Trastuzumab-emtansine and osimertinib combination treatment to target HER2 bypass track resistance in EGFR mutation positive NSCLC

Patients with epidermal growth factor receptor (EGFR) mutation positive
non-small cell lung cancer (NSCLC) respond well to EGFR TKI treatment. However,
despite this high response rate resistance develops in every patient. Multiple
resistance mechanisms have been described, involving two main mechanisms: EGFR
alteration and bypass track activation. Two in vivo studies detected human
epidermal growth factor receptor 2 (HER2)-overexpression and amplification in
~15% of NSCLC-patients with acquired tyrosine kinase inhibitor
(TKI)-resistance. Recently we showed that targeting HER2 with trastuzumab and
paclitaxel in this setting can induce tumor responses in up to 46%. However,
the progression-free survival was rather disappointing, which seems to be
caused by tumor escape through EGFR signaling and limited efficacy of
trastuzumab-paclitaxel in the brain. Isolated brain progression with a partial
response of the extra cerebral disease or a sudden disease flare caused by EGFR
TKI discontinuation were present in 25% of the patients, suggesting that
co-inhibition of EGFR and HER2 might be advantageous. Another question remains
about the optimal HER2 targeting regimen in this setting.
Trastuzumab-emtansine (T-DM1) is a HER2 antibody-drug conjugate that releases a
cytotoxic anti-microtubule agent within HER2 positive tumor cells upon
degradation of the HER2-T-DM1 complex in lysosomes. In-vitro experiments
suggest that T-DM1 can overcome HER2 bypass track resistance in patients with
EGFR mutated NSCLC. In addition, T-DM1 has shown in patients with breast cancer
that the efficacy is equivocal to paclitaxel and trastuzumab and that T-DM1 can
be used as a taxane-free treatment regimen with less toxicity.
In the current study we will evaluate whether combination treatment with T-DM1
and the 3rd generation EGFR TKI osimertinib can improve the results that were
obtained in our previous trial and whether this HER2 targeting regimen can be
put forward in a randomized phase III trial against standard of care treatment.

-To dertermine the objective response rate (ORR) and disease control rate (DCR)
(according to RECIST v1.1) after 3 months of treatment with T-DM1 and
osimertinib in patients with EGFR mutation positive NSCLC and HER2 bypass track
activation
-To assess anti-tumor activity of T-DM1 and osimertinib (the disease controle
rate (DCR), progression free survival (PFS), overall survival (OS)) in the HER2
expression and amplification subgroups
-To evaluate the safety of the combination treatment with T-DM1 and osimertinib
-At baseline and at progression, tumorbiopsies will be analysed for mechanisms
of de-novo and acquired resistance
-At baseline, during treatment and at progresssion, cfDNA will be collected to
analyse possible resistance mechanisms

Single arm, open label, multicenter fase II study

All subjects will receive continuous daily treatment with osimertinib 80 mg
once daily and 3.6mg/kg T-DM1 i.v. tri-weekly until disease progression or
unacceptable toxicity.

The disadvantage of participating in this study is that more blood will be
taken than normal. A new screening biopsy could also be taken if there is no
adequate tumor material available. A biopsy may possibly cause bleeding, low
blood pressure, redness, bruising, swelling and/or infection at the site of
biopsy or other discomfort such as bruising feeling.
The anesthetic may possibly cause allergic reaction. At the site where the
biopsy is performed a scar can occur. If a tumor is punctured in the lung, a
collapsible lung may develop. The patients all get osimertinib and T-DM1 and
can suffer from the most side effects.