Pemetrexed Disodium and Carboplatin or Cisplatin With or Without Erlotinib Hydrochloride in Treating Patient With Stage IV Non-Small Cell Lung Cancer Resistant to First-Line Therapy With Erlotinib Hydrochloride or Gefitinib

PRIMARY OBJECTIVES:

I. To compare the effects of chemotherapy plus erlotinib (erlotinib hydrochloride) vs.
chemotherapy alone on progression-free survival (PFS) in non-small cell lung cancer (NSCLC)
patients harboring activating endothelial growth factor receptor (EGFR) mutations who
developed acquired resistance to first-line therapy with erlotinib or gefitinib.

SECONDARY OBJECTIVES:

I. To determine the overall survival (OS) and response rate in this patient population.

II. To assess the safety of erlotinib in combination with chemotherapy in this patient
population.

TERTIARY OBJECTIVES:

I. To determine whether presence of the T790M resistance mutation can be used to predict
which patients will benefit from the addition of erlotinib to chemotherapy.

II. To determine if patients with NSCLC harboring activating EGFR mutations who develop
acquired resistance to EGFR tyrosine-kinase inhibitors (TKIs) develop additional
mutations/genetic alterations on progression.

III. To determine whether any additional biomarkers (e.g., mesenchymal-epithelial transition
[MET] amplification, EGFR mutations detected in circulating free deoxyribonucleic acid
[DNA]) predict response to second-line therapy in this patient population.

IV. To determine progression-free survival (PFS) in patients on the chemotherapy alone arm
who crossed over to erlotinib after progression as compared to patients on the combination
chemotherapy arm (erlotinib plus chemotherapy) who switched to chemotherapy of choice
(without erlotinib) after progression.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive erlotinib hydrochloride orally (PO) once daily (QD) on days 1-21,
pemetrexed disodium intravenously (IV) and carboplatin IV or cisplatin IV on day 1.
Treatment repeats every 21 days for 4 courses. Patients then receive maintenance erlotinib
hydrochloride orally (PO) once daily (QD) on days 1-21 and pemetrexed disodium IV on day 1.
Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive pemetrexed disodium and carboplatin or cisplatin as in Arm I.
Treatment repeats every 21 days for 4 courses. Patients then receive maintenance pemetrexed
disodium as in Arm I. Courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed until death.

Inclusion Criteria:

- Signed informed consent prior to initiation of any study-specific procedure or
treatment

- Able to comply with the protocol

- Histologically- or cytologically-confirmed stage IV NSCLC with an EGFR exon-19
deletion or L858R mutation

- Must have received at least 6 months of first-line therapy with erlotinib

- Clinical evidence of progression on first-line EGFR TKI therapy

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L AND

- Platelet count >= 100 x 10^9/L AND

- Hemoglobin >= 9 g/dL (may be transfused to maintain or exceed this level)

- Total bilirubin < 1.5 x upper limit of normal (ULN) AND

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN in
patients without liver metastases; < 5 x ULN in patients with liver metastases

- Serum creatinine < 1.25 x ULN or calculated creatinine clearance > 50 mL/min

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Patients with stable, treated brain metastases are eligible for study participation;
patients may not receive ongoing treatment with steroids at screening;
anticonvulsants (at stable dose) are allowed; radiotherapy and stereotactic
radiosurgery must be completed at least 28 days prior to randomization

- Female patients should not be pregnant or breast-feeding; female patients with
childbearing potential should agree to use effective, non-hormonal means of
contraception (intrauterine contraceptive device, barrier method of contraception in
conjunction with spermicidal jelly or surgically sterile) during the study and for a
period of at least 6 months following the last administration of study drugs; female
patients with an intact uterus (unless amenorrheic for the last 24 months) must have
a negative serum pregnancy test within 7 days prior to randomization into the study

- Fertile male patients must agree to use effective contraception during the study and
for a period of at least 3 months following the last administration of study drugs

Exclusion Criteria:

- Any other prior treatment for metastatic NSCLC other than erlotinib; prior adjuvant
therapy is allowed if completed at least 12 months prior to trial enrollment

- Radiotherapy to any site for any reason within 28 days prior to randomization, except
for palliative radiotherapy to bone lesions up to 14 days prior to randomization

- Clinically significant (i.e., active) cardiovascular disease (e.g., cerebrovascular
accident or myocardial infarction within 6 months prior to randomization), unstable
angina, congestive heart failure (New York Heart Association class >= II), or serious
cardiac arrhythmia, that is uncontrolled by medication or may interfere with
administration of study treatment

- Treatment with any other investigational agent or participation in another clinical
trial within 28 days prior to randomization

- Malignancies other than NSCLC within 3 years prior to randomization, except for
adequately treated carcinoma in situ of the cervix, basal or squamous cell skin
cancer, localized prostate cancer treated with radiation or surgically with curative
intent, and ductal carcinoma in situ treated surgically with curative intent

- Evidence of any other disease, neurological or metabolic dysfunction, physical
examination finding or laboratory finding giving reasonable suspicion of a disease or
condition that contraindicates the use of an investigational drug or puts the patient
at high risk for treatment-related complications