The aim of this trial is to identify the maximum tolerated dose (MTD)/recommended phase II dose (RP2D), to define pharmacokinetic (PK) parameters and the preliminary efficacy of a continuous treatment with EGF816 and trametinib in locally advanced or metastatic (stage IIIB or IV) lung cancer patients with activating mutations in the epithelial growth factor receptor (EGFR).

The population of interest for this trial is defined by patients with non-small cell lung cancer (NSCLC) harbouring the sensitizing EGFR mutations del19 or p.L858R. Patients may be enrolled in first- or later lines of therapy and independently of the prior (approved) EGFR inhibitor administered and independently of the EGFR p.T790M-status. Those individuals whose tumors harbour high-level amplifications of MET or other EGFR mutations except for del19, p.L858R or p.T790M will be excluded from the trial. The molecular status must have been determined in a biopsy collected at progression to the last systemic and prior to the initiation of the trial treatment

The aim of the trial is to identify the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) for a continuous treatment with the 3rd generation EGFR inhibitor EGF816 and the MEK inhibitor trametinib.

The recommendations for dose level escalations will be based on an "up-and-down" design proposed by Storer, 1989. The dose limiting toxicity (DLT) period comprises the first 28 days of treatment with EGF816 and trametinib at the designated dose level (Cycle 1).

PK parameters of the combination treatment will be assessed for every dose level in every patient during the dose-escalation part.

Preliminary efficacy of EGF816 and trametinib in the trial population will be assessed by RECIST (v1.1) analysis of scheduled CT scans (every 8 weeks or as clinically indicated.

Throughout the study blood samples will be collected to monitor cell free plasma DNA (cfDNA).

Patients who develop resistance upon treatment with the study drugs will undergo a rebiopsy to identify potential mechanisms of resistance.

Inclusion Criteria:

1. Written informed consent must have been obtained prior to any screening procedures.
2. Patients (male or female) ≥ 18 years of age.
3. Histologically documented, locally advanced or recurrent (stage IIIB who are not eligible for combined modality treatment) or metastatic (stage IV) non-small cell lung cancer.
4. Presence of at least one measurable lesion according to RECIST v.1.1.
5. ECOG performance status ≤ 2
6. Patients must have NSCLC harbouring EGFR p.L858R or EGFR del19 as assessed by local testing.
7. Patients must be EGFR TKI treatment naïve (prior chemotherapy treatment is allowed) or must have progressed while on continuous treatment with a first- or second-generation EGFR TKI (EGFR p.T790M-negative or -positive) or must have progressed while on continuous treatment with osimertinib (EGFR p.T790M-negative or -positive)
8. In patients who have received no prior EGFR TKI treatment, an archival biopsy sample, defined as a sample being obtained prior to any anti-cancer treatment is mandatory. If an archival biopsy fulfilling this criterion is not available, patients must be suitable and willing to undergo baseline biopsy according to the local institution's guidelines (newly obtained biopsy).
9. In patients who have received prior EGFR TKI treatment, an archival biopsy sample, defined as a sample being obtained after or during progression upon the last anti-cancer treatment is mandatory. No consecutive line of treatment must have been given after collection of the rebiopsy and inclusion into this trial. If an archival rebiopsy fulfilling these criteria is not available, patients must be suitable and willing to undergo baseline biopsy according to the local institution's guidelines (newly obtained biopsy).
10. In patients who have received prior EGFR TKI treatment, EGFRp.T790M mutation status must have been assessed by local testing in the tumour sample fulfilling the requirements of inclusion criterion 9.
11. Patients who have received prior osimertinib treatment, may only be eligible if no standard treatment approach outside this trial is available or feasible (e.g. chemotherapy)
12. Patients who have progressed while on continuous treatment with a first- or second-generation EGFR inhibitor and whose tumour has been tested EGFR p.T790M-negative may only be eligible if no standard treatment approach outside this trial is available or feasible (e.g. chemotherapy).
13. In patients who have received prior EGFR TKI treatment, progression of disease according to RECIST v1.1 while on continuous treatment with an EGFR TKI (e.g. erlotinib, gefitinib, afatinib or osimertinib) must be documented.

Exclusion Criteria:

1. History of allergic reactions or hypersensitivity to one of the study drugs or to any component of the study drugs

2. Prior treatment with any investigational agent known to inhibit EGFR (mutant or wild-type)

3. Prior treatment with any agent known to inhibit MEK/ERK or other mediators of RAS pathway.

4. Patients with high level MET amplification in the archival or newly obtained biopsy sample as determined by local testing. High-level MET amplification is defined as: a) a MET/CEN7 ratio ≥2.0 and/or b) an average MET gene copy number per cell of ≥6.0 [modified Schildhaus et al., 2015].

5. Patients with EGFR mutations other than EGFR del19, p.L858R or p.T790M.

6. Patients with brain metastases. However, if radiation therapy and/or surgery has been completed at least 4 weeks prior to screening for the trial and evaluation by CT (with contrast enhancement) or MRI at study baseline demonstrates the disease to be stable and if the patient remains asymptomatic and off steroids, then patients with brain metastases may be enrolled.

7. Patients with presence or history of carcinomatous meningitis.

8. Any acute or chronic medical, mental or psychological condition, which in the opinion of the investigator would not permit the patient to participate or complete the study or understand the patient information

9. History of hepatitis B (HBV) or hepatitis C (HCV) or positive result in mandatory testing for acute or chronic hepatitis B or hepatitis C

10. Known HIV infection or history of HIV infection independent from the cellular immune status

11. Patients who receive any continuous, long term immunosuppressive treatment, including long term treatment with steroids at immunosuppressive doses at the time of study entry

12. Patients who underwent bone marrow or solid organ transplantation, including patients who do not receive any immunosuppressive treatment.

13. Presence or history of any other primary malignancy other than NSCLC within 5 years prior to enrolment into the trial. Except from this: Adequately treated basal or squamous cell carcinoma of the skin or any adequately treated in situ carcinoma

14. Any of the following within 6 months prior to first trial drug administration: Myocardial infarction (NSTEMI or STEMI), severe/unstable angina pectoris, symptomatic congestive heart failure (> NYHA II), uncontrolled hypertension, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, atrial fibrillation of CTCAE Grade ≥ 2, ongoing cardiac dysrhythmias of CTCAE Grade ≥ 2, including corrected QTcF prolongation of > 480 ms,

15. Aortic valve stenosis with mean gradient ≥ 25 mmHg and aortic valve area of ≤ 1.5 cm2

16. Any other cardiac valve abnormality of more than mild degree/stage

17. Left ventricular ejection fraction (LVEF) of < 50 %

18. History of congenital long QT-syndrome or Torsades de Pointes

19. History of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED)

20. Unable or unwilling to swallow tablets or capsules

21. Patients with impaired gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of EGF816 (e.g., ulcerative diseases, uncontrolled nausea, vomiting diarrhoea, or malabsorption syndromes

22. Patients have received anticancer treatment within the following time frames prior to the first dose of study treatment:

    1. Conventional cytotoxic chemotherapy: ≤ 4 weeks (≤ 6 weeks for nitrosoureas, mitomycin-C and suramin)
    2. Biological therapy (e.g., antibodies, excluding PD-1 or PD-L1 antibodies): ≤ 4 weeks
    3. PD-1/PD-L1 antibodies (e.g., nivolumab, pembrolizumab): ≤ 5 half-times
    4. Non-cytotoxic anti-cancer therapeutic (e.g., tyrosine kinase inhibitors): ≤ 5 half-times or ≤ 1 weeks (whichever is longer)
    5. Other investigational agent: ≤ 4 weeks
    6. Radiation therapy (excluding palliative radiation, e.g., of bone metastases): ≤ 4 weeks
    7. Major surgery (excluding minor surgical interventions, e.g., vascular device implantation): ≤ 2 weeks

23. Laboratory values as listed below, that cannot be corrected to normal limits within screening :

    1. Absolute Neutrophil Count (ANC) < 1.5 x 10^9/L
    2. Haemoglobin (Hb) < 9 g/dL
    3. Platelets (PLT) < 100 x 10^9/L
    4. Total bilirubin > 1.5 x upper limit of normal (ULN). For patients with confirmed Gilbert's disease total bilirubin > 2.5 x ULN
    5. AST and/or ALT > 3 x ULN
    6. AST and/or ALT > 5 x ULN in patients with liver involvement
    7. Serum creatinine > 1.5 x ULN
    8. Measured or calculated creatinine clearance ≤ 45 mL/min
    9. Serum amylase and/or lipase CTCAE Grade > 2
    10. Potassium, magnesium, phosphorus, total calcium (corrected from serum albumin) > ULN

24. Patients receiving treatment with any medication that are known to be

    1. Strong inhibitors or inducers of CYP3A4/5
    2. Substrates of CYP2D6 with narrow therapeutic index
    3. and that cannot be discontinued at least 7 days prior to the first dose of the study drugs.
    4. For further information please refer to Section 11.7 and the Concomitant Medication Manual.

25. Patients with a history of or presence of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis

26. Pregnancy or breastfeeding/nursing women

27. Women of child-bearing potential (for definition see Section 8.3.3) unless they use highly effective methods of contraception during treatment and for four months after withdrawal of study treatment (for methods of contraception see Section 8.3.4)

28. Sexually active males unless they use a condom during intercourse for the time of study treatment and for four months after the withdrawal of study treatment.