T-DM1 and Osimertinib Combination Treatment to Target HER2 Bypass Track Resistance in EGFR Mutation Positive NSCLC

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.