Phase I/II study with the combination of afatinib and selumetinib in advanced KRAS mutant positive and PIK3CA wildtype non-small cell lung cancer and colorectal cancer

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) NSCLC and CRC.

Primary objectives:

Part A: To determine the recommended phase 2 dose and schedule (RP2D) of the
selumetinib/afatinib combination in patients with KRASm and PIK3CAwt NSCLC and
CRC

Part B: To determine the progression free survival (PFS) of the
selumetinib/afatinib combination compared to standard of care therapy in
patients with KRASm and PIK3CAwt NSCLC and CRC

Secondary objectives:

* To characterize the safety and tolerability of afatinib in combination with
selumetinib, as assessed by the incidence and severity of adverse events
* To determine the anti-tumor activity of afatinib in combination with
selumetinib, as measured by overall response rate, duration of response, time
to response and overall survival (Part B only)
* To determine the pharmacokinetic profile of afatinib and selumetinib in this
combination, as measured by plasma concentrations of both drugs and relevant
metabolites

Exploratory objectives:

* To explore determinants (gene alteration/expression) and mode of response to
the selumetinib-afatinib combination, as measured by baseline and on-therapy
molecular status (mutation/amplification/expression) in tumor tissue of
potential predictive and indicative markers of tumor response (part A only)
* To explore the potential mechanism of resistance to the selumetinib-afatinib
combination, as measured by gene alterations/expression profiles (e.g.
baseline, relapse) in tumor tissue upon progression (part A only)

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.

In phase I, all patients will be treated with selumetinib and afatinib. Start
doses are selumetinib 25 mg twice daily during the first 21 days of every 28
day cycle and afatinib 20 mg once daily continuously. Guided by toxicity of
this treatment, the doses of both compounds can be escalated in new cohorts of
patients to be able to determine the recommended phase II dose. Subsequently, a
less intensive regimen will be tested in which afatinib will be dosed 20 mg
once daily in an intermittent 4 days on/3 days off regimen (combined with
selumetinib for 21 days out of every 28 days). If deemed rational a third
intermittent regimen will be tested in which afatinib is dosed 1 day on/1 day
off/

In phase II, patiens will be randomized to be treated with the recommended
phase II dose of selumetinib and afatinib or with the standard of care second
line treatment for NSCLC (docetaxel) or CRC (irinotecan). Upon progression
after selumetinib and afatinib, patients will cross-over to the comparator arm
with standard of care therapy and vice versa.

Possible risks with venapunctions is the development of a heamatoma at the
place of venapunction. Possible risks of tumor biopsies are mild pain during
anasthesia and the place where the biopsy is taken can become sensitive an
mildly painful during a few days. With biopsies from pulmonary tissue, there is
a slight risk of a pneumothorax.

Adverse events caused by selumetinib and/or afatinib can be expected. Because
of overlapping toxicity profiles, diarrhea and rash are likely to occur during
therapy. Other adverse events thare are associated with afatinib and selumtenib
is monotherapies are nausea, vomiting, fatigue, pyrexia, dyspnoea,
ophtalmological toxicities and mucositis.