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Nintedanib improves PFS, not OS, in refractory, metastatic colorectal cancer
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COPENHAGEN, Denmark — The addition of nintedanib to best supportive care appeared safe and significantly extended PFS in patients with metastatic colorectal cancer that is refractory to standard therapies, according to results of the phase 3 LUME-colon 1 study presented at the European Society for Medical Oncology Congress.
However, this improvement in PFS did not translate into longer OS.
Angiogenesis plays a key role in colorectal tumor growth and metastasis. Nintedanib (Ofev, Boehringer Ingelheim) — a multiple angiokinase signaling pathway inhibitor — demonstrated similar efficacy as bevacizumab (Avastin, Genentech) when combined with mFOLFOX6 for first-line therapy in a phase 1/phase 2 study.
“In metastatic colorectal cancer, there are still a lot of patients in good condition after failing the treatment options, and there is an unmet need for these patients,” Eric Van Cutsem, MD, PhD, professor of internal medicine at University of Leuven in Belgium, said during his presentation.
Vat Cutsem and colleagues evaluated the safety and efficacy of nintedanib in 768 patients with metastatic colorectal cancer who failed standard treatments, including oxaliplatin, irinotecan, fluoropyrimidines, and anti-VEGF and anti-EGFR therapies. Further, 37% of patients had been pretreated with regorafenib (Stivarga, Bayer Healthcare).
The time from onset of metastatic disease until study randomization was 24 months or longer in most patients (nintedanib, 72%; placebo, 71.2%).
Researchers stratified patients according to previous treatment with regorafenib, time from onset of metastatic disease until randomization (< 24 months vs. 24 months) and disease region.
Patients were randomly assigned 1:1 to receive best supportive care plus placebo (n = 382; median age, 62 years) or 200 mg nintedanib twice daily (n = 386, median age, 62 years).
PFS and OS served as co-primary endpoints. OS was planned after 611 events, with a 90% power to detect a HR of 0.77. PFS was planned after 595 events, with a 95% power to detect a HR of 0.75.
Treatment with nintedanib conferred a statistically significant improvement in PFS (HR = 0.58; 95% CI, 0.49-0.69) by central review.
Factors associated with improved PFS included less than 24 months since development of metastatic disease (P = .019) and having only one metastatic site (P = .005).
However, OS was comparable between the groups (median OS, 6.4 months vs. 6.1 months; HR = 1.01; 95% CI, 0.86-1.19).
Results of a central review showed patients treated with nintedanib achieved better disease control (26% vs. 11%; OR = 2.96; 95% CI, 2-4.4). No patient in either arm achieved an objective response.
Slightly fewer patients assigned nintedanib went on to receive subsequent anticancer therapy (35.8% vs. 39.8%), and median time on subsequent therapy was shorter in the nintedanib cohort (83 days vs. 94 days).
Van Cutsem and colleagues conducted post-hoc analyses to show the effect of subsequent therapies on OS. Results showed that when patients were censored at the start of a subsequent therapy, the HR for OS with nintedanib was 0.79 (95% CI, 0.65-0.96).
Fourteen patients assigned nintedanib discontinued due to adverse events compared with 11% of patients assigned placebo. Serious adverse events occurred in more patients assigned nintedanib (39% vs. 35%). Common grade 3 or worse adverse events included liver-related investigations (16% vs. 8%) and fatigue (9% vs. 6%).
“Because PFS and OS were co-primary endpoints, this study was negative,” Van Cutsem said. “Investigations to fully understand the impact of nintedanib on OS are ongoing. The lack of OS improvement with nintedanib may be linked to the effect of post-study therapies. We are looking for further data and are doing additional analyses on biomarkers and quality-of-life data that will be presented later on.” – by Alexandra Todak
Reference:
Van Cutsem E, et al. Abstract LBA20_PR. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.
Disclosure: Boehringer Ingelheim funded this study. Van Cutsem reports research funding from Amgen, Bayer, Boehringer Ingelheim, Lilly, Merck, Novartis, Roche and Sanofi. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
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Volker Heinemann, MD, PhD
Nintedanib showed activity in refractory, metastatic colorectal cancer with regard to PFS, but failed to improve OS in the intent-to-treat population. In my view, this discrepancy remains essentially unexplained. The frequency of post-study therapies was comparable in this study to previous studies [of trifluridine and tipiraciland (Lonsurf, Taiho Oncology) and regorafenib (Stivarga, Bayer Healthcare)].
The characteristics of nonresponders — almost 50% —should be analyzed to optimize selection criteria in future trials.
Analysis of molecular parameters is key to define predictors of clinical benefit, but I stress that we need to have pre-study biopsies to really come to conclusions.
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