Radiation Therapy and Stereotactic Radiosurgery With or Without Temozolomide or Erlotinib in Treating Patients With Brain Metastases Secondary to Non-Small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. Compare survival in patients with non-small cell lung cancer and brain metastases treated
with whole brain radiotherapy and stereotactic radiosurgery with vs without temozolomide or
erlotinib.

SECONDARY OBJECTIVES:

I. Compare time to CNS progression in patients treated with these regimens. II. Compare
quality-adjusted survival in patients treated with these regimens. III. Compare 3-month
quality of life in patients treated with these regimens. IV. Compare the 6-month performance
status of patients treated with these regimens.

V. Compare 6-month steroid dependence in patients treated with these regimens. VI. Compare
cause of death (neurologic vs other) in patients treated with these regimens.

VII. Determine the effects of non-protocol chemotherapy in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age
and the presence of extracranial metastases (< 65 years old AND no extracranial metastases vs
≥ 65 years old OR extracranial metastases), number of metastases (1 vs 2 or 3), and extent of
extracranial disease (none vs present). Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients undergo whole brain radiotherapy (WBRT) once daily on days 1-5, 8-12, and
15-19. Within 14 days after completion of WBRT, patients undergo stereotactic radiosurgery.

ARM II: Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the
first day of WBRT, patients receive oral temozolomide once daily on days 1-21. Beginning 4
weeks after completion of WBRT, patients may receive oral temozolomide alone once daily on
days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses in the
absence of disease progression or unacceptable toxicity.

ARM III: Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the
first day of WBRT, patients receive oral erlotinib once daily for up to 6 months.

In all arms, patients with recurrent brain metastases may undergo additional stereotactic
radiosurgery.

Quality of life is assessed at baseline and at 3, 6, 9, 12, 18, and 24 months.

Patients are followed every 3 months for 2 years, every 6 months for 2 years, and then
annually thereafter.

Inclusion Criteria:

- Histologically confirmed non-small cell lung cancer

- One to 3 intraparenchymal brain metastases by contrast-enhanced MRI, meeting the
following criteria:

- Well circumscribed tumor(s)

- Maximum diameter ≤ 4.0 cm

- If multiple lesions are present and one lesion is at the maximum diameter,
the other lesions must not exceed 3.0 cm in maximum diameter

- No metastases within 10 mm of the optic apparatus such that a portion of the
optic nerve or chiasm would be included in the high-dose stereotactic
radiosurgery boost field

- No metastases in the brainstem, midbrain, pons, or medulla

- No prior complete resection of all known brain metastases

- Subtotal resection allowed provided residual disease is ≤ 4.0 cm in maximum
diameter

- No clinical or radiographic evidence of progression (other than study lesion[s])
within the past month

- Patients with brain metastases at initial presentation do not require 1 month of
scans documenting stable disease

- Stable extracranial metastases allowed

- No known or pre-existing liver metastases

- No leptomeningeal metastases by MRI or cerebrospinal fluid evaluation

- Synchronous brain metastases at initial diagnosis allowed

- Performance status - Zubrod 0-1

- Hemoglobin ≥ 8 g/dL

- Absolute neutrophil count ≥ 1,000/mm^3

- Platelet count ≥ 100,000/mm^3

- AST < 2 times upper limit of normal (ULN)

- Alkaline phosphatase < 2 times ULN unless due to elevated bone metastases

- Total bilirubin normal

- Lactic dehydrogenase < 2 times ULN

- Creatinine < 1.5 times ULN

- No clinically active interstitial lung disease

- Chronic stable asymptomatic radiographic changes allowed

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- HIV negative

- Neurologic function status 0-2

- No other major medical illness or psychiatric impairment that would preclude study
participation

- No history of allergic reaction attributed to compounds of similar chemical or
biologic composition to erlotinib or temozolomide

- No concurrent immunotherapy

- No concurrent biologic therapy, excluding growth factors and epoetin alfa

- No prior temozolomide or erlotinib

- No other concurrent chemotherapy during study radiotherapy

- Other concurrent chemotherapy allowed after study radiotherapy, except for the
following:

- Temozolomide or erlotinib (arm I only)

- Erlotinib (arm II only)

- Temozolomide (arm III only)

- No prior cranial radiotherapy

- No concurrent intensity-modulated radiotherapy

- Concurrent radiotherapy to painful bone lesions allowed

- No concurrent radiotherapy to more than 15% of bone marrow

- No other concurrent therapy for brain metastases unless a recurrence is detected

- More than 30 days since prior investigational drugs

- No concurrent enzyme-inducing antiepileptic drugs including, but not limited to, any
of the following (for patients randomized to receive erlotinib):

- Phenytoin

- Carbamazepine

- Rifampin

- Phenobarbital

- Primidone

- Oxcarbazepine

- No other concurrent investigational drugs

- No concurrent Hypericum perforatum (St. John's wort)

- No drugs that alter gastric pH (e.g., proton pump inhibitors or H2 antagonists) within
4 hours after erlotinib administration (arm III patients only)