Inclusion Criteria

• No participation in another interventional study while on treatment
• Female subject must
  • Be of nonchildbearing potential
    • Postmenopausal (defined as at least 1 year without any menses) prior to screening
    • Documented surgically sterile
  • If of childbearing potential
    • Agree to not try to become pregnant during the study and for 28 days after the final study drug administration
    • Have a negative serum pregnancy test at screening
  • If heterosexually active
    • Agree to consistently use 2 forms of highly effective birth control
      • At least 1 method must be a highly effective method and one must be a barrier method
      • Used throughout the study period starting at screening and for 28 days after the final study drug administration
  • Must not be breastfeeding at screening or during the study period, and for 28 days after the final study drug administration
  • Must not donate ova starting at screening and throughout the study period, and for 28 days after the final study drug administration
• Males and their female partners who are of childbearing potential
  • Must be using highly effective contraception consisting of 2 forms of birth control (1 of which must be a barrier method) starting at screening and continue throughout the study period and for 90 days after the final study drug administration
  • Must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration
• Has Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Has histologically confirmed, locally advanced, metastatic or unresectable stage IIIB/IV adenocarcinoma NSCLC (newly diagnosed or recurrent)
• Has mixed histology and adenocarcinoma is the predominant histology
• Has predicted life expectancy ≥ 12 weeks in the opinion of the investigator
• Must meet all of the following criteria on the laboratory tests that will be analyzed centrally within 7 days prior to the first dose of study drug
  • In case of multiple laboratory data within this period, the most recent data should be used
    • Neutrophil count > 1,000/mm3
    • Platelet count ≥ 7.5 x 104 /mm3
    • Hemoglobin > 8.0 g/dL
    • Serum creatinine ˂ 2.0 x upper limit of normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 mL/min as calculated by the Cockcroft Gault Method
    • Total bilirubin ˂ 1.5 x ULN (except for subjects with documented Gilbert's syndrome)
    • AST and ALT ˂ 3.0 x ULN or ≤ 5 x ULN if subject has documented liver metastases
    • Serum sodium level is ≥ 130 mmol/L
• Has an EGFR activating mutation (exon 19 deletion or exon 21 L858R), with or without T790M mutation by local or central testing of specimen (archival or fresh biopsy) 
  • Having both exon 19 deletion and exon 21 L858R mutations is not eligible
  • A tissue sample from the same block used to determine eligibility by local testing should be available to send to the central lab for confirmatory testing
  • If randomized based on local results indicating presence of EGFR mutation, may remain on study if central results are discordant
• Must have at least 1 measureable lesion based on RECIST V1.1
  • Previously irradiated lesions will not be considered as measurable lesions

Exclusion Criteria

• Has received intervening anticancer treatment or previous treatment with chemotherapy for metastatic disease other than palliative local radiation to painful bone metastases completed at least 1 week prior to the first dose of study drug
  • The administration of neoadjuvant or adjuvant chemotherapy is allowed as long as it has finalized ≥ 6 months before the first dose of study drug
• Has received a prior treatment with a therapeutic agent targeting EGFR (e.g., afatinib, dacomitinib, ASP8273, etc)
• Has received investigational therapy within 28 days or 5 half-lives prior to the first dose of study drug 
• Has received radiotherapy within 1 week prior to the first dose of study drug
• If radiotherapy was received > 1 week prior to study treatment, the irradiated lesion cannot be the only lesion used for evaluating response
• Has symptomatic central nervous system (CNS) metastasis
  • Previously treated brain or CNS metastases is eligible provided the subject
    • Has recovered from any acute effects of radiotherapy
    • Does not have brain metastasis related symptoms
    • Is not requiring systemic steroids for at least 2 weeks prior to study drug administration
    • Any whole brain radiation therapy was completed at least 4 weeks prior to study drug administration
    • Any stereotactic radiosurgery  was completed at least 2 weeks prior to study drug administration
      • Steroid inhaler use or ointment treatment for other concomitant medical disease is permitted
• Has received blood transfusions or hematopoietic factor therapy within 14 days prior to the first dose of study drug
• Has had a major surgical procedure (other than a biopsy) within 14 days prior to the first dose of study drug, or one is planned during the course of the study
• Has a known history of a positive test for human immunodeficiency virus (HIV) infection
• Has known history of serious hypersensitivity reaction to a known ingredient of ASP8273, erlotinib or gefitinib
• Has evidence of an active infection requiring systemic therapy within 14 days prior to the planned first dose of study drug
• Has severe or uncontrolled systemic diseases including uncontrolled hypertension (blood pressure > 150/100 mmHg) or active bleeding diatheses
• Has history of drug-induced interstitial lung disease (ILD) or any evidence of active ILD
• Has ongoing cardiac arrhythmia that is grade ≥ 2 or uncontrolled atrial fibrillation of any grade
• Currently has class 3 or 4 New York Heart Association congestive heart failure
• Has history of severe/unstable angina, myocardial infarction or cerebrovascular accident within 6 months prior to the planned first dose of study drug
• Has history of gastrointestinal ulcer or gastrointestinal bleeding within 3 months prior to the planned first dose of study drug
• Has concurrent corneal disorder or any ophthalmologic condition which, in the investigator's opinion, makes the subject unsuitable for study participation (i.e., advanced cataracts, glaucoma)
• Has difficulty taking oral medication or any digestive tract dysfunction or inflammatory bowel disease that would interfere with the intestinal absorption of drug 
• Has another past or active malignancy which requires treatment
  • Prior carcinoma in situ or non-melanoma skin cancer after curative resection are permitted
• Has any condition which, in the investigator's opinion, makes the subject unsuitable for study participation
• Has received potent CYP 3A4 inhibitors within 7 days prior to first dose of study drug or proton pump inhibitors such as omeprazole within 14 days prior to first dose of study drug