| Eligibility |
Inclusion Criteria:
1. Histologically or cytologically confirmed stage IV non-squamous NSCLC, characterized
by an activating EGFR mutation.
2. Progressive disease according to RECIST 1.1 on first (gefitinib, erlotinib), second
(afatinib) or third (osimertinib) generation EGFR TKI and still receiving the drug.
3. A rebiopsy after having acquired resistance to a first, second or third generation
TKI-treatment must have been performed and be:
1. Negative for T790M in case of treatment with a first or second generation EGFR
TKI. After progression on a third generation EGFR TKI patients may either be
positive or negative for T790M.
2. Positive for HER2-overexpression (positive membranous immunohistochemistry
staining IHC =2+ (on a scale of 0-3) in =10% of the cells) must have been
detected.
4. There must be at least one measurable disease site, according to RECIST 1.1 criteria.
Patients need At least one lesion, not previously irradiated, that can be accurately
measured at baseline as = 10 mm in the longest diameter (except lymph nodes which must
have short axis = 15 mm) with computed tomography (CT) or magnetic resonance imaging
(MRI) and which is suitable for accurate repeated measurements.
5. Absence of symptomatic brain metastases. All patients will be scanned at baseline with
a brain MRI.
6. Patients must be willing and able to comply with the protocol for the duration of the
study including undergoing treatment and scheduled visits and examinations.
7. World Health Organization (WHO) performance status 0-2.
8. Patients must have a life expectancy =12 weeks.
9. Ability to give written informed consent before patient screening.
10. Patients must be =18 years of age.
11. Men and women of child bearing potential should be willing to take adequate
contraceptive measures during the study and until three months after study drug
discontinuation
Exclusion Criteria:
1. Uncontrolled infectious disease.
2. Other active malignancy. Patients with a history of cancer for which treatment is
complete and with no evidence of malignant disease currently cannot be enrolled if
their chemotherapy was completed less than 6 months prior and/or have received a bone
marrow transplant less than 2 years before the first day of study treatment.
3. Major surgery (excluding diagnostic procedures like e.g. mediastinoscopy or VATS
biopsy) in the previous 4 weeks.
4. Known hypersensitivity to T-DM1 or osimertinib (or drugs with a similar chemical
structure or class) or any excipients of these agents.
5. Previous treatment with a HER2 monoclonal antibody.
6. Clinically significant cardiac disease or:
- Patients with pre-treatment LVEF < 55%.
- Prior history of congestive cardiac failure; LVEF decline to <50% on previous
treatment with HER2 agents
- Conditions impairing LV function e.g. uncontrolled hypertension
- MI/unstable angina within 6 months or serious cardiac arrhythmia
7. Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTc) > 470 msec obtained from 3
electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc
value
- Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG e.g. complete left bundle branch block, third degree heart block and
second degree heart block.
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalaemia, congenital long QT syndrome, family
history of long QT syndrome or unexplained sudden death under 40 years of age in
first degree relatives or any concomitant medication known to prolong the QT
interval.
8. Inadequate bone marrow reserve or organ function, as demonstrated by any of the
following laboratory values:
- Hematology: hemoglobin <5.6 mmol/L, absolute neutrophil count <1.5 x 10^9/L,
platelet count <100 x 10^9/L.
- Biochemistry: alanine aminotransferase, aspartate aminotransferase and bilirubin
= 2.5 x ULN, except in the case of liver metastases where these values must be =
5x ULN.
- Kidney function: serum creatinine >1.5 x ULN concurrent with creatinine clearance
<50 ml/min (measured or calculated by Cockroft and Gault equation).
9. Patients with symptomatic central nervous system metastases who are neurologically
unstable. Unstable brain metastases except for those who have completed definitive
therapy and have had a stable neurological status for 2 weeks after completion of
definitive therapy. Patients may be on corticosteroids to control brain metastases if
they have been on a stable dose for 2 weeks prior to the start of study treatment and
are clinically asymptomatic.
10. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow osimertinib or previous significant bowel resection that would preclude
adequate resorption of osimertinib.
11. Males and females of reproductive potential who are not using an effective method of
birth control and females who are pregnant or breastfeeding or have a positive (serum)
pregnancy test prior to study entry.
12. Judgment by the investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions and
requirements.
13. Treatment with an investigational drug within five half-lives of the compound or 3
months, whichever is greater
14. Currently receiving (or unable to stop use prior to receiving the first dose of study
treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at
least 3 week prior) (Appendix C). All patients must try to avoid concomitant use of
any medications, herbal supplements and/or ingestion of foods with known inducer
effects on CYP3A4.
15. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of
starting study treatment, with the exception of alopecia and grade 2, prior
platinum-therapy-related neuropathy.
16. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled
hypertension and active bleeding diatheses, which in the investigator's opinion makes
it undesirable for the patient to participate in the trial or which would jeopardise
compliance with the protocol, or active infection including hepatitis B, hepatitis C
and human immunodeficiency virus (HIV). Screening for chronic conditions is not
required.
17. Past medical history of interstitial lung disease, drug-induced interstitial lung
disease, radiation pneumonitis which required steroid treatment or any evidence of
clinically active interstitial lung disease.
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