Last updated on November 2016

Afatinib and Selumetinib in Advanced KRAS Mutant and PIK3CA Wildtype Colorectal Non-small Cell Lung and Pancreatic Cancer


Brief description of study

This is a multi-center open-label proof-of-concept study consisting of two parts: PART A - a phase I dose-finding study (3 + 3 classical design) evaluating the RP2D of afatinib in combination with selumetinib; and PART B - a randomized phase II study investigating the progression free survival and safety of selumetinib/afatinib combination therapy compared to standard of care chemotherapy.

Detailed Study Description

In a pre-clinical study, treatment of KRAS mutant (KRASm) colorectal cancer (CRC) cell lines with an inhibitor of multiple epidermal growth factor receptor (ErBb) kinases in combination with a MEK-inhibitor resulted in synthetic lethality. MEK inhibition alone in these cells resulted in a strong feedback activation of human epidermal growth factor receptors (HER)2 and HER3 after about 48 hours. This enables the formation of activating complexes with other ErbB family members such as EGFR, causing primary resistance via subsequent activation of the phosphoinositide 3-kinase (PI3K) pathway. Concomitant treatment with a MEK inhibitor and a multiple inhibitor of ErBbs completely suppressed this feedback activation and resulted in cell death. Among various combinations, the combination of afatinib, an irreversible EGFR/HER2/HER4 inhibitor, and selumetinib, a MEK inhibitor, showed the strongest response in these cell lines by synergistic induction of apoptosis. This effect was observed both after concomitant use and after intermittent exposure to afatinib starting 48 hours after start of exposure to selumetinib. In addition to these observations in KRASm CRC cell lines, the anti-tumor activity of this combination was confirmed in cell lines derived from KRASm non-small cell lung cancer (NSCLC) and in xenografts in mice with KRASm NSCLC cells. Because of the histology-independent activity of this concept and the similarities in cancer cells at a molecular level, the combination of afatinib and selumetinib is likely to be effective in pancreatic cancer as well. Enhanced antitumor activity of the combination of a MEK and an EGFR inhibitor has already been established in pancreatic cancer cell lines in vitro. Therefore it is plausible that the combination of a MEK inhibitor with a multiple epidermal growth factor receptor inhibitor will have enhanced efficacy in KRASm driven and PIK3CA wildtype pancreatic cancer in patients as well. Hence, there is a strong rationale for combining afatinib and selumetinib in patients with KRASm and PIK3CA wildtype (wt) CRC, NSCLC, or pancreatic cancer.

Clinical Study Identifier: NCT02450656

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Carla ML van Herpen, MD, ...

UMC St. Radboud Nijmegen
Nijmegen, Netherlands
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Marije Slingerland, MD, PhD

Leiden University Medical Centre
Leiden, Netherlands
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J.H.M. Schellens, MD, PhD

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Amsterdam, Netherlands
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