A Phase II single-arm trial to investigate tepotinib in advanced (locally advanced or metastatic) non-small cell lung cancer with MET exon 14 (METex14) skipping alterations or MET amplification (VISION)

1. Histologically or cytologically confirmed advanced (Stage IIIB/IV) NSCLC (all
histologies including squamous and sarcomatoid);
2. Treatment naive patients in first-line or pre-treated patients with no
more than 2 lines of prior therapy
3. Subjects with MET alterations, namely METex14 skipping alterations in plasma
and/ or tissue, as determined by the central laboratory or by an assay with
appropriate regulatory status will, be enrolled into the trial. For these
subjects, sufficient tumor tissue and/or plasma is requested to allow
additional testing MET amplification only in plasma defined by a positive LBx
test, as determined by the central laboratory or by an assay with appropriate
regulatory status. Based on the outcome of the interim analysis in 12 LBx
selected subjects; MET amplification only in tissue defined by a positive TBx
with a gain of at least 4 copies of the MET gene, as determined by the central
laboratory or by an assay with appropriate regulatory status.
4. Signed, written informed consent by subject or legal representative
prior to any trial-specific screening procedure;
5. Male or female, >= 18 years of age (or having reached the age of
majority according to local laws and regulations, if the age of majority is
> 18 years of age); [i.e., >= 20 years of age in Japan]);
6. Measurable disease in accordance with RECIST version 1.1;
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of
0 or 1
8. A female subjects is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:
a. Not a woman of childbearing potential as defined in Appendix VIII OR
b. A woman of childbearing potential who agrees to use a highly
effective contraception (i.e., methods with a failure rate of less than 1 %
per year) as detailed in in Appendix VII of this protocol 2 weeks before
start of first dose of study treatment, during the treatment period and
for at least 4 weeks after the last dose of study treatment. Women of
childbearing potential must have a negative pregnancy test (β-HCG test
in serum) prior to enrollment.
9. A male subject must agree to use and to have their female partners of
childbearing potential to use a highly effective contraception (i.e.,
methods with a failure rate of less than 1 % per year) as detailed in
Appendix VII of this protocol from the first dose of study treatment,
during the treatment period and for at least 3 months after the last dose
of study treatment and refrain from donating sperm during this period.
Male subjects should always use a barrier method such as condom
concomitantly.

1. Subjects with characterized EGFR activating mutations that predict
sensitivity to anti-EGFR-therapy, including, but not limited to exon 19
deletions and exon 21 alterations;
2. Subjects with characterized ALK rearrangements; that predict
sensitivity to anti-ALK therapy
3. Subjects with symptomatic brain metastases who are neurologically
unstable, and/or have required an increase in steroid dose within 2
weeks and/or have received prior stereotactic radiosurgery/gamma
knife within 2 weeks and/or other prior treatment for brain metastases
within 4 weeks prior to the start of therapy. Subjects with
leptomeningeal disease are ineligible;

4. Any unresolved toxicity Grade 2 or more according to National Cancer
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE)
from previous anticancer therapy;
5. Need for transfusion within 14 days prior to the first dose of trial
treatment;
6. Prior chemotherapy, biological therapy, radiation therapy, hormonal
therapy for anti-cancer purposes, targeted therapy, or other
investigational anticancer therapy (not including palliative radiotherapy
at focal sites) within 21 days prior to the first dose of trial treatment
7. Subjects who have brain metastasis as the only measureable lesion
8. Inadequate hematological, liver, renal, cardiac function
9. Prior treatment with other agents targeting the HGF/c-Met pathway;
10. Past or current history of neoplasm other than NSCLC, except for
curatively treated non-melanoma skin cancer, in situ carcinoma of the
cervix, or other cancer curatively treated and with no evidence of
disease for at least 5 years (for a full list of exlustion criteria please see
the study protocol)