A phase III, randomized, controlled, open-label, multicenter, global study of capmatinib versus SoC docetaxel chemotherapy in previously treated patients with EGFR wt, ALK negative, locally advanced or metastatic (stage IIIB/IIIC or IV) NSCLC harboring MET exon 14 skipping mutation (MET*ex14)

Lung cancer represents 11.6% of all new cancers and 85% of these lung cancers
are defined as non-small cell lung cancers (NSCLC). Deciphering the oncogenisis
of lung cancer have revealed various oncogenic drives, with mutations in EGFR &
ALK rearrangements as the most common once. Various therapeutic strategies have
been designed to inhibit the signaling pathways of these oncogenic drivers.
MET is a receptor tyrosine kinase involved in embryogenesis, organogenesis and
tissue damage repair and MET dysregulation has been shown to be oncogenic,
promoting cell-cell detachment and metastasis, epithelial-mesenchymal
transition, invasion, angiogenesis, proliferation and survival. MET
dysregulation is considered a poor prognostic factor.
Capmatinib (INC280) is a small adenosine triphosphate (ATP) competitive, orally
bioavailable, highly potent, and selective reversible inhibitor of the MET
receptor tyrosine kinase. Clinical data demonstrate that capmatinib monotherapy
has anti-tumor activity in EGFR wild-type NSCLC harboring MET mutation and
Safety data demonstrate that capmatinib is well tolerated by the target
population at the recommended phase II dose of 400 mg b.i.d. (tablet).

In this study, we want to find out whether the new drug capmatinib is more
effective (i.e. better inhibits the growth of cancer cells) than the widely
used chemotherapy docetaxel. In addition, it will be assessed whether treatment
with capmatinib is sufficiently safe. The effects of capmatinib and docetaxel
will be compared.
The research will be carried out in patients with locally advanced or
metastatic NSCLC with a mutation of the MET gene in the so-called exon 14. Exon
14 is a specific part of the gene. These patients should not have mutations of
other genes (EGFR gene and ALK gene) and must have been previously treated for
their NSCLC.
It is also assessed how much capmatinib remains in the blood and how long it
remains in the blood.
Research is also being conducted into biomarkers. Biomarkers are body
substances, usually proteins or genes, that say something about the progress of
the disease and the influence of research treatment on it.

This is a multicenter, open-label, randomized, active-controlled, global phase
III study. The study will randomize approximately 90 participants globally.
Participants eligible for the study will be randomized in a 2:1 ratio to one of
the two treatment arms: capmatinib (investigational therapy) or docetaxel. The
randomization will be stratified by prior lines of systemic therapy received
for advanced/metastatic disease (one line vs. two lines).
Participants randomized to docetaxel treatment will be eligible to crossover to
receive capmatinib treatment after blinded independent review committee
(BIRC)-confirmed, RECIST 1.1-defined progressive disease (PD) and after meeting
the eligibility criteria.
For all participants, the respective treatment (either with capmatinib or
docetaxel) may be continued beyond initial disease progression as per RECIST
1.1 (as assessed by the investigator and confirmed by BIRC) if, in the judgment
of the investigator, there is evidence of clinical benefit, and the participant
wishes to continue on the study treatment.
After treatment discontinuation, all participants will be followed for safety
evaluations during the safety follow-up period, and the participant*s status
will be collected every 12 weeks as part of the survival follow-up.

Treatment with INC280 (capmatinib)

Risks are possible adverse events of the study medication and study tests. Not
all side effects of the study medicines are known at this time.
Participation in the study also means that patients need to invest time, will
have additional tests and need to adhere to agreements.

Possible side effects of capmatinib:
* Very common side effects (affecting at least 1 in 10 people): Abnormal
physical weakness and/or lack of energy/tiredness (asthenia or fatigue), back
pain, chest pain (unrelated to heart), constipation, cough, decrease in blood
albumin level, decreased appetite, diarrhea, fever (pyrexia), nausea, possible
signs of kidney dysfunction (blood creatinine increased), possible signs of
liver dysfunction/changes in liver function tests (blood transaminase (ALT)
increased), shortness of breath, swelling in arms and legs (peripheral edema),
vomiting, weight decreased
* Common side effects (affects 1 in 10 to 100 people): Sudden decline in kidney
function (acute kidney injury), bacterial skin infection with redness of the
skin (cellulitis), decrease in blood mineral levels involved in body functions
(phosphate, sodium), inflammation of lung tissue (pneumonitis/interstitial lung
disease), possible signs of liver dysfunction/changes in liver function tests
(blood bilirubin increased, transaminase (AST) increased), possible signs of
pancreatic dysfunction/pancreatic enzymes increased (amylase and/or lipase),
raised itchy bumps/hives (urticaria), skin itching
* Unusual side effects (affects 1 in 100 to 1,000 people): Sudden painful
inflammation of the pancreas (acute pancreatitis).
* Other possible side effects of Capmatinib:
o Pneumonitis or interstitial lung disease has been reported during studies
with capmatinib. Until now, the contribution of capmatinib to these events has
not been proven.
o In animal experiments, capmatinib caused skin sensitization to sunlight,
therefore you may sunburn more easily.
o In addition, based on the way capmatinib works and based on information from
animalexperiments, it is highly likely that capmatinib can cause malformation
in fetuses if it is taken during pregnancy.

Possible side effects of docetaxel:
* Very common side effects (affects 1 in 10 people or more): Infections,
decrease in white blood cells (neutropenia), decrease in red blood cells
(anemia), decrease in platelets (thrombocytopenia), decreased appetite
(anorexia), damage to peripheral nerves (peripheral sensory neuropathy),
nausea, sores in the mouth (stomatitis), vomiting, diarrhea, hair loss
(alopecia), skin reaction, pain, feeling of weakness (asthenia), fluid
retention.
* Common side effects (affects 1 in 10 to 100 people): Fever with dangerously
low white blood cell count (febrile neutropenia), hypersensitivity, blood
pressure decreased (hypotension), irregular heartbeats (arrhythmia), damage to
peripheral nerves (peripheral motor neuropathy), nail disorders, constipation,
muscle pains (myalgia), possible signs of liver dysfunction/changes in liver
function tests (blood bilirubin increased).


The examination tests are one of the usual medical tests. Discomforts of
research tests and procedures can be experienced.
* Blood samples: The risks of collecting blood may include fainting, pain,
bruising, and/or dizziness, and in rare cases, infection. Rarely, there may be
a small blood clot or infection at the site of the needle puncture or central
line.
* Tumor biopsy: In general, having a biopsy can cause pain, swelling, bleeding
and/or infection at the site where the biopsy needle penetrates through your
skin. If your Study Doctor decides to use anesthetic, an allergic reaction may
occur. There is also the possibility that having this procedure may shift some
cells from the tumor into the surrounding tissues.
* CT or PET scan: With a CT or PET scan, the patient will be exposed to
radiation, about the same as what we are exposed to in daily life in 2 to 10
years. Radiation can cause damage to genetic material. Some people experience
claustrophobia (fear in a small space). You will receive an injection of
contrast fluid before the scan. This may result in some nausea, fainting, pain,
feeling of heat, swelling, bruise, scab or infection. Occasionally an allergic
reaction to the contrast medium occurs with hot flashes, sweats, rashes,
breathing problems and nausea. A serious allergic reaction can be life
threatening.
* MRI scan: Some people experience claustrophobia. You will receive an
injection of contrast fluid before the scan. This may result in a metallic
taste in the mouth, feeling of heat, nausea, and at the injection site a
burning sensation, pain, swelling, bruise, a crust or an infection. Rarely does
an allergic reaction to the contrast fluid occur with hot flashes, sweats,
rashes, breathing problems and nausea. A serious allergic reaction can be life
threatening.
* X-rays: Patient will be exposed to radiation, about the same as we are
exposed to in daily life in 1 to 2 weeks. Radiation can cause damage to genetic
material.
* Bone scan: Patient will be exposed to radiation, about the same as to which
we are exposed in daily life in 1 to 2 years. Radiation can cause damage to the
body's genetic material.