-02341066 and PF-00299804 for Advanced Non-Small Cell Lung Cancer

* INCLUSION CRITERIA: * Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator s study team before subjects are included in the study. * Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study. * Subjects must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. * Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study: * Disease Criteria: * Dose Escalation Phase: Histologically proven diagnosis of NSCLC that is locally advanced or metastatic, after failure of either at least one prior chemotherapy regimen or targeted therapy. * Expansion Phase: Histologically proven diagnosis of NSCLC that is locally advanced or metastatic and with acquired resistance to erlotinib or gefitinib. Acquired resistance is defined as progression following either an initial response (complete or partial), or stable disease for at least six months, while on single agent erlotinib or single agent gefitinib. In addition to these patients, Cohort 2 will also enroll patients from ongoing trials, including A7471017 and A7471028, who have progressed on single agent PF-00299804. * For the dose escalation phase, any prior treatment (chemotherapy, targeted therapy, radiation or surgery) must have been completed at least 2 weeks prior to initiation of study medication, except patients being treated with single agent PF-02341066 will have the option of continuing single agent PF-02341066 until the combination of PF- 02341066 and PF-00299804 is given. For the expansion phase, patients must not have had any intervening treatmen (chemotherapy, targeted therapy, radiation or surgery) between single agent erlotinib or single agent gefitinib treatment, and biopsy and dosing with study drug, unless agreed by the sponsor. In Expansion Cohort 2, patients who have received PF-00299804 as part of an ongoing clinical trial will continue with single agent therapy with PF-00299804 at their current dose after documentation of progression until the combination is given. * Any acute toxicity from prior treatment must have been recovered to less than or equal to Grade 1 (except alopecia). * At least 1 target lesion used for assessment of antitumor activity must be measurable by RECIST (version 1.1), or considered evaluable by agreement between the investigator and the sponsor. * Target lesions can be chosen from a previous irradiated area if lesions in those areas have documented progression. * Female or male, 18 years of age or older. * ECOG (Zubrod) performance status 0-2. * Adequate organ function as defined by the following criteria measured within 7 days prior to enrollment. * Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) less than or equal to 2.5 times upper limit of normal (ULN), or AST and ALT less than or equal to 5 times ULN if liver function abnormalities are due to underlying malignancy; * Total serum bilirubin less than or equal to 1.5 times ULN (except patients with documented Gilbert s syndrome); * Absolute neutrophil count (ANC) greater than or equal to1000/microL; * Platelets greater than or equal to 30,000/microL; * Hemoglobin greater than or equal to 8.0 g/dl; * Serum creatinine \<2 times institution ULN. * Adequate cardiac function, including: * 12-Lead electrocardiogram (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention; * QTc interval less than or equal to 470 msec and without history of Torsades de Pointes or other symptomatic QTc abnormality; * LVEF (by MUGA or echocardiogram) of greater than or equal to 50%. * All female patients of child-bearing potential are required to have a negative pregnancy test at screening. The test should be repeated whenever one menstrual cycle is missed during treatment or a potential pregnancy is otherwise suspected. * Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, other study procedures and, for enrollment into the Expansion Phase, must be willing to undergo a tumor biopsy. EXCLUSION CRITERIA: Subjects presenting with any of the following will not be included in the study: * Participation in other studies or treatment within 2 weeks before the current study begins and/or during study participation (with the exception of patients who are receiving single agent PF-00299804 and who enroll into Expansion Cohort 2 from ongoing trials including A7471017 and A7471028, and with the exception of patients being treated with single agent PF-02341066 treatment who enroll during the dose escalation phase and exercise the option of continuing single agent PF-02341066 treatment until the combination of PF-02341066 and PF-00299804 is given) to allow for recovery and drug wash-out. * Known interstitial fibrosis or interstitial lung disease. * Patients with known brain metastases who are neurologically stable (asymptomatic) for at least 2 weeks and with no ongoing requirement for corticosteroids may enroll on study before treatment of brain metastases. * History of carcinomatous meningitis, or leptomeningeal disease. * Any of the following within 6 months prior to starting study treatment: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, congestive heart failure, cerebrovascular accident including transient ischemic attack. * Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation or Torsades de Pointes). Diagnosed or suspected congenital long QT syndrome. Ongoing cardiac dysrhythmias of Grade greater than or equal to 2 (CTCAE version 4.02), uncontrolled atrial fibrillation of any grade, or QTc interval \>470 msec. * Hypertension that cannot be controlled by medications (\>150/100 mmHg despite optimal medical therapy). * Patient must not have had major surgery or trauma within 28 days prior to enrollment. * Active uncontrolled infection. * Pregnant or lactating females. * Significant gastrointestinal condition that may impair intake, transit, absorption or ability to tolerate investigational drugs. * Prior malignancy (other than NSCLC): patients will not be eligible if they have evidence of active malignancy (other than non-melanoma skin cancer or in situ cervical cancer, or localized and presumed cured prostate cancer with PSA \< ULN) within the last 3 years. * Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study. * Use of drugs or foods that are known potent CYP3A4 inhibitors within 7 days prior to the first dose of study medication, including but not limited to itraconazole, ketoconazole, miconazole, clarithromycin, erythromycin, indinavir, nefazodone, amprenavir, delavirdine, nelfinavir, ritonavir, saquinavir, diltiazem, verapamil and grapefruit juice. * Use of drugs that are known potent CYP3A4 inducers within 12 days prior to the first dose of study medication, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifabutin, rifampin, tipranavir, ritonavir, and St. John s wort. * Concurrent use of drugs that are CYP3A4 substrates with narrow therapeutic indices, including but not limited to pimozide, aripiprazole, triazolam, ergotamine and halofantrine. * Concurrent use of drug that are highly dependent on CYP2D6 metabolism including S-metoprolol, propafenone, timolol, amitriptyline, clomipramine, desipramine, imipramine, paroxetine, haloperidol, risperidone, thioridazine, codeine, flecainide, mexilletine, tamoxifen, venlafaxine. Dextromethorphan, a CYP2D6, substrate is allowed if medically indicated and no suitable alternative anti-tussive medication is available. However, the dose of dextromethorphan may need to be modified. In a clinical study in healthy volunteers who were extensive metabolizers (A7471039) PF-00299804 increased mean total exposure (AUC(last) and C(max)) of dextromethorphan 855% and 874%, respectively, following concomitant administration with PF-00299804 45 mg compared to exposure of administration of dextromethorphan alone. Extensive metabolizers comprise approximately 80% of the population, with ultra-, intermediate-, and poor-metabolizers accounting for the remaining portion of the general population. Therefore, if no alternative is available dextromethorphan dosing should be initiated at a lower dose (approx 25%) with close monitoring of patient clinical status. Dose increases or decreases of dextromethorphan may be considered based upon individual patient tolerability. Lidocaine may be used systemically with clinical monitoring (including telemetry). Opiates such as morphine, oxycodone, dihydrocodeine, hydrocodone, and tramadol can be used as substitutes to replace codeine. Use of these opiates should be monitored for altered analgesic effect during treatment as they may be partly metabolized by CYP2D6.