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)

• 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.
• 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.
• 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.