Study of Osimertinib and Stereotactic Ablative Radiation (SABR) in EGFR Mutant NSCLC

Patients with EGFR mutant non-small cell lung cancer will receive the current optimal therapy
with osimertinib. After 8 weeks of targeted therapy, there will likely be some persisting
lesions that would not have completely regressed. These persisting lesions would likely
consist of cells that are less sensitive to targeted therapy. From the data summarized above
[14], these persisting lesions are most to subsequently develop resistance and demonstrate
progression.

To delay the onset of clinical progression, lesions that persist after 8 weeks of osimertinib
therapy and are amenable to stereotactic ablative radiation will be radiated. Osimertinib
will be held for 3 days before the first dose of radiation and resumed 3 days after the last
dose.

After radiation, all patients will continue osimertinib therapy. If subsequently there is any
evidence of progression, there will be an assessment of whether a repeat course of radiation
is feasible. If it is feasible to repeat SABR to sites of progression, this will be performed
and osimertinib resumed. If SABR is not possible, then a change in systemic therapy will be
required.

Inclusion Criteria

- Written informed consent

- Age > 18 years

- Advanced EGFR exon 19 or 21 mutant NSCLC, not amenable to curative surgery or
radiotherapy. EGFR mutations may be demonstrated by standard, clinically accepted
methods, including direct gene sequencing, PCR, and NextGen sequencing.

- World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance
status 0-2.

- Patients must have a life expectancy ≥ 12 weeks.

- Females should be using adequate contraceptive measures, should not be breast feeding
and must have a negative pregnancy test prior to start of dosing if of child-bearing
potential or must have evidence of non-child-bearing potential by fulfilling one 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 been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and with LH and FSH levels in the post-menopausal range for the
institution

- Documentation of irreversible surgical sterilisation by hysterectomy, bilateral
oophorectomy or bilateral salpingectomy but not tubal ligation

- Male patients should be willing to use barrier contraception.

- Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.

- At least one lesion, not previously irradiated, that can be accurately assessed at
baseline with computed tomography (CT) or magnetic resonance imaging (MRI) and which
is suitable for accurate repeated measurements.

- Adequate bone marrow reserve or organ function as demonstrated by any of the following
laboratory values:

- Absolute neutrophil count >1.5 x 109/L

- Platelet count >100 x 109/L

- Haemoglobin >9.0 g/dL (transfusion is permitted to achieve Hgb ≥9.0 g/dL)

- Alanine aminotransferase <2.5 times the upper limit of normal (ULN) if no
demonstrable liver metastases or <5 times ULN in the presence of liver metastases

- Aspartate aminotransferase <2.5 times ULN if no demonstrable liver metastases or
<5 times ULN in the presence of liver metastases

- Total bilirubin <1.5 times ULN if no liver metastases or <3 times ULN in the
presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or
liver metastases

- Serum Creatinine <1.5 times ULN concurrent with creatinine clearance >50 ml/min
(measured or calculated by Cockcroft and Gault equation); confirmation of
creatinine clearance is only required when creatinine is >1.5 times ULN.

Exclusion Criteria

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

- Previous treatment with osimertinib or any EGFR TKI.

- Previous treatment with immunotherapy or any check point inhibitors.

- Treatment with an investigational drug within five half-lives of the compound

- Patients currently receiving (or unable to stop use prior to receiving the first dose
of study treatment) medications or herbal supplements known to be potent inducers of
CYP3A4 (at least 3 week prior) (Appendix A). All patients must try to avoid
concomitant use of any medications, herbal supplements and/or ingestion of foods with
known inducer effects on CYP3A4.

- Any unresolved toxicities from prior therapy greater than Common Terminology Criteria
for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the
exception of alopecia and grade 2, prior platinum-therapy related neuropathy.

- 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 jeopardise
compliance with the protocol, or active infection including hepatitis B, hepatitis C
and human immunodeficiency virus (HIV). Screening for chronic conditions is not
required.

- Patients with symptomatic CNS metastases who are neurologically unstable

- Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid
treatment, or any evidence of clinically active ILD

- Any of the following cardiac criteria:

- Mean resting corrected QT interval (QTc using Fredericia's formula) > 470 msec

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

- Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalemia, 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

- Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow the formulated product or previous significant bowel resection that would
preclude adequate absorption of osimertinib

- History of hypersensitivity to osimertinib (or drugs with a similar chemical structure
or class to osimertinib) or any excipients of these agents

- Males and females of reproductive potential who are not using an effective method of
birth control and females who are pregnant or breastfeeding or have a positive (urine
or serum) pregnancy test prior to study entry

- Judgment by the Investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions and requirements

In addition, the following is considered a criterion for exclusion from the exploratory
genetic research:

- Previous allogeneic bone marrow transplant.

- Non-leukocyte depleted whole blood transfusion within 120 days of the date of the
genetic sample collection.