Trial of BIBW 2992 (Afatinib) + Cetuximab in Non-Small Cell Lung Cancer

Inclusion criteria:

1. Pathologically or cytologically confirmed Stage IIIB/IV non-small cell lung cancer or
recurrent disease following locoregional treatment

2. Either or both of the following:

1) A tumor which harbors an Epidermal Growth Factor Receptor (EGFR) -mutation known to be
associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) from
previous tumor biopsy or surgery. A tumor which harbors exon 20 insertion or de novo T790M
mutation is eligible for the treatment in the sequential arm 2) Objective clinical benefit
from treatment with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR
TKI) as defined by either

1. Documented partial or complete response (Response Evaluation Criteria in Solid
Tumors, RECIST), or

2. Stable disease >=6 months as defined by RECIST in absence of radiographic progression
after initiation of gefitinib or erlotinib; or stable disease/PR/CR >=12 weeks as
defined by RECIST after initiation of BIBW 2992 3. Systemic progression of disease
(RECIST v1.1) while on continuous treatment with erlotinib or gefitinib or BIBW 2992
within the last 30 days. Patients whose disease progresses only in the central
nervous system (CNS) are not eligible 4. No intervening systemic therapy between
cessation of gefitinib or erlotinib or BIBW 2992 and initiation of the treatment in
the study 5. Adequate tumor-derived material such as fresh or archived tumor tissue
or pleural fluid from malignant pleural effusion after disease progression on
erlotinib/gefitinib/BIBW 2992 prior to the study entry must be made available for
EGFR mutation analyses 6. Patients aged 18 years or older 7. Life expectancy of at
least three (3) months 8. Eastern Cooperative Oncology Group (ECOG) performance score
0-2 9. Written informed consent that is consistent with ICH-GCP guidelines

Exclusion criteria:

1. Prior treatment with EGFR targeting antibodies; prior severe infusion reaction to a
monoclonal antibody

2. Adverse events due to major surgery (at least 28 days after) or minor surgery not
recovered to CTC grade 1 or less. Surgical wounds must be healing without clinical
evidence of infection prior to study treatment to be eligible.

3. Radiotherapy less than two weeks prior to the start of the study treatment

4. Systemic chemotherapy, hormonal therapy, immunotherapy, or experimental or approved
proteins/antibodies (except erlotinib/gefitinib/BIBW 2992) <=30 days before study
treatment

5. Less than three days from prior treatment with gefitinib or erlotinib. Patients with
adverse events related to gefitinib or erlotinib must recover to CTC AE grade 1 or
less to be eligible. No need to stop BIBW 2992 before start of the study treatment
for patient who progressed on BIBW 2992 from a separate clinical trial/treatment
setting

6. Brain metastases, which are symptomatic. Patients with treated, asymptomatic brain
metastases are eligible if there has been no change in brain disease status for at
least four (4) weeks, no history of cerebral oedema or bleeding in the past four (4)
weeks. Anticonvulsant therapy will be allowed if patient is stable on anticonvulsant
treatment.

7. Other malignancies diagnosed within the past five (5) years (other than non
melanomatous skin cancer, ductal carcinoma in situ and in situ cervical cancer)

8. Known pre-existing interstitial lung disease

9. Significant or recent acute gastrointestinal disorders with diarrhea as a major
symptom e.g., Crohns disease, malabsorption, or Common Toxicity Criteria for Adverse
Events (CTCAE) grade >2 diarrhea of any etiology

10. Women of childbearing potential (WOCBP), or men who are able to father a child,
unwilling to use a medically acceptable method of contraception during the trial;
pregnancy or breast-feeding