlier trials,” he added. “The relatively long overall survival also of patients with placebo in the current trial supports this hypothesis. 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.”

Arnold concluded: “More data is needed to explain the findings and understand how strong the benefit of nintedanib really is.”

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Notes to Editors

References

Abstract LBA20_PR ‘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‘ will be presented by Professor Eric Van Cutsem during the Proffered Paper Session, Gastrointestinal tumours, colorectal 1 on Sunday, 9 October 2016, 14:45 to 16:15 (CEST) in Room Vienna.

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Abstract for LBA20_PR 

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

E. Van Cutsem1, T. Yoshino2, H-J. Lenz3, S. Lonardi4, A. Falcone5, M.L. Limon6, M.P. Saunders7, A. Sobrero8, E. Maiello9, Y.S. Park10, R. Ferreiro Monteagudo11, Y.S. Hong12, J. Tomasek13, H. Taniguchi14, F. Ciardiello15, J. Hocke16, Z. Oum’hamed17, S. Vlassak18, M. Studeny19, J. Tabernero20

1Digestive Oncology, University Hospitals Leuven - Campus Gasthuisberg, Leuven, Belgium, 2Department of GI Oncology, National Cancer Center Hospital East, Kashiwa, Japan, 3Department of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA, 4Oncologia Medica 1, Istituto Oncologico Veneto IRCCS, Padua, Italy, 5Oncologia Medica, Azienda Ospedaliera Universitaria S.Chiara, Pisa, Italy, 6Medical Oncology, Hospital Universitario Virgen del Rocio, Seville, Spain, 7Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK, 8Department of Medical Oncology, Ospedale S. Martino, Genoa, Italy, 9Onco-Hematology, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy, 10Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 11Medical Oncology, Hospital Universitario Ramon y Cajal, Madrid, Spain, 12Department of oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, 13Medical Communications, InVentiv Health, London, UK, 14Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan, 15Medical Oncology, AOU Seconda Università degli Studi di Napoli (AOU-SUN), Naples, Italy, 16Statistics, Boehringer Ingelheim Pharma GmbH & Co. KG, Tübingen, Germany, 17Clinical Trials, Boehringer Ingelheim B.V. France S.A.S, Reims, France, 18Medical Affairs, SCS Boehringer Ingelheim Comm. V., Brussels, Belgium, 19Division of Medicine/Clinical Development Department, Boehringer Ingelheim, Vienna, Austria, 20Oncologia Médica, Vall d`Hebron University Hospital Institut d'Oncologia, Barcelona, Spain

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 1st-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.

Keywords: angiogenesis inhibition, NINTEDANIB, colorectal cancer