Eligibility |
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.
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