Osimertinib Alone or with Chemotherapy for EGFR-Mutant Lung Cancers

Inclusion Criteria: Inital

• Age ≥ 18 years

• Biopsy proven metastatic non-small cell lung cancer, confirmed at enrollinginstitution

• Somatic activating mutation in EGFR in pre-treatment tumor biopsy/ cytology frompleural fluid or cfDNA

• Either have not started a prior EGFR TKI therapy or may have started osimertinibwithin 3 weeks of confirming eligibility and enrollment criteria of measurabledisease per approval of PI, with no prior chemotherapy for treatment of metastaticdisease (adjuvant therapy > 6 months prior to study start is acceptable)

• Measurable (RECIST 1.1) indicator lesion not previously irradiated with measurabledisease determined per treating investigator. If a patient has already started onosimertinib there must be available pre-osimertinib baseline tumor assessments, tobe utilized for RECIST 1.1 assessment.

• Karnofsky performance status (KPS)≥70%,

• Ability to swallow oral medications

• Adequate organ function (use of G-CSF and/or transfusion to meet these criteria arenot allowed)

• Hemoglobin ≥ 9 g/dL

• Platelets ≥ 150,000mm^3 or 150 x 10^9/L

• AST, ALT ≤ 2.5 x ULN with no liver metastases or < 5x ULN with the presence ofliver metastases

• Total bilirubin ≤ 1.5 x ULN if no liver metastases or < 3 x ULN in the presenceof documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or livermetastases

• Absolute neutrophil count (ANC) ≥ 1500 cells/mm^3

• Creatinine ≤ ULN OR calculated creatinine clearance ≥ 60ml/min calculated byCockcroft and Gault equation

• Creatinine clearance ≥ 60 mL/min calculated by Cockcroft and Gault equation

• Willing to use highly effective contraceptive measures if of child-bearing potentialor if the patient's sexual partner is a woman of child-bearing potential:

• Female subjects should be using highly effective contraceptive measures, andmust have a negative pregnancy test and not be breast-feeding prior to start ofdosing through 6 weeks after discontinuing the study drug if of child-bearingpotential or must have evidence of non-child-bearing potential by fulfillingone of the following criteria at screening:

• Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments

• Women under 50 years old would be consider postmenopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and with LH and FSH levels in the post-menopausal range for theinstitution

• Documentation of irreversible surgical sterilization by hysterectomy, bilateraloophorectomy or bilateral salpingectomy but not tubal ligation

• Male subjects should be willing to use barrier contraception and avoid spermdonation prior to the start of dosing through 4 months of discontinuing thestudy drug

Exclusion Criteria: Initial

• Pregnant or lactating women

• Any radiotherapy within 1 week prior to starting treatment on protocol. The washoutwindow only applies for patients who have not started Osimertinib.

• Any major surgery within 2 weeks of starting treatment on protocol. The washoutwindow only applies for patients who have not started Osimertinib.

• Any evidence of clinically significant interstitial lung disease

• Treatment with an investigational drug within five half-lives of the compound or 3months, whichever is greater

• Currently receiving (or unable to stop prior to receiving the first dose of studytreatment) medications or herbal supplements known to be strong inducers of CYP3A4.All patients must try to avoid concomitant use of any medications, herbalsupplements and/or ingestion of foods with known inducer effects on CYP3A4.

• Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the timeof starting study treatment, with the exception of alopecia and grade 2 priorplatinum-therapy- related neuropathy

• Any evidence of severe or uncontrolled systemic diseases, including uncontrolledhypertension and active bleeding diatheses, which in the investigator's opinionmakes it undesirable for the patient to participate in the trial

• active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.

• Screening for chronic conditions is not required.

• In patients with resolved or chronic hepatitis B infection (inactive carrier state)or active controlled HBV infection on treatment with osimertinib

• Recommend monthly monitoring of ALT/AST, HBV DNA levels and HBsAg (if negativeat baseline)

• Where liver signs and symptoms of viral reactivation appear (HBV DNA levelsexceeding 10-fold from baseline or ≥100 IU/ml (if baseline HBV DNA levels areundetectable) or conversion of HBsAg negative to positive):

• Expert hepatologist/specialist oversight of the patient is required

• Consider interruption or discontinuation of study treatment, based onriskbenefit assessment

• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability toswallow the tablets or previous significant bowel resection that would precludeadequate absorption of osimertinib.

• Any of the following cardiac criteria:

• Mean resting corrected QT interval (QTc) > 470 msec where QT interval iscorrected for heart rate using Frederica's formula (QTcF).

• Any clinically important abnormalities in rhythm, conduction or morphology ofresting ECG e.g. complete left bundle branch block, third degree heart blockand second degree heart block.

• Patient with any factors that increase the risk of QTc prolongation or risk ofarrhythmic events such as heart failure, electrolyte abnormalities (including:Serum/Plasma potassium

• Past medical history of interstitial lung disease, drug-induced interstitial lungdisease, radiation pneumonitis which required steroid treatment, or any evidence ofclinically active interstitial lung disease.

• History of hypersensitivity to active or inactive excipients of osimertinib or drugswith a similar chemical structure or class to osimertinib.

• Judgment by the investigator that the patient should not participate in the study ifthe patient is unlikely to comply with study procedures, restrictions andrequirements.

Inclusion Criteria: Randomization

• Patients with detectable plasma EGFR mutations at C2D1

• Karnofsky performance status (KPS) ≥ 70%

• Adequate organ function

• Hemoglobin ≥ 9 g/dL

• Platelets ≥ 100,000mm^3 or 100 x 10^9/L

• Creatinine ≤ ULN OR calculated creatinine clearance ≥ 60ml/min

• AST, ALT ≤ 3x ULN with no liver metastases or ≤ 5x ULN with the presence ofliver metastases

• Total bilirubin ≤ 1.5 x ULN if no liver metastases or ≤ 3 x ULN in the presenceof documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or livermetastases

• Absolute neutrophil count (ANC) ≥ 1500 cells/mm3Must have at least stabledisease per RECIST 1.1 assessment prior to initiating chemotherapy at C4D1

• Eligibility testing (KPS, bloodwork) should be tested at C3D1. If the subject'sevaluation does not meet eligibility criteria, any result obtained between C3and C4 can be used

Please note: All 'Initial' Exclusion Criteria must be re-confirmed prior to randomization.