Phase I study of afatinib combined with nintedanib in patients with advanced solid tumours

Rastislav Bahleda, Antoine Hollebecque, Andrea Varga, Anas Gazzah, Christophe Massard, Eric Deutsch, Nadia Amellal, Françoise Farace, Mahmoud Ould-Kaci, Flavien Roux, Kristell Marzin, Jean-Charles Soria, Rastislav Bahleda, Antoine Hollebecque, Andrea Varga, Anas Gazzah, Christophe Massard, Eric Deutsch, Nadia Amellal, Françoise Farace, Mahmoud Ould-Kaci, Flavien Roux, Kristell Marzin, Jean-Charles Soria

Abstract

Background: This Phase I study evaluated continuous- and intermittent-dosing (every other week) of afatinib plus nintedanib in patients with advanced solid tumours.

Methods: In the dose-escalation phase (n=45), maximum tolerated doses (MTDs) were determined for continuous/intermittent afatinib 10, 20, 30 or 40 mg once daily plus continuous nintedanib 150 or 200 mg twice daily. Secondary objectives included safety and efficacy. Clinical activity of continuous afatinib plus nintedanib at the MTD was further evaluated in an expansion phase (n=25).

Results: The most frequent dose-limiting toxicities were diarrhoea (11%) and transaminase elevations (7%). Maximum tolerated doses were afatinib 30 mg continuously plus nintedanib 150 mg, and afatinib 40 mg intermittently plus nintedanib 150 mg. Treatment-related adverse events (mostly Grade⩽3) included diarrhoea (98%), asthenia (64%), nausea (62%) and vomiting (60%). In the dose-escalation phase, two patients had partial responses (PRs) and 27 (60%) had stable disease (SD). In the expansion phase, one complete response and three PRs were observed (all non-small cell lung cancer), with SD in 13 (52%) patients. No pharmacokinetic interactions were observed.

Conclusions: MTDs of continuous or intermittent afatinib plus nintedanib demonstrated a manageable safety profile with proactive management of diarrhoea. Antitumour activity was observed in patients with solid tumours.

Trial registration: ClinicalTrials.gov NCT00998296.

Conflict of interest statement

MO-K, FR and KM are employees of Boehringer Ingelheim. J-CS has received research funding and compensation for advisory board participation from Boehringer Ingelheim. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Partial response (−58% change in tumour lesionsa) in a patient with squamous cell carcinoma of the epiglottis receiving intermittent afatinib 40 mg QD plus continuous 150 mg nintedanib BID.aChange in measurement from 34.26 mm (16 July 2010) to 14.46 mm (5 October 2010). Abbreviations: BID= twice daily; QD= once daily.
Figure 2
Figure 2
Per cent change from baseline and best overall response in the dose-escalation phasea (A) and expansion phase (B). aIncludes both target and non-target lesions, and the occurrence of new lesions. Abbreviation: NSCLC=non-small cell lung cancer.

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