Hypotheses:

Short-term - Targeted therapy with erlotinib or crizotinib plus PART (Personalized Adaptive Radiation Therapy) will be safe and will yield favorable outcomes in patients with stage III, EGFR (Epidermal Growth Factor Receptor) + or ALK (Anaplastic Lymphoma Kinase) + NSCLC (Non-Small Cell Lung Cancer).

Long-term - In patients with stage III NSCLC harboring driver mutations, treatment with relevant targeted agents plus PART will improve both local-regional and systemic tumor control resulting in improved survival relative to standard chemoradiotherapy.

The proposed trial is a pilot study that will accrue 30 patients with inoperable stage IIIA/B NSCLC harboring either an EGFR mutation (n=20) or an ALK rearrangement (n=10). Patients with EGFR+ tumors will be treated with erlotinib 150 mg orally QD; patients with ALK+ tumors will be treated with crizotinib 250 mg orally BID. Treatment consists of six weeks of concurrent PART plus erlotinib or crizotinib, followed by erlotinib or crizotinib for a total of 1 year. All patients will be treated with response-driven PART with dose intensified to the active (FDG-avid) region based on a mid-treatment FDG-PET/CT scan while maintaining dose limits for organs-at-risk. The primary endpoints will be PFS and OS. Primary analyses will be performed separately for ALK+ and EGFR+ patients. The secondary endpoint of treatment-related toxicity will focus on pneumonitis and esophagitis with a strict stopping rule in place.

Current standard therapy affords suboptimal outcomes for patients with locally advanced NSCLC due to both locoregional and distant recurrences. Since targeted therapy is more effective than chemotherapy in patients with relevant driver mutations, the best way to significantly improve outcomes in this subgroup of patients is to optimize systemic therapy with targeted agents while improving local control with PET-adapted, high-dose RT.

Inclusion Criteria:

• Patients with FDG-avid (radioactive glucose) and pathologically proven stage IIA-IIB or IIIA-IIIB non-small cell lung cancer (according to AJCC [American Joint Committee on Cancer] staging, 7th edition).
• Patients with tumors that harbor either EGFR sensitizing mutations or ALK rearrangement.
• Patients must be considered unresectable or medically inoperable; patients who decline surgery are also eligible.
• Patients must be 18 years of age or older.
• Patients with ECOG (Eastern Cooperative Oncology Group) performance status of 0-2.
• Patients must have adequate organ function.
• Patients must be able to take oral medications.
• Women with reproductive capability must be willing to use effective contraception.
• Patients must be informed of the investigational nature of this study and sign written informed consent in accordance with institutional and federal guidelines.
• Patients must be willing to comply with study procedures.

Exclusion Criteria:

• Patients with tumors that have a component of small cell carcinoma.
• Patients wtih stage I, II, or IV disease, including malignant pleural or pericardial effusion.
• Prior radiotherapy to the thorax such that composite radiation would significantly over-dose critical structures, either per estimation of the treating radiation oncologist or defined by failure to meet normal tissue tolerance constraints.
• Patients who cannot tolerate thoracic radiotherapy or targeted therapy.
• Patients wtih a prior diagnosis of interstitial lung disease or pulmonary fibrosis.
• Patients who cannot take oral medication, require intravenous alimentation, had prior surgical procedures affecting gastrointestinal absorption, or have active peptic ulcer disease.
• Hypersensitivity to erlotinib, crizotinib, or to any of the excipients.
• Pregnant women are excluded from this study because radiation has the potential for teratogenic or abortifacient effects.
• Prisoners are excluded from this study.