A Trial of Integrating SBRT With Targeted Therapy in Stage IV Oncogene-driven NSCLC

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational intervention to learn whether the intervention works
in treating a specific disease. The investigational intervention in this study is SBRT with
proton or photon radiation (explained below). "Investigational" means that the intervention
is being studied. SBRT and proton radiation therapy are FDA approved radiation delivery
systems. However, using it as a treatment for stage IV NSCLC is still investigational.

SBRT is a specialized, technologically advanced type of external beam radiation therapy that
pinpoints high doses of radiation directly on the cancer. Because of high precision, these
treatments spare healthy tissue and are associated with fewer side effects. SBRT is very
different from conventional therapy where radiation is delivered in small doses given daily
over the course of several weeks. For SBRT, the total dose of radiation is typically
administered in 4-5 daily sessions. SBRT can be delivered with standard, so called photon
radiation, or proton beam. Neither of these two types of radiation is generally superior over
the other. There are technical differences between these two, and depending on tumor
location, size, shape, and other factors, the investigators will decide which type of
radiation to use for which treatment.

After the screening procedures confirm you are eligible to participate in the research study:

- Each participant will receive stereotactic treatment course (SBRT with protons or photons)
to the area of their tumor.

Inclusion Criteria:

- Histologically or cytologically confirmed non-small cell lung cancer (NSCLC) with any
actionable mutation or translocation in EGFR, ALK, or ROS1

- Stage IV disease (AJCC Staging system 7th edition)

- Within 6 months of initiating their first TKI treatment regimen

- Stable or responding systemic disease to TKI (no evidence of progression) on the most
recent staging studies. The complete extent of the current residual systemic disease
must be deemed amenable to SBRT as per review of imaging studies by a radiation
oncologist, based on the following criteria:

- Lung: 1-3 lesions (including the primary) of maximum size 5 cm in longest
diameter. A minimum size 1 cm in the longest diameter is recommended. (Patients
with a malignant pleural effusion prior to the start of TKI therapy will be
considered eligible for SBRT if there is complete radiographic resolution of the
effusion while on systemic therapy);

- Spine: Bone lesions must be limited to the spine. A maximum of 2 spinal
metastases will be considered for SBRT, with each site spanning 1-3 vertebral
bodies. A minimum size of 1 cm in longest diameter is recommended. SBRT may
target sclerotic lesions that persist following TKI therapy;

- GI: 1-4 liver metastases of maximum size 5 cm in longest diameter and/or 1-2
adrenal metastases of maximum 4 cm size in longest diameter. A minimum size of 1
cm in longest diameter is recommended.

In addition:

- CNS: 1-4 brain metastases of maximum size 3cm in longest diameter. However, these
should be treated with standard-of-care SRS and will not be defined as target lesions
for purposes of this protocol.

- A maximum number of 5 target lesions outside the brain, excluding the lung primary, is
recommended to ensure that enrollment is limited to patients with low-burden disease
and that treatments can be delivered within the specified time frame.

- History of prior radiation therapy to brain or skeleton is allowed, but should
have occurred > 2 months from enrollment.

- Age at least 18 years.

- Life expectancy of greater than 6 months.

- ECOG performance status ≤ 2.

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry
and for the duration of study participation. Should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately. A negative serum or urine pregnancy test within 2
weeks of registration for women of childbearing potential is required.

- Ability to understand and the willingness to sign a written informed consent
document.

Exclusion Criteria:

- Residual hilar or mediastinal lymph node disease (size > 1cm in short-axis diameter on
CT). Non-malignant etiologies for enlarged lymph nodes may be evaluated per standard
clinical practice.

- Participants who have received prior radiation therapy to anatomical sites other than
brain or skeleton.

- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Patients who are pacemaker or defibrillator-dependent as these devices may not be
operated concurrently with delivery of proton beam radiation.

- Pregnant or lactating women, as treatment involves unforeseeable risks to the embryo
or fetus.