Afatinib in pretreated patients with advanced NSCLC harbouring HER2 exon 20 mutations

Primary lung cancer is the most common malignancy after non-melanocytic skin
cancer, with the highest number of deaths worldwide. Lung cancer accounts for
12% of all incident cases of cancer. Non-small cell lung cancers (NSCLC)
account for 80-85% of lung cancers.

Advanced stage NSCLC is traditionally treated by systemic palliative
chemotherapy, with cisplatin as basis. Chemotherapy efficacy seems to have
reached a plateau though. In unselected patients, response rates are only
15-30% and median survival (i.e. 50% of the patients are still alive) is 10-12
months, while the majority of patients suffer severe side effects with no
therapeutic benefit. The treatment of cancer patients is characterized by great
inter-individual variability. Since 1994, molecular research has centered on
the identification of predictive biomarkers that can be successfully used to
tailor treatment in these patients.

Previous clinical studies of NSCLC have shown that patients with tumors
harboring specific gene mutations (changes) showed better results after
treatment with tyrosine kinase inhibitors (TKIs), compared with classical
treatment with chemotherapy. The treatment with TKI has become a new
standard-of-care for patients with advanced lung cancer and specific mutations,
such as epithelial growth factor receptor (EGFR) or anaplastic lymphoma kinase
(ALK).

HER2 (human epidermal growth factor 2), a protein of the so called ErbB
receptor tyrosine kinase family, is a lung cancer biomarker which remains
poorly described. HER2 overexpression or gene amplification is widely known to
be associated with sensitivity to HER2-targeting drugs (trastuzumab, lapatinib,
pertuzumab and T-DM1) in breast cancer. Involvement of HER2 in lung
carcinogenesis has been known for many years, but clinical research was slowed
down when the first clinical trials with trastuzumab were negative. Indeed, the
addition of trastuzumab to gemcitabine-cisplatin or to docetaxel failed to show
any survival benefit in HER2 Immuno-Histo-Chemistry-positive (IHC) lung cancer
patients. However, HER2 mutations may be more relevant in lung carcinogenesis
than HER2 amplification or overexpression. HER2 mutations are identified in
about 2% of non-small-cell lung cancers.

Afatinib has a marketing authorization for a different use in non-small cell
lung cancer. Afatinib, the study drug, is a TKI which is approved by the
European and the Swiss Medicines Agencies for the treatment of adult patients
with non-small cell lung cancer with a mutation in the gene for EGFR, either as
first-line treatment or as second-line treatment if prior chemotherapy has been
insufficient. This trial aims at confirming the role of afatinib in HER2
mutated advanced NSCLC patients previously treated with platinum based
chemotherapy.

The primary objective is to evaluate the ability of afatinib to control disease
in pretreated patients with advanced non-small cell lung cancer harbouring HER2
exon 20 mutations.

Secondary objectives are:
* To evaluate secondary measures of clinical efficacy including progression
free survival (time from the date of enrolment until documented progression or
death, if progression is not documented), objective response rate (best overall
response across all assessment time-points from enrolment to termination of
trial treatment) and overall survival (time from the date of enrolment until
death from any cause)
* To assess the safety and the tolerability of the treatment.

This is a multicenter phase II single-arm trial in patients with advanced stage
non-small cell lung cancer, harbouring HER2 exon 20 mutations.

Participating sites will screen patients for HER2 exon 20 mutations in their
local laboratory. Tumor tissue will also be sent to a central laboratory at the
Medical University of Gdansk (Poland) for later confirmation of the mutations.
If this central analysis does not confirm the presence of HER2 mutation, and
thus deviates from the local analysis, the subject can still take part in the
study if the investigator agrees with it.

If the subject meets the criteria to take part in the study, he/she will
receive afatinib 40 mg orally, daily. Week 0 is the week of trial treatment
start and subsequent visits will take place at 3, 6, 9 and 12 weeks after first
dose, then every 4 weeks until stop of treatment. At the end of trial treatment
and irrespective of the reason for stopping treatment, an end of treatment
visit should be done within 30 days following the last dose.

Follow-up visits after trial treatment stop but before progression will take
place every 8 weeks until progression. Follow-up visits after progression will
take place every 3 months until death, or until 6 months from enrolment of the
last patient, whichever occurs first.

All patients in this study will be treated in the same way. If the subject
meets the criteria to take part in the study, he/she will receive afatinib 40
mg orally, daily. Treatment with the study medication should start within 7
days after enrolment. Afatinib should be taken at a fixed time and at least 1
hour before and 3 hours after the ingestion of food. The tablets should be
swallowed whole with water. If swallowing of whole tablets is not possible,
these can be dispersed in approximately 100 ml of noncarbonated drinking water.
No other liquids should be used.

Physical, radiological and lab examinations will be performed at the time of
study entry. In women who could become pregnant, a pregnancy test will be done
(on serum or urine) within 7 days prior to receiving study treatment. During
the study treatment, patients must visit the study doctor every 3 weeks for the
first 12 weeks for a physical examination and routine blood analysis,
thereafter every 4 weeks. Inpatient admission into a hospital is not envisaged,
but can potentially become necessary. Patients must take afatinib tablets
((study drug) at a fixed time each day (at least 1 hour before or 3 hours after
the ingestion of food) and record the intake in the patient diary. All empty,
full and partly used boxes of afatinib tablets must be returned at the next
visit to the study center.

At the end of trial treatment and irrespective of the reason for stopping
treatment, an end of treatment visit should be done within 30 days following
the last dose. Follow-up visits after trial treatment stop but before
progression will take place every 8 weeks until progression. Follow-up visits
after progression will take place every 3 months until death, or until 6 months
from enrolment of the last patient, whichever occurs first.

Radiological examinations (CT of the chest and upper abdomen) will be conducted
every 6 weeks (week 6 and 12) and later every 8 weeks until tumour progression.
These examinations are carried out as part of medical routine and can be
performed more frequently, if the study doctor considers this appropriate.
Before the start of the study treatment, a CT or MRI of the brain will be
performed. Compared to the standard treatment, an additional radiological
examination (CT of thorax and upper abdomen) will be performed 6 weeks after
the first dose of afatinib and at the end of the study treatment, if the last
CT was performed more than 6 weeks before.

Afatinib has a marketing authorization for a different use in non-small cell
lung cancer. Afatinib is approved by the European and the Swiss Medicines
Agencies for the treatment of adult patients with non-small cell lung cancer
with a mutation in the gene for EGFR, either as first-line treatment or as
second-line treatment if prior chemotherapy has been insufficient. HER2
mutations offer a new treatment strategy beyond the standard chemotherapy.
Afatinib is relatively well tolerated and presents a manageable toxicity
profile. In the small series available to date, afatinib looks like being the
most promising anti-HER2 treatment. Based on available data, afatinib is
comparable or superior to classical second line chemotherapy (docetaxel), with
a significantly better toxicity profile. Afatinib potentially offers a
significant activity in terms of disease control and long term outcome.
Therefore this treatment option offers a good benefit to risk ratio in patients
with HER2-mutated advanced non-small cell lung cancer.