A Study of ASP8273 vs. Erlotinib or Gefitinib in First-line Treatment of Patients With Stage IIIB/IV Non-small Cell Lung Cancer Tumors With EGFR Activating Mutations

Inclusion Criteria:

• Subject agrees not to participate in another interventional study while ontreatment.

• Female subject must either:

• Be of nonchildbearing potential: postmenopausal (defined as at least 1 yearwithout any menses) prior to Screening, or documented surgically sterile

• Or, if of childbearing potential: Agree not to try to become pregnant duringthe study and for 28 days after the final study drug administration; And have anegative serum pregnancy test at Screening; And, if heterosexually active,agree to consistently use 2 forms of highly effective birth control (at least 1of which must be a highly effective method and one must be a barrier method)starting at Screening and throughout the study period and for 28 days after thefinal study drug administration.

• Female subject must not be breastfeeding at Screening or during the study period,and for 28 days after the final study drug administration.

• Female subject must not donate ova starting at Screening and throughout the studyperiod, and for 28 days after the final study drug administration.

• Male subject and their female spouse/partners who are of childbearing potential mustbe using highly effective contraception consisting of 2 forms of birth control (1 ofwhich must be a barrier method) starting at Screening and continue throughout thestudy period and for 90 days after the final study drug administration.

• Male subject must not donate sperm starting at Screening and throughout the studyperiod and for 90 days after the final study drug administration.

• Subject has Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

• Subject has histologically confirmed locally advanced, metastatic or unresectableStage IIIB/IV adenocarcinoma NSCLC (newly diagnosed or recurrent). Subjects withmixed histology are eligible if adenocarcinoma is the predominant histology.

• Subject has predicted life expectancy ≥ 12 weeks in the opinion of the investigator.

• Subject must meet all of the following criteria on the laboratory tests that will beanalyzed centrally within 7 days prior to the first dose of study drug. In case ofmultiple 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 glomerularfiltration rate (eGFR) of > 50 mL/min as calculated by the Cockcroft GaultMethod

• Total bilirubin ˂1.5 x ULN (except for subjects with documented Gilbert'ssyndrome)

• AST and ALT ˂ 3.0 x ULN or ≤ 5 x ULN if subject has documented liver metastases

• Serum sodium level is ≥ 130 mmol/L

• Subject has an EGFR activating mutation (exon 19 deletion or exon 21 L858R), with orwithout T790M mutation, by local or central testing on examination of a NSCLC FFPEspecimen (archival or fresh biopsy). Subjects harboring both exon 19 deletion andexon 21 L858R mutations are not eligible. A tissue sample from the same block usedto determine eligibility by local testing should be available to send to the centrallab for confirmatory testing. Subjects randomized based on local results indicatingpresence of EGFR mutation may remain on study if central results are discordant.

• Subject must have at least 1 measureable lesion based on RECIST V1.1. Previouslyirradiated lesions will not be considered as measurable lesions.

Exclusion Criteria:

• Subject has received intervening anticancer treatment or previous treatment withchemotherapy for metastatic disease other than palliative local radiation to painfulbone metastases completed at least 1 week prior to the first dose of study drug. Theadministration of neoadjuvant or adjuvant chemotherapy is allowed as long as it hasfinalized ≥ 6 months before the first dose of study drug.

• Subject has received a prior treatment with a therapeutic agent targeting EGFR (e.g., afatinib, dacomitinib, ASP8273, etc).

• Subject has received investigational therapy within 28 days or 5 half-lives prior tothe first dose of study drug.

• Subject has received radiotherapy within 1 week prior to the first dose of studydrug. If the subject received radiotherapy > 1 week prior to study treatment, theirradiated lesion cannot be the only lesion used for evaluating response.

• Subject has symptomatic central nervous system (CNS) metastasis. Subject withpreviously treated brain or CNS metastases are eligible provided that the subjecthas recovered from any acute effects of radiotherapy, does not have brain metastasisrelated symptoms, is not requiring systemic steroids for at least 2 weeks prior tostudy drug administration, and any whole brain radiation therapy was completed atleast 4 weeks prior to study drug administration, or any stereotactic radiosurgery (SRS) was completed at least 2 weeks prior to study drug administration. Steroidinhaler use or ointment treatment for other concomitant medical disease ispermitted.

• Subject has received blood transfusions or hematopoietic factor therapy within 14days prior to the first dose of study drug.

• Subject has had a major surgical procedure (other than a biopsy) within 14 daysprior to the first dose of study drug, or one is planned during the course of thestudy.

• Subject has a known history of a positive test for human immunodeficiency virus (HIV) infection.

• Subject has known history of serious hypersensitivity reaction to a known ingredientof ASP8273, erlotinib or gefitinib.

• Subject has evidence of an active infection requiring systemic therapy within 14days prior to the planned first dose of study drug.

• Subject has severe or uncontrolled systemic diseases including uncontrolledhypertension (blood pressure > 150/100 mmHg) or active bleeding diatheses.

• Subject has history of drug-induced interstitial lung disease (ILD) or any evidenceof active ILD.

• Subject has ongoing cardiac arrhythmia that is Grade ≥ 2 or uncontrolled atrialfibrillation of any grade.

• Subject currently has Class 3 or 4 New York Heart Association congestive heartfailure.

• Subject has history of severe/unstable angina, myocardial infarction orcerebrovascular accident within 6 months prior to the planned first dose of studydrug.

• Subject has history of gastrointestinal ulcer or gastrointestinal bleeding within 3months prior to the planned first dose of study drug.

• Subject has concurrent corneal disorder or any ophthalmologic condition which, inthe investigator's opinion, makes the subject unsuitable for study participation (i.e., advanced cataracts, glaucoma).

• Subject has difficulty taking oral medication or any digestive tract dysfunction orinflammatory bowel disease that would interfere with the intestinal absorption ofdrug.

• Subject has another past or active malignancy which requires treatment. Priorcarcinoma in situ or non-melanoma skin cancer after curative resection arepermitted.

• Subject has any condition which, in the investigator's opinion, makes the subjectunsuitable for study participation.

• Subject has received potent CYP 3A4 inhibitors within 7 days prior to first dose ofstudy drug or proton pump inhibitors such as omeprazole within 14 days prior tofirst dose of study drug.