Osimertinib in Treating Participants With Stage I-IIIA EGFR-mutant Non-small Cell Lung Cancer Before Surgery

PRIMARY OBJECTIVES:

I. To evaluate the efficacy of osimertinib as neoadjuvant therapy in patients with surgically
resectable EGFR-mutant non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVES:

I. To evaluate the safety of osimertinib given as neoadjuvant therapy in early stage
EGFR-mutant NSCLC participants.

II. To evaluate whether neoadjuvant osimertinib treatment increases the frequency of tumors
that are unresectable due to adverse events or disease progression.

III. To evaluate secondary measures of clinical efficacy in early stage EGFR-mutant NSCLC
patients treated with osimertinib induction therapy.

TERTIARY OBJECTIVES:

I. To evaluate long-term measures of efficacy in patients treated with osimertinib
neoadjuvant therapy.

II. To explore tissue and cell-free biomarkers that may be predictive of response or primary
resistance to osimertinib neoadjuvant therapy.

OUTLINE:

Participants receive osimertinib orally (PO) once daily (QD) on days 1-28. Treatment repeats
every 28 days for up to 2 cycles in the absence of disease progression or unacceptable
toxicity. Patients then undergo surgical resection of their cancer.

After completion of study treatment, participants are followed up at 30 days then every 3
months for up to 1 year.

Inclusion Criteria:

- Histologically or cytologically confirmed non-small cell lung cancer, performed on a
biopsy that occurred within the last 60 days

- Documented activating EGFR mutation (Exon 19 deletion, T790M, or L858R) on tumor
samples by Food and Drug Administration (FDA)-approved test

- Positron emission tomography (PET)-computed tomography (CT) within the last 60 days
showing radiographic stage I to IIIa lung cancer (mediastinal staging biopsy is
allowed but not required)

- Brain magnetic resonance imaging (MRI) (or CT if contraindication to MRI) within the
last 60 days showing no evidence of metastatic disease

- Documentation that the patient is a candidate for surgical resection of their lung
cancer by an American Board of Thoracic Surgery certified surgeon

- Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST)
1.1 criteria

- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1

- Resolution of all acute toxic effects of prior chemotherapy, radiotherapy or surgical
procedures to National Cancer Institute (NCI) Common Terminology Criteria for Adverse
Events (CTCAE) Version 4.03 grade 1

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
limit of normal (ULN)

- Bilirubin =< 1.5 x ULN, (Patients with documented Gilbert?s syndrome and conjugated
bilirubin within the normal range may be allowed into the study; in this event, it
will be documented that the patient was eligible based on conjugated bilirubin levels)

- Potassium and magnesium within normal range, patients may receive supplements to meet
this requirement

- Leukocytes > 3,000/mcL

- Hemoglobin >= 9 g/dL, with no blood transfusions in the 28 days prior to study entry

- Absolute neutrophil count > 1,500/mcL

- Platelets > 100,000/mcL

- Creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance > 50
mL/min/1.73 m2 for patients with creatinine levels =< 1.5 x upper limit above
institutional normal

- Ability to swallow oral medications

- Women of childbearing potential (WoCBP) must have a negative serum pregnancy test
within 3 days prior to the first dose of study treatment and agree to use highly
effective contraception, during the study and for 90 days following the last dose of
osimertinib

- Women of childbearing potential (WoCBP): women between menarche and menopause who
have not been permanently or surgically sterilized and are capable of procreation

- Women NOT of childbearing potential: women who are permanently or surgically
sterilized or postmenopausal

- Permanent sterilization includes hysterectomy and/or bilateral oophorectomy
and/or bilateral salpingectomy but excludes bilateral tubal occlusion; tubal
occlusion is considered a highly effective method of birth control but does
not absolutely exclude possibility of pregnancy; (the term occlusion refers
to both occluding and ligating techniques that do not physically remove the
oviducts)

- Women who have undergone tubal occlusion should be managed on trials as if they
are of WoCBP (e.g. undergo pregnancy testing etc., as required by the study
protocol)

- Women will be considered postmenopausal if they are amenorrhoeic for 12 months
without an alternative medical cause; the following age-specific requirements
apply:

- Women under 50 years old will be considered postmenopausal if they have been
amenorrhoeic for 12 months or more following cessation of exogenous hormonal
treatments and with luteinizing hormone and follicle-stimulating hormone
levels in the postmenopausal range

- Women over 50 years of age will be considered postmenopausal if they have
been amenorrhoeic for 12 months or more following cessation of all exogenous
hormonal treatments

- Acceptable contraception methods are:

- Total sexual abstinence (abstinence must be for the total duration of the
trial and the follow-up period)

- Vasectomized sexual partner plus male condom (with participant assurance
that partner received post-vasectomy confirmation of azoospermia)

- Tubal occlusion plus male condom

- Intra-uterine device - provided coils are copper-banded, plus male condom

- Intra-uterine system (IUS) levonorgestrel IUS (e.g., Mirena), plus male
condom

- Medroxyprogesterone injections (Depo-Provera) plus male condom

- Etonogestrel implants (e.g., Implanon, Norplan) plus male condom

- Normal and low dose combined oral contraceptive pills, plus male condom

- Norelgestromin / ethinylestradiol transdermal system plus male condom

- Intravaginal device (e.g., ethinylestradiol and etonogestrel) plus male
condom

- Cerazette (desogestrel) plus male condom (Cerazette is currently the only
highly efficacious progesterone based pill)

- Unacceptable Contraception Methods The following methods are considered not to be
highly effective and are therefore not acceptable contraceptive methods:

- Triphasic combined oral contraceptives

- All progesterone only pills except, Cerazette

- All barrier methods, if intended to be used alone

- Non-copper containing intra-uterine devices

- Fertility awareness methods

- Coitus interruptus

- Men with a female partner of childbearing potential must have either had a prior
vasectomy agree to use effective contraception as described in the full protocol for
at least 14 days prior to administration of the first dose of study treatment, during
the study, and for 90 days following the last dose of osimertinib

Exclusion Criteria:

- Leptomeningeal carcinomatosis or other central nervous system (CNS) metastases

- Stage IIIB, or distant metastases (including malignant pleural effusion) identified on
PET-CT scan or biopsy (PET abnormalities that are negative for malignancy on biopsy
will be considered on a case by case basis

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

- History of confirmed, corneal ulceration

- Patients who are known to be serologically positive for human immunodeficiency virus
(HIV)

- Active second malignancy, i.e. patient known to have potentially fatal cancer present
for which he/she may be (but not necessarily) currently receiving treatment; patients
with a history of malignancy that has been completely treated, with no evidence of
that cancer currently, are permitted to enroll in the trial provided all chemotherapy
for prior malignancy was completed > 12 months prior and/or bone marrow transplant > 2
years prior

- Patients who are currently receiving treatment with contraindicated corrected QT
interval (QTc) prolonging medications or potent CYP3A4 inducers, if that treatment
cannot be either discontinued or switched to a different medication prior to first day
of study treatment

- Any of the following cardiac abnormalities or history:

- Mean resting corrected QT interval (QTc) > 470 msec, obtained from 3
electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc
value

- Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG e.g. complete left bundle branch block, third degree heart block and
second degree heart block

- Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalaemia, congenital long QT syndrome, family
history of long QT syndrome or unexplained sudden death under 40 years of age in
first degree relatives or any concomitant medication known to prolong the QT
interval

- Treatment with prohibited medications (concurrent anticancer therapy including
chemotherapy, radiation, hormonal treatment [except corticosteroids and
megesterolacetate], or immunotherapy) =< 14 days prior to treatment with osimertinib

- Prior treatment with osimertinib or other drugs that target EGFR mutant non-small cell
lung cancer (including erlotinib, afatinib, gefitinib, rocelitinib)

- Any evidence of severe or uncontrolled systemic diseases, including uncontrolled
hypertension and active bleeding diatheses, which in the investigator?s opinion makes
it undesirable for the patient to participate in the trial or which would jeopardize
compliance with the protocol, or known active infection including chronic active
hepatitis B, hepatitis C and human immunodeficiency virus (HIV); screening for chronic
conditions is not required; patients with chronic hepatitis B virus (HBV) with
negative HBV viral load on appropriate antiviral therapy will be permitted, if able to
continue appropriate antiviral therapy throughout treatment period

- Active tuberculosis

- Signs or symptoms of infection within 2 weeks prior to first day of study

- Therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to first day of
study treatment:

- Patients receiving prophylactic antibiotics (eg, to prevent a urinary tract
infection or chronic obstructive pulmonary disease exacerbation) are eligible

- Class II to IV heart failure as defined by the New York Heart Association functional
classification system

- Patients with known coronary artery disease, congestive heart failure not meeting the
above criteria, or left ventricular ejection fraction (LVEF) < 50% must be on a stable
medical regimen that is optimized in the opinion of the treating physician, in
consultation with a cardiologist if appropriate, to be eligible

- Patients who have experienced untreated and/or uncontrolled cardiovascular conditions
and/or have symptomatic cardiac dysfunction (unstable angina, congestive heart
failure, myocardial infarction within the previous 3 months; coronary angioplasty, or
stenting or bypass grafting within the past 6 months; cardiac ventricular arrhythmias
requiring medication; any history of second (2nd) or third (3rd) degree
atrioventricular conduction defects)

- Females who are pregnant or breastfeeding

- Presence of active gastrointestinal (GI) disease (including GI bleeding or ulceration)
or other condition that could affect GI absorption (e.g. malabsorption syndrome,
history of biliary tract disease), including refractory nausea or vomiting, or chronic
GI disease which may affect absorption or tolerance to oral medications

- History of hypersensitivity to active or inactive excipients of osimertinib or drugs
with a similar chemical structure or class to osimertinib

- Involvement in the planning and/or conduct of the study (applies to both investigator
staff and/or staff at the study site)

- Participation in another clinical study with an investigational product during the
last 2 months or within five half-lives of the compound, whichever is longer

- Uncontrolled medical, psychological, familial, sociological, or geographical
conditions that interfere with the patient?s safety, ability to provide informed
consent, or ability to comply with the protocol