Erlotinib Therapy and Subsequent Development of Mechanisms of Secondary Resistance in Patients With NSCLC

PRIMARY OBJECTIVE

-To prospectively assess the frequency of different genetic mechanisms of secondary
resistance in patients' tumors during treatment with erlotinib (e.g., T790M mutations, MET
amplification).

- Correlate these genetic changes with patient demographic data and clinical outcomes
(time to progression, survival, sites of recurrence/progression).

- Search for novel mechanisms of acquired resistance to erlotinib.

- Identify whether these genetic changes are present at low levels in initial pretreatment
tumor specimens.

SECONDARY OBJECTIVE(S)

1. To measure the steady-state plasma concentrations of erlotinib during the course of
patients' treatment.

- Determine if the development and/or resolution of skin toxicity is related to
plasma erlotinib concentrations.

- Determine if the development of disease progression while on erlotinib is
correlated with declines in plasma erlotinib concentrations.

- Assess the plasma levels in patients whose smoking status has been biochemically
verified to determine if smoking is associated with lower erlotinib plasma
concentration.

2. To analyze from both free plasma DNA and DNA from circulating tumor cells of
erlotinib-treated patients for the original sensitizing EGFR mutations and genetic
changes associated with secondary resistance.

3. To measure clinical outcomes in patients with known sensitizing mutations in their tumor
EGFR when treated with first-line erlotinib.

- Response rate

- Time to progression

- Median overall survival

Inclusion Criteria:

- Histologically or cytologically confirmed non-small cell lung cancer, stage IV or IIIB
with a malignant pleural or pericardial effusion. Patients with stage I or II
non-small cell lung cancer who have undergone surgical resection but who subsequently
relapse with metastatic disease or a malignant pleural effusion are also eligible.

- Documentation of a sensitizing mutation of the epidermal growth factor receptor. In
addition, there must be a sufficient tissue for analysis of KRAS (the oncogene from
the Kirsten rat sarcoma virus) mutations and MET amplification.

- At least one measurable or evaluable site of disease as defined by revised RECIST
(version 1.1) criteria.

- 18 years of age or older

- No more than one prior systemic therapy regimen for advanced non-small cell lung
cancer. Chemotherapy delivered as part of concurrent chemoradiation will also count as
a prior systemic therapy regimen. Adjuvant therapy for resected NSCLC will not count
towards this total as long as it was completed at least 6 months prior to enrollment
and did not include therapy with an EGFR-targeted agent. Adjuvant therapy completed
less than 6 months prior to the time of screening will count as a prior regimen.

- 3 or more weeks since prior major surgery

- 2 or more weeks since prior radiation

- ECOG performance status 0-1

- Life expectancy > 8 weeks

- Adequate hematologic, renal, and hepatic function

- Willingness to undergo repeat tumor biopsy at the time of disease progression.

Exclusion Criteria:

- Untreated and/or uncontrolled central nervous system metastases. Patients with prior
brain metastases must have had definitive treatment (radiation or surgery) and must be
clinically stable off steroids for at least 1 week prior to enrollment.

- More than one prior systemic chemotherapy for advanced non-small cell lung cancer. ,
Chemotherapy delivered as part of concurrent chemoradiation will also count as a prior
systemic therapy regimen. Adjuvant therapy for resected NSCLC willnot count towards
this total as long as it was completed at least 6 months prior to enrollment and did
not include therapy with an EGFR-targeted agent. Adjuvant therapy completed less than
6 months prior to the time of screening will count as a prior regimen.

- Prior exposure to erlotinib or other treatments targeting the HER family axis.

- Active malignancies within the past 3 years, except for adequately treated carcinoma
of the cervix or basal or squamous cell carcinomas of the skin.

- Any process that compromises the ability to swallow and/or absorb oral medication.

- Incomplete healing from previous surgery

- A history of any of the following autoimmune skin disorders: Sjogren's syndrome,
scleroderma, dermatomyositis, and systemic lupus erythematosus.

- Significant medical history or unstable medical conditions.

- Concurrent use of warfarin. Patients must be off warfarin for at least one week prior
to initiation of erlotinib. Other non-warfarin anticoagulants are permitted.

- Patients who require ongoing concomitant use of one of the strong inhibitors/inducers
of CYP3A4.

- Pregnant or breastfeeding. Women of child-bearing potential must agree to use adequate
contraception prior to study entry and for the duration of study participation.