Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically confirmed non-small cell lung cancer of the following non-squamous
subtypes:

- Adenocarcinoma

- Bronchioloalveolar carcinoma

- Large cell carcinoma

- Stage IV disease including any of the following:

- M1a (separate tumor nodule in a contralateral lobe, tumor with pleural nodules,
or malignant pleural or pericardial effusion)

- M1b (distant metastasis)

- Measurable disease, defined as ≥ 1 lesion (outside of irradiated areas) that can be
measured in ≥ 1 dimension as ≥ 10 mm (≥ 15 mm in case of lymph nodes) according to
RECIST 1.1

- Paraffin-embedded or formalin-fixed diagnostic biopsy collected in the past 2 months
must be available

- Must have EGFR-mutation status (mutated or wild type) confirmed by the central
pathologist in Basel

- Must consent to tumor biopsy at progression

- No intrathoracic tumors invading or abutting major blood vessels

- No CNS metastases by mandatory CT scan (MRI within the past 3 weeks is acceptable)

PATIENT CHARACTERISTICS:

- WHO performance status 0-1

- Hemoglobin ≥ 100 g/L

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT ≤ 3 times ULN (≤ 5 times ULN if liver metastases are present)

- Alkaline phosphatase ≤ 3 times ULN (≤ 5 times ULN if liver metastases are present)

- Calculated creatinine clearance ≥ 60 mL/min

- Urine dipstick for proteinuria < 2+

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 12 months after
completion of study therapy

- Must be compliant and have geographic proximity to allow proper staging and follow-up

- No active bleeding, including hemoptysis ≥ grade 2 (defined as bright red blood of ≥
5 mL per episode within the past 4 weeks)

- Minor hemoptysis is allowed

- No prior malignancy within the past 5 years, except adequately treated cervical
carcinoma in situ or localized non-melanoma skin cancer

- No psychiatric disorder precluding understanding of information on trial-related
topics, giving informed consent, or interfering with compliance for oral drug intake

- No other medical condition that would impair the ability of the patient to
participate in the trial or might preclude therapy with trial drugs, including any of
the following:

- Unstable or uncompensated respiratory, cardiac, hepatic, or renal disease

- Active infection

- Uncontrolled diabetes mellitus

- Uncontrolled arterial hypertension (i.e., BP ≥ 150/100 mm Hg despite optimal
medical therapy)

- History of myocardial infarction in the last 3 months

- History of hemorrhagic disorders

- Non-healing wound, ulcer, or bone fracture

- Significant traumatic injury within the past 28 days

- No known hypersensitivity to trial drugs or to any other component of the trial drugs

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No prior chemotherapy or molecular-targeted therapy for metastatic disease
(neoadjuvant or adjuvant chemotherapy allowed if terminated > 6 months ago)

- No prior radiotherapy to lesion(s) selected for measurement

- At least 30 days since prior yellow fever vaccination

- At least 30 days since prior experimental drugs, anticancer therapy, or treatment in
a clinical trial

- More than 28 days since major surgical procedure or open biopsy

- No concurrent full-dose oral, intravenous, or subcutaneous anticoagulants (low-dose
heparin or aspirin [≤ 325 mg p.o. daily] allowed)

- No concurrent herbal extracts or drugs contraindicated for use with trial drugs

- No concurrent investigational agents

- No other concurrent anti-neoplastic or anti-tumor agents, including chemotherapy,
immunotherapy, or hormonal anticancer therapy

- No concurrent Asasantin® (acetylsalicylic acid and dipyridamole) or Plavix®
(clopidogrel bisulfate)

Inclusion criteria

- Before registration, patient must give written informed consent for participation in
the trial including tumor biopsy at progression.

- Patient must have the capability to understand informed consent and information given
by the investigator on the trial.

- Non-small cell lung cancer (NSCLC), predominant non-squamous subtype (adenocarcinoma,
bronchioloalveolar carcinoma, and large cell carcinoma) confirmed by the central
pathologist in Basel.

- NSCLC stage IV according to the 7th edition of the TNM classification, including M1a
(separate tumor nodule in a contralateral lobe, tumor with pleural nodules or
malignant pleural or pericardial effusion) and/or M1b (distant metastasis).

- Most recent diagnostic biopsy paraffin-embedded or only formalin-fixed and sufficient
for further molecular analysis as determined by central pathologist in Basel.

- EGFR mutation status determined by local or central pathologist in Basel.

- EDTA blood samples (2 x 5 mL) for translational research projects will be taken
before treatment start.

- WHO performance status 0-1 (see Appendix 4).

- Age ≥ 18 years and legally competent person.

- Measurable disease, defined as at least one lesion (outside of irradiated areas) that
can be measured in at least one dimension as ≥ 10 mm (≥ 15 mm in case of lymph
nodes)according to RECIST v1.1

- Adequate hematological values: Hemoglobin ≥ 100 g/L, neutrophils ≥ 1.5 x 109/L,
platelets ≥ 100 x 109/L

- Adequate hepatic function: Bilirubin ≤ 1.5 x ULN, ALT and AP ≤ 3 x ULN (≤ 5 x ULN in
case of liver metastases)

- Adequate renal function: Calculated creatinine clearance ≥ 60 mL/min (according to
the formula of Cockroft-Gault)

- Urine dipstick for proteinuria < 2+

- Women are not breastfeeding. Women with child-bearing potential are using effective
contraception (see 9.2.4 and 9.3.5), are not pregnant and agree not to become
pregnant during participation in the trial and during the 12 months thereafter. A
negative pregnancy test before inclusion into the trial is required for all women
with childbearing potential. Men agree not to father a child during participation in
the trial or during the 12 months thereafter.

- Patient compliance and geographic proximity allow proper staging and follow-up.

Exclusion criteria

- Diagnosis of SCLC, predominantly squamous NSCLC (>50% by central pathology review) or
combined SCLC-NSCLC.

- Patients with intrathoracic tumors invading or abutting major blood vessels.

- Prior chemotherapy or molecular targeted therapy for metastatic disease, with the
exception of neoadjuvant or adjuvant chemotherapy if terminated 6 months before
registration. Prior radiotherapy to lesion(s) selected for measurement.

- CNS metastases by mandatory CT-scan (MRI is acceptable).

- Anticoagulation, with the exception of low dose heparin or aspirin (≤ 325 mg p.o.
daily).

- Active bleeding, including hemoptysis ≥ grade 2 (defined as bright red blood of at
least 5 mL per episode within the last 4 weeks of registration). Minor hemoptysis is
allowed.

- Yellow fever vaccination within the 30 days prior to registration.

- Previous malignancy within 5 years with the exception of adequately treated cervical
carcinoma in situ or localized non-melanoma skin cancer.

- Psychiatric disorder precluding understanding of information on trial related topics,
giving informed consent, or interfering with compliance for oral drug intake.

- Concurrent treatment with other experimental drugs or other anti-cancer therapy,
treatment in a clinical trial within 30 days prior to trial entry.

- Evidence of other medical condition which would impair the ability of the patient to
participate in the trial or might preclude therapy with trial drugs (e.g. unstable or
uncompensated respiratory, cardiac, hepatic or renal disease, active infection,
uncontrolled diabetes mellitus; uncontrolled arterial hypertension ≥ 150/100 mmHg,
history of myocardial infarction in the last 3 months, history of hemorrhagic
disorders, non healing wound, ulcer or bone fracture)

- Major surgical procedure, open biopsy or significant traumatic injury within 28 days
prior to registration

- Known hypersensitivity to trial drugs or hypersensitivity to any other component of
the trial drugs.

- Any concomitant drugs contraindicated for use with the trial drugs according to the
Swissmedic-approved product information.