A Phase II Trial of Integrating Stereotactic Body Radiation Therapy With Selective Targeted Therapy in Stage IV Oncogene-driven Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer Metastatic, Targetable Oncogenes (EGFR, ALK, ROS1)
Sponsor: Massachusetts General Hospital

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NCI Protocol #:
N/A 
Local Protocol #:
14-370
TITLE:  A Phase II Trial of Integrating Stereotactic Body Radiation Therapy with Selective 
Targeted Therapy in Stage IV Oncogene-driven Non-Small Cell Lung Cancer
Coordinating Center:
N/A
*Principal Investigator (PI):
Henning Willers, MD
Massachusetts General Hospital (MGH)
Dept. of Radiation Oncology, Cox 3
55 Fruit Street
Boston, MA 02114
Telephone – 617-726-5184
Fax – 617-726-3603
hwillers@partners.org
Other Key Investigators:
MGH:
Theodore Hong, MD; GI Radiation Oncology
Kevin Oh, MD; CNS Radiation Oncology
Helen Shih, MD; CNS Radiation Oncology
Lecia Sequist, MD, MPH; Medical Oncology
Alice Shaw, MD, PhD; Medical Oncology
Amita Sharma, MD; Interventional Radiology
Statistician: 
Beow Yeap, ScD
MGH
byeap@partners.org
Study Coordinator/Data Manager: Kelly Hill, CRC  
Agent(s):  Stereotactic Body Radiation Therapy (SBRT) at the Massachusetts General Hospital
Study Exempt from IND Requirements per 21 CFR 312.2(b).  
Protocol Type / Version # / Version Date:
[Revision /   6/26/18 ]
*Protocol types:  Original, Revision, or Amendment
Funding Support: Federal Share of Program Income earned by Massachusetts General Hospital 
on C06 CA059267, Proton Therapy Research and Treatment Center
NCT02314364

SBRT for oncogene-driven NSCLC
 6/26/2018
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SCHEMA
Phase II trial of integrating SBRT into the management of stage IV oncogene-driven 
NSCLC
      Frequency of patients with distant failures (in new sites) 
      as first site of failure at 12 months
* Recommended maximum number of metastatic target lesions outside the brain is 5. Any new brain 
metastases will be treated with stereotactic radiosurgery (SRS) as part of standard-of-care therapy, which 
is not part of protocol treatment
** TKI will be held on days of SBRT. TKI is part of standard-of-care therapy, which is not part of 
protocol treatment. 
Stage IV Oncogene-driven NSCLC 

On selective TKI, within 6-12 months of starting TKI, depending on specific drug

Residual disease on TKI limited to:
PULM – primary or/and 1-2 metastases (max 5 cm each), and/or
GI – 1-4 liver metastases (max 5 cm each) or/and 1-2 adrenal metastases (max 4 cm each), and/or
Spine – 1-2 spine metastases (1-3 vertebral bodies each), and/or
CNS – up to 4 brain metastases, max size 3 cm *
1. Stereotactic Treatment Course*
Limited to 1 anatomical site (1-3 isocenters):

Pulmonary SBRT, 6-12 Gy x 4-10 fractions, or

GI SBRT 5-10 Gy x 5-10 fractions, or

Spine SBRT 18 Gy x 1 fraction
2. Stereotactic Treatment Course*
3. Stereotactic Treatment Course*
Resume TKI
Interval: min 1 week, max 2 months
Resume TKI in interval
Maximum
Duration:
4 months
Interval: min 1 week, max 2 months
Resume TKI in interval
Interval: min 1 week, max 2 months
Resume TKI in interval
Continued until all active disease treated

SBRT for oncogene-driven NSCLC
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CNS, central nervous system; GI, gastrointestinal; NSCLC, non-small cell lung cancer; 
PULM, pulmonary; SBRT, stereotactic body radiation therapy; TKI, tyrosine kinase inhibitor

SBRT for oncogene-driven NSCLC
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TABLE OF CONTENTS
1.
OBJECTIVES......................................................................................................................................................5
1.1
Study Design................................................................................................................................................5
1.2
Primary Objectives......................................................................................................................................6
1.3
Secondary Objectives...................................................................................................................................6
2.
BACKGROUND..................................................................................................................................................7
2.1
Study Agent(s:) Stereotactic Body Radiation Therapy ................................................................................8
2.2
Study Disease: Oncogene-driven Stage IV  NSCLC..................................................................................13
2.3
Rationale....................................................................................................................................................16
2.4
Correlative Studies Background................................................................................................................17
3.
PARTICIPANT SELECTION.........................................................................................................................19
3.1
Eligibility Criteria .....................................................................................................................................19
3.2
Exclusion Criteria...................................................................................................................................20
3.3
Inclusion of Women, Minorities and Other Underrepresented Populations.............................................21
4.
REGISTRATION PROCEDURES .................................................................................................................22
4.1
General Guidelines for DF/HCC Institutions............................................................................................22
4.2
Registration Process for DF/HCC  Institutions ......................................................................................22
4.3
General Guidelines for Other Participating Institutions....................................................................23
4.4
Registration Process for Other Participating Institutions.....................................................................232
5.
TREATMENT PLAN .......................................................................................................................................24
5.1
Pre-treatment Criteria .............................................................................................................................24
5.2
SBRT Planning and Treatment................................................................................................................24
5.3
General Concomitant Medication and Supportive Care Guidelines.........................................................26
5.4
Duration of Therapy...................................................................................................................................26
5.5
Duration of Follow Up ..............................................................................................................................27
5.6
Criteria for Removal from Study ...............................................................................................................27
6.
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS....................................27
6.1
Anticipated Toxicities ................................................................................................................................29
6.2
Toxicity Management.................................................................................................................................30
6.3
Dose Modifications/Delays........................................................................................................................31
7.
DRUG FORMULATION AND ADMINISTRATION ..................................................................................32
8.
CORRELATIVE/SPECIAL STUDIES...........................................................................................................33
9.
STUDY CALENDAR........................................................................................................................................34

SBRT for oncogene-driven NSCLC
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10.
MEASUREMENT OF EFFECT......................................................................................................................35
10.1
Antitumor Effect– Solid Tumors ................................................................................................................35
10.2
Antitumor Effect – Hematologic Tumors...................................................................................................41
10.3
Other Response Parameters ......................................................................................................................41
11.
ADVERSE EVENT REPORTING REQUIREMENTS...........................................................................43
11.1
Definitions..................................................................................................................................................43
11.2
Procedures for AE and SAE Recording and Reporting.............................................................................45
11.3
Reporting Requirements ............................................................................................................................45
11.4
Reporting to the Study Sponsor .................................................................................................................45
11.5
Reporting to the Institutional Review Board (IRB) ...................................................................................46
11.6
Reporting to the Food and Drug Administration (FDA)...........................................................................46
11.7
Reporting to the NIH Office of Biotechnology Activities (OBA) ...............................................................46
11.8
Reporting to the Institutional Biosafety Committee (IBC) ........................................................................47
11.9
Reporting to Hospital Risk Management...................................................................................................47
11.10
Monitoring of Adverse Events and Period of Observation........................................................................47
12.
DATA AND SAFETY MONITORING......................................................................................................48
12.1
Data Reporting ..........................................................................................................................................48
12.2
Safety Meetings..........................................................................................................................................48
12.3
Monitoring.................................................................................................................................................49
13.
REGULATORY CONSIDERATIONS......................................................................................................50
13.1
Protocol Review and Amendments ............................................................................................................51
13.2
Informed Consent.......................................................................................................................................51
13.3
Ethics and Good Clinical Practice (GCP) ................................................................................................51
13.4
Study Documentation.................................................................................................................................51
13.5
Records Retention......................................................................................................................................51
13.6
Multi-center Guidelines.............................................................................................................................51
13.7
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA)..........51
14.
STATISTICAL CONSIDERATIONS........................................................................................................52
14.1
Study Design/Endpoints.............................................................................................................................52
14.2
Sample Size/Accrual Rate..........................................................................................................................53
14.3
Stratification Factors.................................................................................................................................53
14.4
Analysis of Secondary Endpoints...............................................................................................................53
14.5
Reporting and Exclusions..........................................................................................................................54
15.
PUBLICATION PLAN................................................................................................................................56
16.
REFERENCES .............................................................................................................................................58

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17.
APPENDICES...............................................................................................................................................65
Appendix A: AJCC 7th Edition Lung Cancer Staging ..............................................................................................65
Appendix B: Performance Status Criteria ...............................................................................................................67

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1. OBJECTIVES
1.1
Study Design
Stereotactic body radiation therapy (SBRT) is an advanced radiation therapy modality 
that involves the delivery of ablative individual doses of radiation to tumors in various 
extracranial sites with high precision and in a shorter amount of time than with traditional 
radiation. The precision used in SBRT minimizes the radiation dose received by a volume 
of the normal surrounding organs and tissues, thus limiting radiation toxicity (1-4).
SBRT has emerged as a standard therapy for medically inoperable patients with 
peripherally located stage I non-small cell lung cancer (NSCLC) (5-9). Recently, a 
number of studies have explored the benefits of metastasis-directed SBRT in low 
metastatic burden or oligometastatic stage IV NSCLC. These studies have shown that 
SBRT can achieve high rates of local control of treated lesion (typically 70-90%) in  
patients with limited pulmonary, hepatic, adrenal, and spinal metastases (4-7, 10-26). It 
has been hypothesized that maximum cytoreduction through local control of metastases 
will result in longer progression free survival (PFS) and better outcomes in patients with 
low burden metastatic NSCLC (14).
Oncogene-driven cancers represent a unique subset of NSCLC that responds well to targeted 
tyrosine kinase inhibitors (TKI) (27). These include NSCLC with activating mutations in the 
epidermal growth factor recetor (EGFR) and EML4-ALK or ROS1 translocations. The 
initial TKI response is typically associated with a prolonged PFS in oncogene-driven cancers 
(7-13 months) compared to the general population of NSCLC, and is better than expected 
with conventional chemotherapy (~3-4 months) (28-32). Recent data demonstrate even 
longer median PFS times for newer TKIs, such as ~18 months for first-line osimertinib used 
against EGFR-mutant NSCLC (32a), and a range of PFS times for different ALK-directed 
TKIs, with at least ~18-20 months for first-line alectinib (32b,c). Oncogene-driven NSCLC 
therefore represents a potentially ideal patient population for consolidative SBRT as TKI are 
effective in eliminating micrometastatic disease, and may convert patients whose disease 
extent is too large at diagnosis to candidates with low metastatic burden that could be targeted 
with SBRT. Furthermore, consolidative SBRT to residual metastases following TKI therapy 
may eradicate cell clones with acquired TKI resistance which is a major clinical challenge in 
the management of this patient population (33-36). 
Therefore, SBRT to residual sites of originally present cancer (“original sites”) will not only 
decrease the frequency of failure in these sites, but it also hypothesized to decrease the 
probability of hematogenous spread from persistent original disease to anatomical sites that 
were not originally involved by cancer (“distant sites”) . However, despite the overall 
theoretical benefits of SBRT in stage IV NSCLC, there are no published prospective clinical 
trials of SBRT for stage IV NSCLC, and more specifically in patients with oncogene-driven 
NSCLC (14-16). 
SBRT can be delivered using either photons or protons. The main benefit of protons over 
photons is the absence of exit dose and avoidance of a low-dose bath in the patient. This 

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offers the opportunity for highly conformal (i.e., precise) dose distributions while 
simultaneously irradiating less normal tissue (37-39). High dose conformality is achieved 
through the use of a lower number of beams (2-3) compared to photon-based SBRT (~6-
11), which leads to a reduction of the integral dose of radiation delivered to patients (39). 
In a setting where multiple metastatic sites are to be treated, the use of proton SBRT may 
therefore be advantageous (37-39).
We hypothesize that an SBRT regimen that integrates proton radiation for treatment of 
sites of residual disease following initiation of targeted TKI treatment will decrease the 
frequency of distant failures as first site of failure in stage IV oncogene-driven NSCLC 
patients from 40% to 20% by 1 year post-SBRT. To test this hypothesis, we propose to 
conduct a phase II prospective study of 30 patients to investigate the benefits as well as 
safety of consolidative SBRT in the management of low metastatic burden stage IV 
oncogene-driven NSCLC.   
1.2
Primary Objectives
To determine the 12-month frequency of patients with distant failures as first site of 
failure associated with a treatment regimen of a targeted TKI and consolidative SBRT in 
patients with stage IV oncogene-driven NSCLC.
1.3
Secondary Objectives
1) To describe toxicities of treatment using CTCAE v4.0
2) To determine median PFS time
3) To analyze the pattern of original and distant site failures
4) To determine 2-year local control rate of irradiated lesions
5) To determine median overall survival time and 2-year overall survival

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2.
BACKGROUND
2.1
Study Agent(s)
Proton Beam Radiation
There have been unprecedented efforts in radiation oncology to develop sophisticated, 
conformal techniques in order to improve the outcome for cancer patients. The aim of 
these new techniques is to concentrate the radiation dose distribution more completely 
on the disease target, thereby sparing critical normal tissues and increasing the target 
dose. To this end, there are an increasing number of centers in the United States seeking 
to take advantage of the superior physical characteristics of proton beam radiation.
The basis for the advantages of proton beam radiation lies in the physical laws that 
determine the absorption of energy in tissues exposed to photon or proton beams. In a 
specific tissue, photons are absorbed exponentially whereas protons have a finite range 
dependent upon the initial proton energy. Therefore, the depth dose characteristics of the 
two beams are qualitatively different (Figure 1A). 
Protons lose their energy in tissue mostly by coulombic interactions with electrons in the 
constituent atoms; however, a small fraction of energy is transferred through nuclear 
collisions. The energy loss per unit path length is relatively small and constant as the 
proton traverses the tissue until near the end of the proton range where the residual energy 
is lost over a short distance (approximately 0.7 cm in width at 80% of the maximum dose) 
and the proton comes to rest, resulting in a distinctive sharp rise in the tissue absorbed 
Fig. 1. Illustration of the therapeutic advantages of proton beam radiation. (A) Depth dose 
characteristics of a single proton portal versus a photon beam. Note the lack of exit dose with protons 
allowing sparing of distal normal tissue structures. The proton Bragg peak is spread out (SOBP), so 
that the entire tumor is encompassed by the desired dose. (B) Isodose distributions for a 70 year-old 
man with extremely poor lung function and oxygen dependence of 6 L NC. The 1.5 cm lung cancer 
was encompassed by two right anterior oblique (RAO) and posterior oblique (RPO) beams. Only 5% 
of the right lung was exposed to a dose of 20 Gy or more while the left lung received zero dose.

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dose (energy absorbed per unit mass) - known as the Bragg peak. In physical terms, the 
magnitude of the transfer of energy to tissue per unit path length traversed by the protons 
is inversely proportional to the square of the proton velocity. The low dose region 
between the entrance and the Bragg peak is called the plateau of the dose distribution and 
the dose there is 30-40% of the maximum dose. The Bragg peak is too narrow in extent 
to irradiate any but the smallest of targets, ablation of the pituitary gland for example. 
For the irradiation of larger targets/tumors the beam energy is modulated - several beams 
of closely spaced energies (ranges) are superimposed to create a region of uniform dose 
over the depth of the target. These extended regions of uniform dose are called "spread-
out Bragg peak" (SOBP) (39). 
The main benefit of proton therapy over photon beam radiotherapy is the absence of exit 
dose, which offers the opportunity for highly conformal (i.e., precise) dose distributions, 
while simultaneously irradiating less normal tissue. This technology therefore reduces 
irradiation to normal tissue, while permitting dose escalation to levels not achievable with 
standard techniques (39). Of note, high dose conformality can be commonly achieved 
through the use of only 2-3 protons beams, compared to multiple beams required for 
photon-based radiation therapy, which leads to a reduction of radiation exposure to 
healthy normal tissues. This principle is illustrated in Figure 1B, in which the use of 2 
proton beams achieved high precision dose delivery to a small peripheral lung tumor 
while achieving maximum lung sparing in a patient with extremely poor lung function. 
Due to their evident superiority, protons are being increasingly used in a variety of 
disease sites with excellent clinical outcomes reported to date (reviewed in (39)). 
Stereotactic Body Radiation Therapy
Early-Stage NSCLC
In recent years, stereotactic body radiation therapy (SBRT) has emerged as a highly 
promising treatment for medically inoperable patients with early-stage NSCLC 
(reviewed in (5, 7-9, 17, 40-45)). SBRT is a specialized type of radiation therapy that 
pinpoints high “ablative” doses of radiation directly on the cancer in a shorter amount of 
time than traditional radiation. Typically 45-60 Gy are delivered at 10-18 Gy per fraction, 
thus needing only 3-5 fractions distributed over 1-2 weeks. The delivery of large dose 
fractions is the major feature that separates SBRT from conventional radiation treatment. 
In order to minimize normal tissue toxicity, conformation of high doses to the tumor 
target and rapid fall-off of doses away from the target is critical. The practice of SBRT, 
therefore, requires a high level of confidence in the accuracy of the entire treatment 
delivery process. In SBRT, confidence in this accuracy is accomplished by the integration 
of modern imaging, simulation, treatment planning, and delivery technologies into all 
phases of the treatment process (2, 7, 43, 46). Reported treatment outcomes have been 
excellent, with 3-year local failure rates of ~10%, regional failure rates of < 10%, cause-
specific survival rates of > 80%, and overall survival rates at 3 years of > 50% (3, 5, 6, 
17, 44). 
Stage IV Cancer

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A number of studies have been conducted to explore the benefits of using SBRT in the 
treatment of metastatic disease (11, 12, 15, 16, 18-26, 47-49). Published studies of 
metastasis-directed SBRT can be divided into three types. First, studies in which various 
types of primary tumors or a range of metastatic locations are treated. Second, studies in 
which a single metastatic site is treated, such as the lungs or liver. Third, studies in which 
investigators focus on one histological type. To date, phase I and II data have been 
published for hepatic, pulmonary, spinal, adrenal and multiple-organ metastatic sites (11-
13, 15, 16, 18-26, 49). Tables 1 and 2 show an overview of published case series in 
patients with oligometastases (defined for the purpose of this study as 1-5 metastases) 
(15, 16, 21, 22, 25, 26, 49-66). Although the studies reviewed are heterogeneous in terms 
of site, primary histology, and dose, control rates for treated metastases are generally 
around 80%. 
At present, there exist no standardized SBRT techniques and dosing schemes for patients 
with metastatic disease. This is because metastases vary in volume, location within an 
organ and proximity to surrounding organs that have various tolerances to radiotherapy. 
Most studies published to date using various radiation dosing schemes have resulted in 
high rates of tumor control across many different organs (Tables 1 and 2). Even large-
volume metastases (>5 cm diameter) have been shown to be well-controlled using SBRT 
with minimal toxicity (11, 12, 18, 22, 44). A study of patients with large-volume 
metastases treated with SBRT found that 50 Gy in 5 Gy fractions or three fractions of 
12–16 Gy could be delivered safely and effectively with 87% treated-metastasis control 
(67). Taken together, the results of SBRT for multiple-organ metastases are similar to 
those reporting on surgical removal of single-organ metastases. However, unlike patients 
selected for surgical metastatectomy, these series include patients medically unfit for 
surgery or patients who have technically unresectable tumors. Thus, these data include 
patient populations previously unable to receive effective metastasis-directed therapy 
(68). 
Pulmonary and Hepatic Metastases
The lung is the most widely studied organ for the delivery of SBRT to metastases because 
the imaging characteristics of pulmonary metastases enable direct targeting via integrated 
imaging on radiotherapy devices or indirect targeting with fiducial markers. Both 
prospective single-dose and dose-escalation studies have demonstrated high rates of 
treated-metastasis control (89–96%) with promising 2-year survival rates (38–39%, 
Table 1) (15, 16, 21, 49-52). Another commonly investigated target organ for SBRT for 
metastases is the liver. SBRT for hepatic metastases is a challenging process for 
radiotherapy planning and delivery because defining the anatomical extent of the 
metastases often requires diagnostic MRI fusion and incorporation of respiratory motion 
management techniques (18, 21, 69, 70). Phase I and II studies based on fixed doses, dose 
escalation and normal tissue complication probabilities have demonstrated high rates of 
treated-metastasis control (71–92%) as shown in Table 1. The long-term liver function 
remains normal in treated patients without hepatic insufficiency prior to SBRT, as long 
as standard radiation dose constraints are observed (16, 18, 21, 70). 

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Spinal Metastases 
To date, phase I and II studies for spinal SRS and multi-fraction SBRT have 
demonstrated favorable treated-metastasis control rates (86–90%) for patients without 
spinal-cord compression (Table 1). Doses varied but in most studies were delivered in 
one to five fractions, often 16–20 Gy in one fraction or 27 Gy in three fractions. Similar 
to intracranial SRS, spine SBRT has been shown to be effective in the retreatment of 
metastases that progress following fractionated radiation therapy. In addition, SBRT has 
been shown to be very effective in palliating pain associated with spinal metastases (53-
55). 

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Table 1: Selected series of extracranial SBRT for metastases in specific organs
Study
# 
Metastases 
Treated
#Metastases 
Treated
 per Patient 
(range)
SBRT Dose 
Fractionation
Control Rates 
for Treated 
Metastases (%)
Overall Survival 
(%)
Lung Metastasis
Rusthoven et al. (15) multicentre 
(n = 38)
63
2 (1–5)
48–60 Gy in 3 fractions
2-year: 96
2-year: 39
Wulf et al. (50) single centre (n = 
41)
92
1 (1–2)
12–30 Gy in a single 
fraction
1-year: 89
1-year: 84
Okunieff et al. (26) single centre 
(n = 30)
125
2.6 (1–5)
50–55 Gy in 10 
fractions
3-year: 91
2-year: 38
Inoue et al. (49) single centre 
(n=22)
31
1(1-2)
48 Gy in 4 fractions
NR
3-year: 72
Takahashi et al. (51) single 
centre (n=42)
52
1 (1-2)
20-56Gy in 1-6 fractions
2-year: 87
2-year: 65
Liver Metastasis
Rusthoven et al. (16) multicentre 
(n = 47)
63
1 (1–3)
36–60 Gy in 3 fractions
2-year: 92
2-year: 30
Katz et al. (21) single centre (n = 
69)
174
2.5 (1–6)
50 Gy in 10 fractions
1-year: 76
14-month: 50
Lee et al. (52) single centre (n = 
68)
143
1 (1–8)
Based on normal tissue 
complication probability 
(6 fractions)
1-year: 71
1.5-year: 47
Spine Metastasis
Wang et al. (53) single centre (n 
= 149)
166
1
27–30 Gy 3 fractions
1-year: 86
1-year: 68.5
Yamada et al. (54) single centre 
(n = 93)
103
1
18–24 Gy 1 fraction
15 month: 90
45-month: 36
Gibbs et al. (55) single centre (n 
= 74)
102
1
16–25 Gy in 1–5 
fractions
NR
1-year: 46.3
Adrenal Metastasis
Holy et al. (56) single centre 
(n=13)
13
1(62-66)
Median dose 40 Gy in 5 
fractions
21-month:77
Median OS: 23 
months
Casamassima et al. (57) single 
center (n=48
?
1 (1-2)
36 Gy in 3 fractions
2-year: 90
2-year: 14·5
Rudra et al. (58) single centre 
(n=10)
13
1 (1-2)
?
1-year: 73%
1-year: 90%
Multiple organ
Salama et al. (59) single centre 
(n = 61)
113
2 (1–5)
24–48 Gy in 3 fractions
2-year: 52.7
2-year: 57
Milano et al. (25) single centre (n 
= 121)
293
2 (1–5)
50 Gy in 10 fractions 
preferred
2-year: 67
4-year: 28
Kao et al. (60) single centre (n = 
21)
36
1 (1–5)
40–60 Gy in 10 
fractions
1-year: 85
1-year: 75
Inoue et al. (61) single centre 
(n=44)
60
NR (1-5)
48 Gy in 4 fractions 
(adrenal)
35-60 Gy in 4-8 
fractions
3-year: 80
3-year: 39

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Table 2: Selected series of extracranial stereotactic radiosurgery or stereotactic body radiation 
therapy for metastases from NSCLC.
Multiple Organ Metastases
The largest series of mixed oligometastatic disease is that of Milano and colleagues (22). 
The investigators recruited 121 patients with ≤5 metastases and delivered a median dose 
of 50 Gy in 5 Gy fractions over 2 weeks. These doses are at the lower end of the dose 
range presently used for SBRT. Most patients had lung, liver, or lymph-node metastases. 
The only grade 3 toxic effect was a non-malignant pleural and pericardial effusion, and 
no higher-grade adverse effects occurred. The 2-year and 4-year treated metastasis 
control rates were 77% and 74%, respectively, and the 4-year overall survival was 59%. 
Salama and colleagues (59) performed a dose-escalation trial in 61 patients with 113 
metastases. Initially, patients were given 24 Gy in three fractions, which was increased 
sequentially to 48 Gy in three fractions. For those who received 24 Gy in three fractions, 
control of the treated metastases was poor at 45.7%, whereas in the four patients given 
48 Gy in three fractions, 100% control was achieved. 
Study
Number of 
Metastasis 
Treated
Sites Treated
SBRT Dose
Treated 
Metastasis 
Control Rate 
(%)
Median 
Survival 
(months)
Overall 
Survival 
Rate (%)
Hasselle et al. (64) 
single centre (n = 
25)
62
Lung, brain, 
bone, liver, 
adrenal, lymph 
nodes, Spleen 
and muscle 
50 Gy (5 Gy per 
dose)
or
24–48 Gy (8–16 Gy 
per dose)
1.5-year: 71
23
1.5-year: 
52.9
Cheruvu et al. (65) 
single centre (n = 
52)
70
Lung, brain, 
bone and liver
50–60 Gy in 5–10 
fractions
NR
20
2-year: 43
Wang et al. (66) 
single centre (n=14)
14
Lung, brain and 
bone
45-60 Gy in 3–5  
fractions
1-year: 83.9
19
1-year: 
69.6
Weickhardt et al. 
(62) single centre 
(n=25)
31
Lung, brain, 
bone, liver, 
adrenal and 
lymph nodes
15-54 Gy in 1-5 
fractions for 
SBRT/SRS (n=23)
WBRT (n=6) and 
conventional RT 
(n=2) also used
NR
Median 
PFS: 10.3 
months
NR
Yu et al. (63) single 
centre (n=18)
18 (only 3 
received RT)
Lung, brain, 
bone, liver, 
adrenal and 
lymph nodes 
NR
SBRT (n=1)
Conventional RT 
(n=2)
41 months
5-year: 40
Overall 
median 
survival of 
41 months

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In general, the toxicity of SBRT is mild to moderate.  The proportion of patients with 
grade 3 acute or late adverse effects is less than 10%, and in many studies no grade 3 
toxicity was recorded (3, 11, 15, 16, 55).
The simultaneous delivery of SBRT to multiple targets in multiple organs can be much 
more complicated than treating a single metastasis in a single organ. The entrance and 
exit dose contributions from the 5–13 (or more) radiation beams required to tightly 
conform the radiation dose around each tumor site must be considered (37-39). Although 
this planning is not particularly difficult if the metastases have wide anatomical distances 
between them, treating metastases in close proximity to each other, particularly when 
organ motion must be accounted for, can be complex (71). Thus, in the clinical settings 
described above, there is a need to explore the use of alternative dose/fractionation 
schemes and SBRT modalities. Proton beam radiation has not only the potential for 
normal tissue sparing that cannot be achieved with conformal photon techniques but also 
allows for treating multiple target sites and escalation of dose to levels that cannot be 
safely achieved with photons (37, 39). To date, there are no published studies on the use 
of proton beam SBRT in the management of oligometastatic disease. 
Overall, these data suggest that SBRT can be an effective metastasis-directed therapy for 
patients with metastatic cancer. Similar to surgery, SBRT, when delivered to all known 
metastases, can result in long-term disease control (11). Further studies are needed to 
comprehensively integrate this therapy. Moreover, determining an optimal patient 
population for metastasis-directed SBRT is important as these treatments are resource-
intensive, labor-intensive, and are associated with treatment-related toxicity. 
2.2
Study Disease
Stage IV NSCLC
Lung cancer is the most frequent cause of cancer death amongst both men and women in 
the United States. An estimated 226,160 new cases were diagnosed, and 160,340 
Americans were expected to die from lung cancer in 2012, accounting for approximately 
28% of all cancer deaths (72, 73). About 87% of lung cancers are non-small cell in 
histology. About 35-40% of patients with NSCLC present with metastatic, stage IV 
disease. These patients are treated with cytotoxic, immunomodulatory, or targeted 
biological therapeutics, with the goals of limiting the progression of cancer and 
improving overall survival (74-76). 
Although radiotherapy has been an integral treatment for patients with metastatic cancer 
over the past century, it is usually reserved for palliation of pain, dyspnea, bleeding, or 
neurological deficits among other indications. Definitive local therapies are effective in 
the eradication of early-stage primary NSCLC (6, 7, 9, 45). In the metastatic setting, 
however, local therapies such as surgery and SBRT can only be justified if patient 
outcomes are improved (68). 

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15
Mehta et al. used serial CT to monitor the number of individual metastatic sites and the 
number of organs involved in patients with advanced NSCLC who had been treated with 
chemotherapy (77). Of these patients, 50% had disease limited to the primary tumor and 
three or fewer metastatic lesions. In addition, 50% patients had stable or progressive 
disease in initially involved sites with no development of new metastatic lesions. 
Importantly, following first line chemotherapy, up to 64% of patients who develop 
disease progression did so in either the primary tumor or original sites of metastases. 
These observations support the clinical state of ‘oligometastasis’, elucidated by Hellman 
and Weichselbaum, who hypothesized that local control of oligometastasis could 
improve systemic control, progression free survival (PFS), and consequently prolong 
overall survival (OS) in a subset of patients (78, 79). Theoretically, if radical intervention 
(i.e., SBRT) could be delivered during an oligometastatic phase, the intervention could 
directly delay local disease progression in these patients (14, 80). 
Few studies have evaluated the benefits of SBRT in the treatment of oligometastatic 
disease in stage IV NSCLC only. The most prominent study was reported by Hasselle et 
al. (64) who evaluated 22 stage IV NSCLC patients who received SBRT for the control 
of 62 individual lesions (median size 2.7cm) within the brain, lung, bone, liver, adrenal, 
lymph nodes, spleen, and muscle. The median dose and fraction dose to extracranial 
lesions were 50 and 5 Gy. Median OS and PFS were 22.7 and 7.6 months, respectively. 
The 18-month local control, distant control, OS, and PFS rates were 66.1%, 31.7%, 
52.9%, and 28.0%, respectively. Results of this study and others demonstrate that SBRT 
to oligometastatic NSCLC provides durable local control of treated lesions and may 
provide long-term PFS in some patients (51, 59, 61, 65). What remains to be identified 
is the ideal population of stage IV NSCLC patients who are most likely to achieve 
prolonged disease free survival with SBRT.
Oncogene-driven NSCLC
Mutations and/or chromosomal rearrangements resulting in oncogene activation are 
responsible for the oncogenicity of a subset of NSCLC. These include activating 
mutations of the epidermal growth factor receptor (EGFR) tyrosine kinase, in addition to 
chromosomal rearrangements resulting in the activation of the anaplastic lymphoma 
kinase (ALK), and the c-ros oncogene 1 (ROS1) receptor tyrosine kinase.  
EGFR mutations are the second most common oncogene mutations found in NSCLC, 
occurring in ~10% of all tumors. Patients with EGFR-mutant NSCLC respond well to 
EGFR tyrosine kinase inhibitors (TKI) such as erlotinib or afatinib. This has established 
EGFR mutations as a biomarker for TKI responsiveness (27, 32, 33, 81). Clinically, the 
use of EGFR TKI in EGFR-mutant patients is associated with an often dramatic response 
rate in ~70% of cases, compared to 20-30% response seen with the use of conventional 
chemotherapy. Importantly, EGFR TKI therapy prolongs the median PFS of EGFR 
mutant patients to 9-13 months for first/second generation inhibitors such as erlotinib and 
afatinib and about 18 months for third-generation osimertinib, which is significantly better 
than the 3-5 months median PFS of patients treated with chemotherapy regimens. 
Osimertinib is FDA approved as of April 2018 for use in first-line therapy. In addition, 

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the use of EGFR TKI is associated with better quality of life and less toxicity than 
conventional chemotherapy. EGFR TKI are used as first line treatment in the 
management of stage IV EGFR-mutant NSCLC (29, 31, 32, 82)(32a). 
ALK chromosomal rearrangements are found in approximately 5% of NSCLC and define 
a distinct molecular subtype of lung cancer (33, 83, 84). Crizotinib is an oral small-
molecule tyrosine kinase inhibitor which targets ALK, and ROS1 tyrosine kinases (85-
88). Recently, a phase 3 trial comparing conventional chemotherapy to crizotinib in ALK 
positive advanced NSCLC reported response rates of 65% with crizotinib, compared to 
20% with chemotherapy. Importantly, the median PFS was 7.7 months in patients treated 
with crizotinib and only 3.0 months in the chemotherapy group (89). Additional TKIs 
have become available in the past few years with subsequent prolongation of PFS, 
including alectinib which in first line therapy has a median PFS of at least 18-20 months 
(32b,c). These results and others have established the role of several TKIs in the systemic 
management of ALK positive advanced NSCLC patients. 
ROS1 rearrangements occur in 1-2% of NSCLC and they represent another unique 
molecular subset of lung cancers (83, 90, 91). Crizotinib has also been shown to be 
effective in inhibiting the ROS1 tyrosine kinase thus providing anti-tumoral activity in 
ROS1 positive cancers. The preliminary results of a phase I trial of crizotinib 
(NCT00585195) in patients with advanced NSCLC harboring ROS1 gene 
rearrangement, were presented at ASCO and ESMO 2012 and demonstrated promising 
results with an objective response rate of 57% and a disease control rate of 80% after 2 
months (Shaw et al, unpublished).
An important challenge to the success of TKI therapy is the development of drug 
resistance. Disease progression while on TKI therapy is thought to result from the growth 
of resistant clones that most commonly arise within sites of persistent disease (primary 
and metastatic) (34-36, 92-95). Of significance, failure to eradicate persistent disease has 
been associated with an increased risk of developing distance metastasis in various types 
of cancer (96). This highlights the importance of optimizing local disease control in order 
to lower the rate of distant failures and achieve prolonged PFS (96-98). SBRT is effective 
in controlling localized metastatic disease (80) and can potentially eliminate residual 
TKI-resistant clones, thereby reducing original site failure and potentially reducing the 
frequency of distant spread resulting from persistent original disease (Figure 2A). 
Therefore, the adjuvant use of SBRT for local control of residual disease in original sites 
following TKI therapy may extend PFS and OS of oncogene-driven stage IV NSCLC 
patients. 
Of interest, there is room for potential synergy between SBRT and TKI in the 
management of metastatic oncogene-drive NSCLC. Effective targeted therapy against 
oncogene-driven NSCLC can eradicate micrometastatic disease and reduce metastatic 
lesions to a limited number that becomes amenable to aggressive local therapy with SBRT. 
Furthermore, according to the Norton–Simon hypothesis, the effectiveness of systemic 
agents is proportional to the growth rate of the tumor and the fastest tumor growth rates occur 
when tumors are not bulky (99, 100). Therefore, if aggressive local therapy (SBRT) can 

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downsize the primary tumor, the remaining tumor cells may become more sensitive to 
maintenance TKI therapy. As such, oncogene-driven NSCLC represents a potentially ideal 
patient population for consolidative SBRT aimed at decreasing the overall risk of distant 
failure by eradication of persistent and potentially drug resistant original disease, thereby 
improving PFS.
As SBRT has shown to benefit certain patients with metastatic disease, the development 
of treatment algorithms integrating SBRT with optimal systemic therapies based on 
histology-specific or molecular data are needed. Only three retrospective studies have 
reported results on stage IV oncogene-driven (EGFR-mutant) NSCLC patients treated 
with metastasis-directed SBRT and TKI (Table 2). Weickhardt et al. (62) retrospectively 
investigated the benefits of SBRT/SRS, whole brain radiation therapy, and palliative 
radiation therapy in 10 EGFR-mutant NSCLC patients deemed suitable for local therapy to 
central nervous system and/or limited systemic metastasis with continued treatment with 
erlotinib. Patients were only treated with SBRT upon disease progression and this was 
associated with more than 6 months of additional disease control. Yu et al. (63) treated 18 
oligometastatic EGFR-mutant NSCLC patients who had developed acquired resistance to 
EGFR TKI with elective local therapy. Only 1 patient was treated with SBRT (to the lung) 
in this series. However, local therapy in these patients was associated with median time to 
progression of 10 months and a median survival time of 41 months. Wang et al. (66) treated 
14 NSCLC patients (not limited to EGFR-mutant disease) with disease progression after 
platinum-based chemotherapy with gefitinib and SBRT directed at progressive metastatic 
disease. Treatment was well tolerated. The 1-year local control and OS rates were 83.9% and 
69.6%, respectively, and the median PFS and OS times were 7 and 19 months, respectively. 
Together, these limited data suggest that oncogene-driven NSCLC is amenable to SBRT for 
the treatment of oligometastatic disease when used in conjunction with continued TKI 
therapy. Combining radiation with TKI such as erlotinib has been shown to be safe and well 
tolerated by patients. In addition, this approach has been associated with seemingly 
prolonged PFS at least in EGFR-mutant NSCLC, and there is no data to suggest that ALK 
or ROS1-translocated cancers would behave differently
The patterns of disease failure following TKI treatment in oncogene-driven NSCLC 
patients is poorly described in the literature. In review of a cohort of 47 patients with 
EGFR-mutant NSCLC treated with EGFR TKI at the Massachusetts General Hospital, 
we defined progression in sites of original disease (primary and metastatic sites) as 
"original sites failure" (OF) and the development of new metastases outside areas that 
originally contained disease as "distant failures" (DF) (Sequist et al., unpublished) 
(Figure 2). The cumulative frequency of OF only as the first site of recurrence was 39%, 
DF only was 13%, and concurrent DF and OF was 28%, observed at 18 months after 
initiation of TKI therapy, which is 6 months after a median PFS of about 12 months for 
first/second-generation EGFR TKIs. This pattern of failure is consistent with other 
reports on the general population of NSCLC progressing after chemotherapy.
2.3
Rationale

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18
SBRT is established as a therapy for medically inoperable early-stage NSCLC, and its 
role has been recently explored in stage IV NSCLC with low metastatic burden or 
oligometastatic disease. Studies have shown that SBRT can achieve high rates of treated-
metastasis control for patients with limited pulmonary, hepatic, adrenal, and spinal 
metastases (11, 15, 16, 18, 53, 58). Stereotactic radiosurgery (SRS) is used for the 
treatment of intracranial metastases (101). 
SBRT is generally well tolerated and associated with a low risk of severe toxicity. The 
use of metastasis-directed SBRT was shown to improve disease-free survival in selected 
NSCLC patients with low burden metastatic disease (64). However, the ideal population 
of stage IV NSCLC patients who are most likely to achieve prolonged disease free 
survival with SBRT remain to be identified.
Targeted therapy against oncogene-driven NSCLC may eradicate micrometastatic disease 
and reduce metastatic lesions to a limited number that becomes amenable to aggressive local 
therapy. Furthermore, SBRT can downsize the primary tumor and metastatic sites making 
the remaining tumor cells more sensitive to targeted therapies. In addition, SBRT to residual 
disease following TKI therapy may eradicate drug resistant clones that give rise to TKI 
resistant disease and eventual treatment failure in original and new, distant sites of disease. 
As such, oncogene-driven NSCLC represents a potentially ideal patient population for 
consolidative SBRT aimed at decreasing the probability of distant spread by reducing 
locally persistent and potentially drug resistant disease that can spread hematogenously. 
In summary, we hypothesize that persistent tumor in sites of original disease can give 
rise to distant metastases and that localized SBRT to residual, active sites of original 
disease may reduce the incidence of  DF occurring concurrently or in close temporal 
sequence with OF (96-98). The local control rate of metastases treated by SBRT is 
generally reported to be 80% (11, 15, 16, 26, 70, 80). Therefore, based on our own and 
literature data and assuming that EGFR-mutant NSCLC will behave similarly as other 
oncogene-driven NSCLC, we hypothesize that we can reduce the frequency of patients 
with concomitant OF and DF by 20%. This will lower the frequency of all DF (with or 
without concomitant OF) from 40% to 20% (Figure 2). The frequency of patients with 
DF with or without OF as site of first failure will be assessed at 12 months after initiation 
of SBRT, which will be approximately 18 months after initiation of TKI (to be 
comparable with our historical data, see Section 2.2).
Reported studies of combined therapy with EGFR TKI and SBRT in stage IV NSCLC 
patients showed improved disease control and disease-free survival with the addition of 
SBRT (62, 63, 66).  These studies however only used SBRT to treat metastases at time of 
progression. To our knowledge, the proposed study will be the first to prospectively assess 
the impact of consolidative SBRT (to sites of residual, non-progressive primary and/or 
oligometastatic disease) in stage IV EGFR-mutant and other oncogene-driven NSCLC 
patients undergoing TKI therapy. It will also be the first study to utilize proton beam SBRT 
in the treatment of metastatic lung cancer. Furthermore, the study may improve the outcome 
of a subgroup of metastatic oncogene-driven NSCLC patients and may identify 
oligometastatic oncogene-driven NSCLC as an ideal population for consolidative SBRT.

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A
B
Figure 2. Overall hypothesis and preliminary data. (A) Illustration of hypothesized indirect effect 
of local therapy (SBRT) on DF. SBRT may directly reduce OF frequency by eliminating residual 
sites of disease. SBRT may indirectly reduce DF by eliminating residual sites of disease containing 
TKI resistant tumor that can give rise to subsequent DF. (B) Patterns of failure from a MGH cohort 
of patients with advanced EGFR-mutant NSCLC treated with first-generation TKIs (n=47) and 
hypothesized effect of SBRT. OF, failure in original sites; DF, failure in (new) distant sites. 
12-month Failures: 
Failure 
Failure
Percent of all
Type
Frequency
Failures
OF
28%
44%
DF+OF
24%
38%
DF
11%
17%
All
63%
100%
18-month Failures: 
Failure 
Failure
Percent of all
Type
Frequency
Failures
OF
39%
49%
DF+OF
28%
35%
DF
13%
16%
All
80%
100%
}~40%
EGFR TKI
Initiation
EGFR TKI
Initiation
SBRT
Starting at ~ 6 months,
directed at residual original 
sites that could give rise to 
DF
Hypothesized 18-month Failures: 
Failure 
Failure
Type
Frequency
OF
< 39% (direct SBRT effect)
DF+OF
~6%    (indirect effect)
DF
13%
12-month
study 
evaluation
period for 
primary 
endpoint 
}~20%
                       
      Residual disease = target for SBRT
      In complete remission after TKI                                  DF
local OF
DF
without SBRT
Original disease
treated with TKI

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2.4
Correlative Studies Background
N/A
3.
PARTICIPANT SELECTION
3.1
Eligibility Criteria
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study:
3.1.1
Participants must have histologically or cytologically confirmed non-small cell 
lung cancer (NSCLC) with any actionable mutation or translocation in EGFR, 
ALK, or ROS1
3.1.2
Documented history of clinical stage IV (Any T, any N, M1a/b) disease as per 
AJCC Staging system 7th edition (Appendix A). 
3.1.3
Participants must be within 6 months of initiating treatment with a traditional TKI 
such as erlotinib, gefinitib, afatanib or crizotinib, which specifically targets the 
actionable mutation their tumor harbors. Participants receiving TKIs typically 
associated with a long PFS, such as first-line osimertinib or alectinib, should be 
within 12 months of TKI treatment. Other TKIs are acceptable with approval of 
Study PI..   
3.1.4
Participants must have stable or responding systemic disease to TKI (no evidence 
of progression) on the most recent staging studies. The required staging studies are: 
(1) A re-staging CT scan of the chest +/- abdomen with IV contrast (unless 
medically contraindicated) within 2 months of study enrollment; and (2) in patients 
with known brain metastasis, or to investigate patients with new onset of neurologic 
symptoms that may suggest metastasis to the brain, Brain MRI with gadolinium, 
or head CT scan with IV contrast will be required within 2 months of study 
enrollment. 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 involved in this trial. This will be 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 

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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.  There is no minimum 
size requirement for treatment of brain lesions but small foci of potential disease 
(1-4 mm size) detected on high-resolution MRI may not be clinically relevant and 
do not count towards the maximum number of 4 brain metastases as per the 
treating radiation oncologist’s discretion and in line with institutional practice.        
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. This is not an absolute requirement as situations may exist when 
more than 5 metastatic targets are appropriate in the treating radiation 
oncologist’s clinical judgment, for example when nearby lesions can be 
included in a single treatment field. 
3.1.5
History of prior radiation therapy to brain or skeleton is allowed, but should have 
occurred > 2 months from enrollment. 
3.1.6
Age at least 18 years. 
3.1.7
Life expectancy of greater than 6 months. 
3.1.8
ECOG performance status <2 (see Appendix B).
3.1.9
Radiation is a known teratogenic agent. Thus, 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 
treatment. Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately.
3.1.10 Ability to understand and the willingness to sign a written informed consent 
document.
3.2 Exclusion Criteria
Participants who exhibit any of the following conditions at screening will not be eligible 
for admission into the study.
3.2.1
Subjects deemed to have residual hilar or mediastinal lymph node disease (defined 
as nodal size > 1cm in short-axis diameter on CT scan), since SBRT to mediastinal 
or hilar structures is potentially associated with high toxicity. Non-malignant 
etiologies for enlarged lymph nodes may be evaluated per standard clinical 
practice.
3.2.2
Participants who have received prior radiation therapy to anatomical sites other 
than brain or skeleton.

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3.2.3
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.
3.2.4
Patients who are pacemaker or defibrillator-dependent as these devices may not 
be operated concurrently with delivery of proton beam radiation.
3.2.5
Pregnant or lactating women, as treatment involves unforeseeable risks to the 
embryo or fetus. Female subjects of childbearing potential must indicate to their 
physician that there is not a possibility of being pregnant at the time of enrollment 
or have a negative pregnancy test prior to the initiation of radiation therapy. 
3.3
Inclusion of Women, Minorities and Other Underrepresented Populations
Both men and women of all races and ethnic groups are eligible for this trial.  Lung cancer 
affects men and women, and people of all race and socioeconomic class. We do not expect the 
inclusion and exclusion criteria to negatively affect enrollment of underrepresented 
populations.
4.
REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC  Institutions
Institutions will register eligible participants in the Clinical Trials Management 
System (CTMS) OnCore. Registration must occur prior to the initiation of protocol 
therapy. Any participant not registered to the protocol before protocol therapy begins 
will be considered ineligible and registration will be denied. 
An investigator will confirm eligibility criteria and a member of the study team will 
complete the protocol-specific eligibility checklist.
Following registration, participants may begin protocol therapy. Issues that would 
cause treatment delays should be discussed with the Overall Principal Investigator 
(PI). If a participant does not receive protocol therapy following registration, the 
participant’s registration on the study must be canceled. Registration cancellations must 
be made in OnCore as soon as possible.
4.2
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject 
Protocol Registration (SOP #: REGIST-101) must be followed.

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4.3
General Guidelines for Other Participating Institutions
N/A
4.4
Registration Process for Other Participating Institutions
N/A

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5.
TREATMENT PLAN
Treatment will be administered on an outpatient basis. Expected toxicities and potential risks 
as well as dose modifications are described in Section 6 (Expected Toxicities and Dosing 
Delays/Dose Modification). No investigational or commercial agents or therapies other than 
those described below may be administered with the intent to treat the participant’s malignancy.
This is a phase II prospective trial of 30 patients to establish the efficacy and safety of 
integrating consolidative SBRT into the management of Stage IV oncogene-driven NSCLC 
with low-burden metastatic disease. Proton beam radiation will be administered in the Francis 
H. Burr Proton Therapy Center (FHBPTC) at MGH. Linear-accelerator-based SBRT with 
photons, if needed, will be administered in the MGH Clark Center for Radiation Oncology. 
SBRT will be delivered as once-daily treatments over 1-10 fractions.
5.1
Pre-treatment Assessment
This trial will accrue patients with pathologically confirmed oncogene-driven metastatic NSCLC 
that meet the eligibility criteria listed in Section 3.1. All accrued patients will be evaluated by a 
radiation oncologist within 1 month of study registration. This preliminary evaluation will 
include history and physical examination, including weight and assessment of ECOG 
performance status. A re-staging CT scan of the chest with/without abdomen with IV contrast 
(unless medically contraindicated) will be obtained as per standard of care within 2 months of 
study enrollment to determine the extent of disease (including spinal metastasis) and aid in 
radiation planning. Brain MRI with gadolinium, or head CT scan with IV contrast will be 
required within 2 months of study registration in patients with known brain metastasis, or to 
investigate patients with new onset of neurologic symptoms that may suggest metastasis to the 
brain. Spine MRI with gadolinium may be obtained at baseline for radiation planning purposes if 
a subject has spine metastasis as well as in follow-up as per standard clinical practice. Imaging 
will be obtained as per standard of care within 2 months of study enrollment. 
SBRT-eligible sites are limited to lungs, liver, adrenals, and spine (limits outlined in Table 
3). A total number of 5 targets outside the brain and excluding the lung primary is 
recommended. Patients with newly diagnosed brain metastases (1-4 lesions), may be 
treated with standard-of-care SRS. There is no minimum size requirement for treatment of 
brain lesions but small foci of potential disease (1-4 mm size) detected on high-resolution 
MRI may not be clinically relevant and do not count towards the maximum number of 4 
brain metastases as per the treating radiation oncologist’s discretion and in line with 
institutional practice.
5.2
SBRT Planning and Treatment
5.2.1
Simulation and Treatment Planning
5.2.1.1 Simulation: All simulations will be performed according to standard 
institutional practice for the different anatomical sites of this protocol 
(Lung, Liver, Adrenals, Spine). This may include placement of fiducials 
markers prior to simulation to guide precise radiation delivery to tumor 

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targets that move with respiration, such as tumors in the liver and the lungs. 
Fiducials placement will typically be done via a CT-guided transcutaneous 
approach as per institutional practice and as per standard-of-care for 
stereotactic and stereotactic-like treatments (109-111).
5.2.1.2 Delineation of tumor target volumes and organs at risk (OAR): Gross tumor 
and OAR for each anatomical site will be contoured according to standard 
institutional practice. For each anatomical site, 2 or more of the target 
lesions can be irradiated concurrently at the discretion of the treating 
physician.  
5.2.1.3 Treatment planning: Passively or actively scanned proton beam radiation 
should be used for all anatomical sites unless for a given subject the use of 
conformal photon techniques (3D conformal, intensity-modulated radiation 
therapy, or volumetric arc) is judged superior by the treating physician, or 
unless there would be undue delay of treatment due to resource availability. 
Treatment planning will be performed according to standard institutional 
practice for each anatomical site. SBRT planning will vary among patients 
with multiple metastases based on the size, geometry and location of these 
metastases. When metastases are widely separated in the body (for example, 
one in the upper lobe of the lung and another in the adrenal gland) little 
overlap can be expected and each may be planned independently of each 
other. However, in other cases, such as concurrent lung tumor and thoracic 
spine metastasis, careful consideration should be given to the avoidance of 
beam overlap.
5.2.1.4 Dose Prescription and Fractionation:
-
The optimal dose and fractionation for each anatomical site will be dictated 
by the OARs in close proximity to the target site, and thus will vary between 
subjects according to institutional practice and standard-of-care (112)..
-
Depending on size and location, it is recommended that the tumor target be 
covered by one of the dose fractionations listed in Table 3.
Table 3. Recommended criteria and dose fractionation for SBRT targeted sites 
Site
Target
Dose and Fractionation
Lung
Primary plus 1-2 metastatic targets 
Maximum size: 5 cm largest diameter
6-12 Gy x 4-10 fractions
Liver
1-4 targets
Maximum size: 5 cm largest diameter
6-10 Gy x 5-10 fractions
Adrenals
1-2 targets
Maximum size: 4 cm largest diameter
5-8 Gy x 5-10 fractions
Spine
1-2 targets, each target can span 1-3 vertebral 
bodies. 
18 Gy single fraction

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A minimum size of 1 cm in largest diameter is recommended for all sites mainly due minimum 
field size constraints that could affect dosimetry. It may be clinically indicated to treat lesions < 
1 cm for example if they are avid on FDG-PET. This is at the discretion of the treating radiation 
oncologist in accordance with departmental routine clinical care guidelines.
5.2.2
Treatment delivery
5.2.2.1 Location: All treatments will be delivered at the Francis H. Burr Proton Treatment 
Center or the Clark Center for Radiation Oncology at MGH.
5.2.2.2 Treatment Start: Following enrollment, radiation treatment should be initiated at 
the earliest possible time as per standard-of-care, which in most cases is expected 
to be within 4 weeks though a longer interval is acceptable. Because of the need 
to assess TKI response it is unlikely that treatments will start within 4-5 months 
of TKI treatment. For participants enrolling at the end of the 6-month TKI window 
for traditional drugs such as erlotinib, afatainib, or crizotinib, treatment will likely 
commence > 6 months after TKI start. Taken together, it is anticipated that 
radiation treatments will commence on average by 6 months (in most cases, 
between 5 and 7 months), so that primary endpoint assessment at 12 months after 
SBRT start will be comparable to historical outcomes at 18 months after TKI start 
(see 14.1 Primary Endpoint). For the same reason, participants who are on TKIs 
associated with longer PFS times, such as osimertinib, treatment should occur 
within about 12 months of TKI treatment.
5.2.2.3 Timing: Treatments may be given on subsequent days with approximately 24 
hours inter-fraction interval. A more protracted course is allowed also. Treatments 
may commence on any day of the week. Treatments may be delivered with 1-3 
isocenters per session at the treating physician’s discretion. However, only one 
anatomical site should be treated at a given time. For treatment of any two 
anatomical sites, the minimum and maximum interval between the last treatment 
of the previously anatomical site and the first treatment of the next anatomical site 
should be 1 week and 2 months, respectively. The overall treatment duration, i.e., 
1st day of SBRT delivery until final day of SBRT delivery for all anatomical sites 
to be treated should not exceed 4 months. 
5.2.2.4 On rare occasion, proton beam radiation becomes unavailable due to technical 
problems. Photon-based SBRT may be used as a back-up only if the duration of 
proton unavailability would make the overall treatment time for a given site 
treatment extend beyond 14 elapsed days (counted from day of the first to the last 
fraction for a given anatomical site). 
5.2.2.5 Quality Assurance:  All SBRT treatment plans will be reviewed for QA per the 
standard Department of Radiation Oncology practices for all patients treated.
5.3
General Concomitant Medication and Supportive Care Guidelines

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Eligible subjects will be on specific TKI treatments corresponding to their driver 
mutation. TKI will be held on days when patients are receiving SBRT. 
5.4
Duration of Therapy
Treatments may be given on subsequent days with approximately 24 hour interfraction 
interval or spread out over 2 weeks. Missed treatments due to technical problems, 
patient factors, or other factors will be added at the end of the treatment course. It is 
recommended that the overall duration of each treatment course (per anatomical site) 
should not exceed 14 elapsed days. The total duration of SBRT courses, i.e., first day 
of any SBRT until final day of any SBRT, should not exceed 4 months.
Participants will be followed by the treating radiation oncologist prior to the start and 
upon completion of each SBRT course. Patients receiving a 4-10 fraction SBRT course 
will also be evaluated during weekly treatment visits. Assessments during and 
immediately following the completion of SBRT are intended to record and manage 
acute side effects that patients may experience. 
Treatments may be discontinued for any of the following events:
•
Development of additional sites of metastasis during the 4-month SBRT 
course.
•
Intercurrent illness that prevents further administration of treatment,
•
Unacceptable adverse event(s),
•
Participant decides to withdraw from the study, or
•
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator
5.5
Duration of Follow Up
Participants will be followed for 2 years after the completion of treatment. 
Participants removed from study treatment for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event.
Follow up assessments will include physical examinations, toxicity and adverse event 
assessment, and imaging tests, as described in Section 9. If needed, participants will be 
assessed and managed for any treatment related acute toxicity 6 weeks after completion 
of SBRT. Participants will be evaluated clinically and radiographically for tumor 
progression and assessed and managed, if necessary, for any SBRT-related late toxicity 
every 3 months. It is unlikely that many patients with metastatic NSCLC will be alive 
beyond 2-3 years. Participants distant to MGH will be encouraged to follow up at the 
treating center, or send medical records and imaging studies obtained locally at the 
specified follow-up times. 
5.6
Criteria for Removal from Study

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Participants will be removed from study when any of the criteria listed in Section 5.5 
applies. The reason for study removal and the date the participant was removed must be 
documented in the study-specific case report form (CRF). Alternative care options will 
be discussed with the participant.
In the event of unusual or life-threatening complications, participating investigators 
must immediately notify the Principal Investigator, 
Henning Willers, M.D.
617-726-5184
hwillers@partners.org

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6.
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS
Toxicity assessments will be done using the CTEP Active Version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) which is identified and located on the 
CTEP website at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used.
All adverse events experienced by participants will be collected from the time of the first dose 
of study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible.
6.1
Anticipated Toxicities
Radiation side effects are divided into those that occur acutely (during radiation and up 
to 3 months after radiation) and those that occur later (>3 months post-radiation). Acute 
side effects are typically common and transient, while late normal tissue complications 
are generally rare but they can be severe and/or permanent. Late complications are 
considered dose-limiting (102).
Late toxicity is relatively uncommon and reported rates of grade ≥3 complications 
following SBRT as per this protocol are generally <5%. Treatment related deaths are 
very rare, occurring in less than 1% of cases (11, 15, 16, 22, 59). 
6.1.1
Expected Toxicities of SBRT
Abnormalities in blood work may or may be a direct or indirect effect of 
SBRT. 
Pulmonary 
Common (>10%)
-
Fatigue
-
Dermatitis
Uncommon (<10%)
-
Nausea/decrease appetite
-
Cough
-
Esophagitis
-
Moist skin desquamation
-
Pneumonitis 
-
Dyspnea

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-
Hypoxia
-
Hemoptysis
-
Rib fracture/chest wall pain
-
Pericarditis
Rare (<1%)
-
Fistula
-
Brachial plexopathy
-
Transverse myelitis
-
Congestive heart failure
-
Heart attack
-
Vascular aneurysm or rupture
Gastrointestinal 
Common (>10%)
-
Abdominal pain
-
Fatigue
-
Skin irritation
-
Nausea and vomiting
-
Uncommon (<10%)
-
Esophagitis
-
Dysphagia
-
Loose stools
Rare but serious (<1%)
-
Kidney damage
-
Bowel scarring, obstruction and/or perforation requiring surgery
-
Veno-occlusive disease
-
Radiation-induced liver disease/cirrhosis
-
Transverse myelopathy
Spine 
The side effects or risks of spine SBRT are variable and dependent on the 
vertebral level being treated. This includes:
 Common (>20%)
-
Pain flare
-
Fatigue
-
Skin irritation

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Uncommon (<20%)
-
Mucositis
-
Esophagitis
-
Nausea and vomiting
-
Loose stools
-
Transient neuropathy
-
Dysphagia 
-
Vertebral fracture 
Rare but serious (<1%)
-
Transverse myelopathy 
-
Kidney damage
-
Bowel scarring requiring surgery
6.2
Toxicity Management
No side effects specific to proton SBRT, as compared to photon SBRT which is in routine 
clinical use, are expected.
No serious acute side effects are expected during the short course of treatment. In the 
unlikely event of any grade 3 or 4 acute toxicity, there will be a treatment break until the 
toxicity resolves to grade 2 or less.
No specific therapy exists for radiation-induced fatigue. Mild to moderate dermatitis, 
typically occurring 3-4 weeks after radiation, may be managed with an alcohol-free 
emollient such as Aquaphor® or hydrocortisone ointment as needed. Pneumonitis should 
be managed per standard clinical practice, including a trial of antibiotic, prednisone 60 
mg daily by mouth until symptom improvement followed by a slow taper, with or without 
oxygen support. All expected side effects as listed above will be managed according to 
standard institutional practice for each anatomical site.
6.3
Dose Modifications/Delays
Any grade 3 or 4 acute toxicity, related to radiation therapy, will result in a treatment 
break until it resolves to grade 2 or less. If a treatment break of > 14 days is needed, the 
patient will be removed from study.
7.
DRUG FORMULATION AND ADMINISTRATION
N/A 

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8.
CORRELATIVE/SPECIAL STUDIES
 8.1 Participants are allowed to enroll on separate IRB-approved protocols as long as those do 
not involve investigational or commercial agents or therapies intended to treat the participant’s 
residual cancer.
8.2 Research Biopsy
As part of the current protocol, participants will be offered an optional tumor biopsy at the time 
of standard-of-care fiducials placement for guiding stereotactic radiation treatments (109-111). 
There exists strong scientific rationale for studying the response of oncogene-addicted tumors 
to TKI before drug resistance and clinical progression occur. 
Currently, it is standard-of-care to re-biopsy a progressive primary tumor or metastasis to 
determine the mechanism of acquired TKI resistance and guide selection of next-line treatment 
(113). The identification of T790M resistance mechanism in EGFR-mutated NSCLC which can 
be targeted by third-generation TKI, is an example of this approach. However, treatment of TKI 
resistance remains challenging: Resistance mechanisms may be unknown or cannot be currently 
targeted, more than one resistance mechanism may occur in an individual, or resistance to third-
generation TKI will develop (114-116). The vast majority of current research efforts are being 
directed at targeting tumors with acquired resistance to TKI. In contrast, opportunities to 
prevent the emergence of resistance remain vastly understudied. Tumor cells that survive 
inhibition of the oncogenic kinase may persist in a drug-tolerant state for some time and 
ultimately give rise to clones with acquired TKI resistance (117). This “persister” state has 
remained underappreciated as a potential therapeutic opportunity even though the stress 
responses to shutting down the driving oncogene likely create multiple survival dependencies. 
The purpose of obtaining a research biopsy before clinical progression therefore is to identify 
novel therapeutic targets, which may benefit future patients. A potential benefit to the 
participant undergoing a biopsy is that evolving resistance mechanisms, such as T790M, may 
be identified prior to progression, which could inform treatment selection at the time of 
recurrence after protocol SBRT (i.e, obviating the need for a separate re-biopsy at time of 
clinical progression).
Tumor tissues for the analysis of TKI persisters will be obtained at the time of fiducials 
placement for SBRT, which will typically be a transcutaneous CT-guided approach. As fiducial 
placement will occur in or nearby the tumor, there will be the opportunity to obtain a needle 
biopsy from adjacent tumor. This will be done through the established needle access site and 
will not require an additional transcutaneous pass. No increase in bleeding risk is anticipated as 
fiducials will be placed away from pulmonary vessels. The length of the procedure will be 
minimally prolonged (by ~10 minutes), which poses no more than a minimal additional risk to 
the subject. In our own and published experience, combined fiducials placement and needle 
biopsy do not have a complication rate higher than either procedure alone (118, 119).
Expected toxicities for needle biopsy/fiducials placement are:

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Common (>10%)
-Mild lung collapse (pneumothorax) not requiring treatment
-Localized minor bleeding within the biopsied organ not requiring treatment
-Self-limited mild blood coughing (hemoptysis)
-Localized mild pain at biopsy site
Uncommon (<10%)
-Lung collapse (pneumothorax) which may be painful and causing shortness of breath 
requiring hospital admission or/and placement of a drainage tube (chest tube)
Rare but serious (~1% or less)
-Major organ bleeding requiring transfusion or other intervention
-Entry of air into vessels and causing serious harm to organs such as brain or heart (air 
embolism)
Tumor biopsies will be fixed, frozen or cultured, and analyzed in the Engelman and Willers 
Laboratories at the MGH using an array of cellular, molecular, and other assays. These studies 
may include the generation of cell lines and xenografts. For complete analysis, samples may 
need to be sent to outside institutions such as the Broad Institute for genomic analysis and the 
National Institute of Standards and Technology for detection of oxidative DNA damage. 
Appropriate steps will be followed to protect health information. Collectively, these studies 
have the ultimate goal of identifying novel therapeutic targets to delay or prevent acquired TKI 
resistance.  

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9.
STUDY CALENDAR
Baseline evaluation tests and scans are to be conducted within 2 months prior to 
registration as specified for each assessment. Exceptions are noted in the Table below. 
All assessments must be performed prior to administration of protocol treatment. All study 
assessments should be done within +4 weeks of the protocol-specified date, unless 
otherwise noted. 
Pre-Study
During each SBRT course 
(4-10 fractions)
Follow up 
EGFR/ALK/ROS1 genotype
X
Documentation of stage IV NSCLC
X
TKI therapy A
X
X
Evaluation by radiation oncologist  
XB
XC
XD
Physical exam
(including weight, and performance 
status)
X
XD
Medical history 
X
XD
CBC, chemistry 
XF
XG
Toxicity and adverse events 
evaluation
X
X
XD
CT chest +/- abdomen
XH
XE
Brain MRI or Head
CT I
X
X
Spine MRI J
X
X
Informed study consent
X
Tumor Measure 
X
XK
A. All patients must be receiving a TKI specifically targeting the actionable mutation harbored by their 
advanced NSCLC. The original date of TKI start should be recorded. SBRT must be initiated within 
approximately 6-12 months of TKI start, depending on the specific TKI treatment. TKI will be held on 
days of SBRT, resumed in the interval and resumed on the day after the final SBRT delivery.
B. The initial radiation oncology assessment should indicate that all radiation oncologists that will be 
involved in SBRT treatment for a given subject have reviewed the imaging studies and determined that all 
active disease in each anatomical site is amenable to SBRT. This assessment should be done within 1 
month of registration. 
C. Subjects will be seen by his/her radiation oncologist at least once and every 5 fractions during each 
SBRT course, and may be seen by his/her medical oncologist as per standard clinical care.
D. Following completion of all stereotactic treatments, subjects should continue follow-up as per standard 
of care, which typically includes surveillance scans every 3 months. This should entail visits with either 
medical oncology or radiation oncology or both. For assessment and management, if necessary, of any 

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acute toxicity, subjects may be seen if needed at 6 weeks (+/- 4 weeks) after the final day of SBRT. 
Imaging does not need to be performed at this follow-up unless clinically indicated. For subsequent study 
evaluations, subjects should be seen every 3 months (+/- 4 weeks). Each follow-up visit should be 
associated with toxicity and adverse events monitoring and history & physical.
E. CT scan of the chest +/- abdomen will be obtained every 3 months +/- 4 weeks, per standard of care. 
CT scans outside this schedule will be allowed if needed per standard of care, and will not be marked as a 
minor deviation.
F. At baseline, CBC with differential, basic metabolic panel (Na, K, Cl, CO2, BUN, creatinine, glucose, 
calcium), liver function tests (albumin, total protein, alkaline phosphatase, total bilirubin, ALT, AST). 
G. During follow-up visits, CBC and chemicals will be drawn at the discretion of the treating physician. 
H. CT scan of the chest with or without abdomen with intravenous contrast depending on disease extent 
as per standard practice (unless medically contraindicated or subject refuses). Additional scans such as 
CT neck or pelvis may be added based on disease extent and per standard-of-care. An additional PET 
scan may be obtained if clinically indicated as per standard clinical practice. Imaging will be obtained as 
per standard of care within 2 months of study enrollment. 
I. Brain MRI with gadolinium or CT of the head with intravenous contrast should be obtained at baseline 
and in follow up of patients known to have brain metastasis or to investigate patients with neurologic 
symptoms that may suggest the development of new brain metastasis. Imaging will be obtained as per 
standard of care within 2 months of study enrollment and at the discretion of the treating physician. 
J. Spine MRI with gadolinium may be obtained at baseline for radiation planning purposes if a subject has 
spine metastasis as well as in follow-up as per standard clinical practice. Imaging will be obtained as per 
standard of care within 2 months of study enrollment and at the discretion of the treating physician.
K. Tumor measurements are not required for every scan in follow up. Tumor measurements will be 
conducted when changes are visible to assess for tumor response and progression. For study data 
purposes, any scan reporting progression, as well as the scan immediately prior to that scan, will be 
assessed as described in Section 10 below. 

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10. MEASUREMENT OF EFFECT
10.1 Antitumor Effect– Solid Tumors
Tumor response and progression will be evaluated in this study using the new 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (103). Changes in the diameter (one-dimensional 
measurement) of the tumor lesions are used in the RECIST criteria. Additional 
definitions beyond the RECIST guidelines are incorporated to define local lung 
primary and metastasis control (LC) following SBRT. Local response and control of 
lung tumors are often difficult to define due to radiographic radiation pneumonitis 
and fibrosis. Furthermore, the development of mass-like consolidation after lung 
SBRT has been reported (104, 105), further complicating the assessment of local 
control. In addition, RECIST assessments will not apply to the development of brain 
metastases and are limited for spine metastases.  
10.1.1 Definitions
Evaluable for toxicity: All participants who receive at least one fraction of 
SBRT will be evaluable for toxicity from the time of their first treatment.
Evaluable for objective response: Only those participants who have 
measurable residual disease in response to TKI therapy, have completed their 
prescribed SBRT course, and have had their disease re-evaluated will be 
considered evaluable for response. These participants will have their response 
classified according to the definitions stated below. (Note: Participants who 
exhibit objective disease progression in targeted sites of residual disease or die 
prior to completion of SBRT will also be considered evaluable. However, 
patients that develop new sites of metastasis prior to the end of their SBRT 
course will be disqualified from the study).
As detailed below, for the purpose of this protocol, we will use the following 
definitions:
1. Original sites = extent of disease at presentation before TKI was started
1a. Original sites that persist after start of TKI and that will be treated by SBRT 
= target lesions
1b. Original sites in which there has been a complete response during TKI 
treatment = non-target lesions
Failure in these sites will be classified as OF.
2. Distant sites = new sites of distant metastases distinct from original sites 
developing after SBRT = non-target lesions.
Failure in these sites will be classified as DF.
10.1.2
Disease Parameters

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Measurable disease: 
Measurable disease is the presence of at least one (1) lesion that can be 
accurately measured in at least one dimension with longest diameter >=10 mm 
using conventional techniques (CT, MRI). Measurable lesions must be at least 2 
times the slice thickness in mm. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters).
Patients enrolled to this protocol will have stage IV NSCLC (Ant T, any N, and 
M1) NSCLC. At time of treatment, they should have stable residual 
primary/metastatic disease in no more than 4 extra-cranial anatomical sites within 
the lung (primary and metastatic), liver, adrenals, and spine. 
Non-measurable disease: 
All other lesions (or sites of disease), including small lesions (longest diameter <10 
mm using spiral CT scan), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis, 
inflammatory breast disease, abdominal masses identified by physical exam that 
are not measurable by reproducible imaging techniques, and cystic lesions are all 
considered non-measurable. 
Non-measurable disease may occur as disease progression (nodal or distant) after 
completion of SBRT, but should not be present prior to therapy.
Target lesion:
The primary lung tumor in addition to the metastatic tumor sites treated with SBRT 
should be identified as the target lesions, and recorded and measured at baseline 
and with each follow-up imaging evaluation. Target lesions for the specified organs 
will be limited to 3 lesions in the lung (primary and 2 metastatic targets), 4 in the 
liver, 2 in the adrenal and 2 in the spine (Table 3). The longest diameter (LD) for 
the target lesions will be calculated from the pre-study CT scan obtained at time of 
study enrollment, following initial response to TKI and prior to initiating SBRT. 
This will be reported as the baseline LD. If there is appreciable interval growth of 
the target lesion seen at the time of CT planning for SBRT, this will be used as the 
new baseline LD. The baseline LD will be used as a reference by which to 
characterize the objective tumor response. 
For follow-up assessment, diagnostic CT scans performed using a <5 mm 
contiguous reconstruction algorithm taken as part of scheduled protocol follow-up 
are preferred as the method of evaluation for response of lung, liver and adrenal 
lesions. MRI scans will be performed for the follow up evaluation of response in 
treated spinal metastasis as per institutional practice.

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Local treatment effects in the vicinity of the tumor target may make determination 
of tumor dimensions difficult. For example, in lung tumors bronchial or bronchiolar 
damage typically cause patchy consolidation around the tumor that over time may 
coalesce with the residual tumor. In cases in which it is indeterminate whether 
consolidation represents residual tumor or treatment effect, additional assessments, 
such as PET/CT scanning and/or biopsy should be considered as per standard 
clinical practice.
Non-target lesions: 
All other lesions (or sites of disease), including small lesions (longest diameter 
<10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis, as well 
as truly non-measurable lesions, which include leptomeningeal disease, ascites, 
pleural or pericardial effusion, lymphangitic involvement of lung, abdominal 
masses identified by physical exam that are not measurable by reproducible 
imaging techniques. 
More specifically, the definition of non-target lesions also applies to sites of 
original disease (diagnosed at presentation, before TKI therapy initiation), 
which following response to TKI become non-measurable disease and therefore 
are not targeted with SBRT. Such lesions should be identified as non-target 
lesions and should also be recorded at baseline and at each follow-up. Disease 
progression in this specific type of non-target lesions will be taken into 
consideration for the evaluation of local failure and original site failure (defined 
below).
10.1.3
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation, using a ruler, 
calipers, or digital measurement tool. All baseline evaluations should be performed 
as closely as possible to the beginning of treatment.
Conventional CT: Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm, with axials cuts of no more than 5 mm, and 2.5 mm cuts 
are recommended as per institutional practice at MGH. Intravenous contrast should 
be used unless there is a medical contraindication or the patient refuses.
FDG PET and PET/CT: The acquisition of FDG PET and FDG PET/CT scans 
should follow the NCI Guidelines for using FDG PET as an indicator of therapeutic 
response (106). Patients should avoid strenuous exercise and be on a low 
carbohydrate diet for 24 hours prior to the scan. Patients should fast for 4 hours or 
longer prior to the FDG injection and should have serum glucose of less than 200 
mg/dL at the time of FDG injection. A 10-20 mCi dose of FDG should be injected 
for typical adult patients. For longitudinal studies with multiple scans, particular 

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attention should be paid to ensure consistent patient preparation and acquisition 
parameters between the follow-up scan and the baseline scan. However, PET scans 
will only be ordered as part of standard clinical care.
Cytology, Histology: Biopsy confirmation may be sought, as clinically indicated, 
to document local recurrence or disease progression elsewhere.
MRI: Spine MRI with gadolinium may be used for diagnosis and to aid in the 
SBRT planning for treatment of active spinal metastasis, unless medically contra-
indicated or the participant refuses. MRI with gadolinium may be used for the 
assessment of liver metastasis not well visualized on CT scans.
Special consideration will be used for the evaluation of bone lesions, based on the 
following:
•
Bone scan, PET scan, or plain films are not considered adequate imaging 
techniques to measure bone lesions. However, these techniques can be used 
to confirm the presence or disappearance of bone lesions.
•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques 
such as CT or MRI can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above.
•
Blastic bone lesions are non-measurable.
10.1.4 Response Criteria
10.1.4.1 Evaluation of Target Lesions
Primary and metastatic lung target lesions
Complete Response (CR): Disappearance of the target lesion on CT 
image evaluation.
Partial Response (PR): At least a 30% decrease in the LD of the target 
lesion, taking as reference the baseline LD. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for CR/PR 
above nor sufficient increase to qualify for LE below, taking as 
reference the smallest LD since the treatment started.
Local Enlargement (LE): At least a 20% increase in the LD of target 
lesion, taking as reference the smallest LD recorded since the treatment 
started; based on CT image evaluation. Local response and control of 
lung tumors are often difficult to define due to radiographic radiation 
pneumonitis and fibrosis. Therefore, if the criteria for LE are met, the 
patient may undergo a PET scan imaging or a direct biopsy of the targeted 

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tumor if clinically indicated. This information may be used for a 
determination as to whether original site failure (OF) exists as defined 
below.
Local Control (LC): The absence of LE in a target lesion treated with 
SBRT.
Metastatic liver/adrenal target lesions
Complete Response (CR): Disappearance of the target lesion on CT 
image evaluation.
Partial Response (PR): At least a 30% decrease in the LD of the target 
lesion, taking as reference the baseline LD; ideally, this determination will 
be made based on CT image evaluation.
Stable Disease (SD): Neither sufficient shrinkage to qualify for CR/PR 
above nor sufficient increase to qualify for PD below, taking as 
reference the smallest LD since the treatment started.
Progressive Disease (PD): At least a 20% increase in the sum of the 
largest diameters of target lesions, taking as reference the smallest sum on 
study this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression).
Local Control (LC): The absence of PD in SBRT treated target lesions.
Metastatic spine target lesions
Spine MRI of the spinal region treated will be done as per standard 
clinical care but 3-month intervals in the first 2 years are recommended. 
Disease will be evaluated as:
Complete Response (CR): Disappearance of the target lesion on MRI 
image evaluation.
Responsive Disease: At least a 30% decrease in the LD of the target 
lesion, taking as reference the baseline LD. Evaluation will be made 
based on MRI scans.
Stable Disease: Neither sufficient shrinkage to qualify for CR/PR above 
nor sufficient increase to qualify for PD below, taking as reference the 
baseline LD.

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Progressive Disease/Local Failure: At least a 10% increase in the sum of 
the largest diameters of target lesion seen on each of 2 consecutive MRI 
scans, taking as reference the baseline LD. 
Marginal Failure: the appearance of new lesions within one vertebral 
body space above or below the PTV
Local Control: the absence of progressive disease and/or marginal 
failure.
10.1.4.2 Evaluation of Non-Target Lesions
Definition of New Lesion: The finding of a new lesion should be 
unequivocal (i.e. not due to difference in scanning technique, imaging 
modality or findings thought to represent something other than tumor (ex: 
new bone lesions may be healing or flare of pre-existing lesions). 
However, a lesion identified on a follow-up scan in an anatomical 
location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size, etc.), 
follow-up evaluation will clarify if it truly represents new disease and if 
PD is confirmed, progression should be declared using the date of the 
initial scan on which the lesion was discovered. 
Complete Response (CR): Disappearance of all non-target lesions. All 
lymph nodes must be non-pathological in size (< 10 mm short axis).
Incomplete Response/Stable Disease (SD): Persistence of one or more 
non-target lesions.
Progressive Disease (PD): Appearance of one or more new lesions 
(new lesions must be > slice thickness) and/or unequivocal progression 
of existing non-target lesions and /or overall level of substantial 
worsening that merits change of therapy. A useful test that can be 
applied when assessing non-targets for unequivocal progression is to 
consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase 
that would be required to declare PD for measurable disease.
Unknown (UN): Assessment of non-target lesions cannot be made due to 
insufficient or unevaluable data. In this case, a concise explanation must 
be given.
10.1.4.3 Evaluation of Best Overall Response
N/A

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10.1.5
Duration of Response
N/A
10.1.6
Progression-Free Survival
Progression-Free Survival (PFS) is defined as the duration of time from start of TKI 
therapy to time of objective progressive disease. 
10.1.7
Patterns of First Failure:
Progression will be divided into two categories: Original sites failure (OF) and 
distant failure (DF) (with and without concomitant OF). Death will also be 
regarded as a progression event.
Original Sites Failure (OF): 
Refers to both target and non-target lesions (Table 4).
Target lesions: OF is defined as evidence of progressive disease (PD) (as 
defined above) within the primary and/or individual metastatic target 
lesions treated with SBRT. For primary lung lesions, PET-positive or 
biopsy-confirmed marginal failures within 2 cm of the gross target 
volume (GTV), will be counted as OF. The EORTC criteria for post-
treatment PET evaluation may be used as a basis for evaluation in cases 
more difficult to assign as to whether the uptake is pathologic for cancer 
recurrence vs. inflammation (107).
Non-Target lesions: OF is defined as evidence of progressive disease (PD) 
in metastatic sites that were diagnosed at presentation, prior to TKI 
therapy, but deemed non-target lesions (defined above), and therefore 
were not treated with SBRT. 
Distant failure (DF): This is defined as the radiographic appearance of a new 
metastatic lesion having a dimension of at least 1 cm, in a site that was not 
identified at disease presentation prior to initiating TKI therapy (Table 4). For 
primary lung lesions, intra-thoracic failure at least 2 cm away from the GTV 
will also be scored as DF. Failure with intracranial metastasis should be 
confirmed by MRI with gadolinium.
10.1.8
Response Review
All response assessments will be made by the study PI or a protocol co-
investigator. Biopsy of suspected local failures or progressive disease will only 
be done if indicated per standard clinical practice, for example to determine 
mechanisms of resistance to TKI.

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10.2 Antitumor Effect – Hematologic Tumors
N/A
10.3 Other Response Parameters
N/A

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Table 4: Evaluation of overall response and patterns of failure
Target Lesions
Non-Target 
Lesions
New Lesions
Overall 
Response
Pattern of First 
Failure
CR
CR
None
CR
None
CR
Non-CR/Non-PD
None
PR
None
CR
Not evaluated
None
PR
None
PR
Non-CR/Non-
PD/Not 
evaluated
None
PR
None
SD
Non-CR/Non-
PD/Not 
evaluated
None
SD
None
PD
Any
None
PD
OF
Any
PD*
None
PD
OF
Any 
Any
Yes
PD
DF (+/- OF)
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression

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11. ADVERSE EVENT REPORTING REQUIREMENTS
11.1 Definitions
11.1.1
Adverse Event (AE)
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of study 
treatment or any procedure specified in the protocol, even if the event is not 
considered to be related to the study. 
Abnormal laboratory values or diagnostic test results constitute adverse events only 
if they induce clinical signs or symptoms or require treatment or further diagnostic 
tests. 
An AE of Special Interest includes hepatic injury defined by the following 
alterations of liver parameters (measured in the same blood draw sample): for 
patients with normal AST/ALT and bilirubin at baseline, an elevation of AST 
and/or ALT above > 3 fold ULN combined with an elevation of bilirubin above > 
2 fold ULN. Patients showing these lab abnormalities need to be followed up 
appropriately.
11.1.2
Serious adverse event (SAE)
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that: 
•
Results in death
•
Is life-threatening. Life-threatening means that the person was at immediate 
risk of death from the reaction as it occurred, i.e., it does not include a 
reaction which hypothetically might have caused death had it occurred in a 
more severe form.
•
Requires or prolongs inpatient hospitalization (i.e., the event required at 
least a 24-hour hospitalization or prolonged a hospitalization beyond the 
expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior to 
study entry are not considered SAEs if the illness or disease existed before 
the person was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (e.g., surgery performed earlier than 
planned).
•
Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions.
•
Is a congenital anomaly or birth defect; or
•
Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 

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intervention to prevent one of the outcomes listed above. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home; blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
Events not considered to be serious adverse events are hospitalizations for:
•
routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures
•
elective or pre-planned treatment for a pre-existing condition that did not 
worsen
•
emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission
•
respite care
11.1.3
Severity of adverse events
The severity of the AE should be classified and recorded according to the    
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
11.1.4
Expectedness
Adverse events can be 'Expected' or 'Unexpected.' 
11.1.4.1 Expected adverse event
Expected adverse events are those that have been previously identified as 
resulting from administration of study treatment (SBRT). For the purposes 
of this study, an adverse event is considered expected when it appears in 
the current adverse event list or is included in the informed consent 
document as a potential risk.
Refer to Section 6.1 for a listing of expected adverse events associated 
with the study treatment.
11.1.4.2 Unexpected adverse event
For the purposes of this study, an adverse event is considered unexpected 
when it varies in nature, intensity or frequency from information provided 
in the current adverse event list or when it is not included in the informed 
consent document as a potential risk.  
11.1.5 Attribution
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows:

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• Definite – The AE is clearly related to the study treatment.
• Probable – The AE is likely related to the study treatment.
• Possible – The AE may be related to the study treatment. 
• Unlikely - The AE is doubtfully related to the study treatment.
• Unrelated - The AE is clearly NOT related to the study treatment.
11.2 Procedures for AE and SAE Recording and Reporting
Reporting participating investigators will assess the occurrence of AEs and SAEs at all 
participant evaluation time points during the study. 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-specific 
case report forms. 
The descriptions and grading scales found in the CTEP Active Version of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE 
reporting. The CTEP Active Version of the CTCAE is identified and located on the CTEP 
website at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All appropriate treatment areas should have access to a copy of the CTEP Active Version 
of CTCAE.
11.3 Reporting Requirements
For multi-site trials where a DF/HCC investigator is serving as the principal investigator, 
each participating investigator is required to abide by the reporting requirements set by 
the DF/HCC. The study must be conducted in compliance with FDA regulations, local 
safety reporting requirements, and reporting requirements of the principal investigator. 
Each investigative site will be responsible to report SAEs that occur at that institution to 
their respective IRB. It is the responsibility of each participating investigator to report 
serious adverse events to the study sponsor and/or others as described below. 
11.4 Reporting to the Study Sponsor
11.4.1
Serious Adverse Event Reporting

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All serious adverse events that occur after the initial dose of study treatment, during 
treatment, or within 30 days of the last dose of treatment must be reported to the 
DF/HCC Overall Principal Investigator on the local institutional SAE form. This 
includes events meeting the criteria outlined in Section 11.1.2, as well as the 
following:
•
Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and at 
least possibly related/associated with the intervention.
•
All Grade 4 (life-threatening or disabling) events that are unexpected or not 
specifically listed in the protocol as not requiring reporting.
•
All Grade 5 (fatal) events while the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the last 
study intervention. 
Note: If the participant is in long term follow up, report the death at the time 
of continuing review. 
Participating investigators must report each serious adverse event to the DF/HCC 
Overall Principal Investigator within 24 hours of learning of the occurrence. In the 
event that the participating investigator does not become aware of the serious 
adverse event immediately (e.g., participant sought treatment elsewhere), the 
participating investigator is to report the event within 24 hours after learning of it 
and document the time of his or her first awareness of the adverse event. Report 
serious adverse events by telephone, email or facsimile to:
Henning Willers, MD, PI
Tel. 617-726-5184
Fax. 617-726-3603
hwillers@partners.org
Within the following 24-48 hours, the participating investigator must provide 
follow-up information on the serious adverse event. Follow-up information should 
describe whether the event has resolved or continues, if and how the event was 
treated, and whether the participant will continue or discontinue study participation.
11.4.2
Non-Serious Adverse Event Reporting 
Non-serious adverse events will be reported to the DF/HCC Overall Principal 
Investigator on the toxicity Case Report Forms.
11.5 Reporting to the Institutional Review Board (IRB)
Investigative sites within DF/HCC will report all serious adverse events directly to the 
DFCI Office for Human Research Studies (OHRS).

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11.6 Reporting to the Food and Drug Administration (FDA)
N/A
11.7 Reporting to the NIH Office of Biotechnology Activities (OBA)
N/A
11.8 Reporting to the Institutional Biosafety Committee (IBC)
N/A
11.9 Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy.
11.10 Monitoring of Adverse Events and Period of Observation
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 30 days of the last study 
intervention should be followed to their resolution, or until the participating investigator 
assesses them as stable, or the participating investigator determines the event to be 
irreversible, or the participant is lost to follow-up. The presence and resolution of AEs 
and SAEs (with dates) should be documented on the appropriate case report form and 
recorded in the participant’s medical record to facilitate source data verification. 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or autopsy 
report). 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the DF/HCC Overall Principal Investigator and their respective IRB of any 
unanticipated death or adverse event occurring after a participant has discontinued or 
terminated study participation that may reasonably be related to the study. 

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12. DATA AND SAFETY MONITORING
12.1 Data Reporting
12.1.1
Method 
The Office of Data Quality (ODQ) will collect, manage, and monitor data for 
this study. 
12.1.2 Data Submission
The schedule for completion and submission of case report forms (paper or 
electronic) to the ODQ is as follows:
Form
Submission Timeline
Eligibility Checklist
Complete prior to registration with OnCore
On Study Form
Within 14 days of registration
Treatment Form
Within 10 days of completion of treatment
Toxicity and Adverse Event 
Report Form
Within 10 days of completion of treatment 
and within 10 days of protocol specified 
follow up visit
Measurement/Response Form
Within 14 days of registration and within 10 
days of protocol specified follow up visit
Off Treatment/Off Study 
Form
Within 14 days of completing treatment or 
being taken off study for any reason
Follow up/Survival Form
Within 14 days of the protocol defined 
follow up visit date or call
12.2 Safety Meetings
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the 
study. Information that raises any questions about participant safety will be addressed 
with the Principal Investigator and study team.

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The DSMC will meet as required to review toxicity and accrual data.  Information to be 
provided to the committee may include:  up-to-date participant accrual; current dose 
level information; DLT information; all grade 2 or higher unexpected adverse events 
that have been reported; summary of all deaths occurring within 30 days for Phase I or 
II protocols; for gene transfer protocols, summary of all deaths while being treated and 
during active follow-up; any response information; audit results, and a summary 
provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.
12.3 Monitoring
Involvement in this study as a participating investigator implies acceptance of 
potential audits or inspections, including source data verification, by representatives 
designated by the DF/HCC Overall Principal Investigator (or Protocol Chair) or 
DF/HCC. The purpose of these audits or inspections is to examine study-related 
activities and documents to determine whether these activities were conducted and 
data were recorded, analyzed, and accurately reported in accordance with the protocol, 
institutional policy, Good Clinical Practice (GCP), and any applicable regulatory 
requirements.
All data will be monitored for timeliness of submission, completeness, and adherence 
to protocol requirements. Monitoring will begin at the time of participant registration 
and will continue during protocol performance and completion. 

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13. REGULATORY CONSIDERATIONS
13.1 Protocol Review and Amendments
This protocol, the proposed informed consent and all forms of participant 
information related to the study (e.g., advertisements used to recruit participants) and 
any other necessary documents must be submitted, reviewed and approved by a 
properly constituted IRB governing each study location. 
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) 
will disseminate protocol amendment information to all participating investigators. 
All decisions of the IRB concerning the conduct of the study must be made in 
writing.
13.2 Informed Consent
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed decision 
about their participation in this study. The formal consent of a participant, using 
the IRB approved consent form, must be obtained before the participant is 
involved in any study-related procedure. The consent form must be signed and 
dated by the participant or the participant’s legally authorized representative, and 
by the person obtaining the consent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file. 
13.3 Ethics and Good Clinical Practice (GCP)
This study is to be conducted according to the following considerations, which 
represent good and sound research practice:
•
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf
•
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki
o
Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html
o
Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html

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o
Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html
o
Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html
o
Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html
•
State laws
•
DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy. 
13.4 Study Documentation
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified.
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 
recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays. 
13.5 Records Retention
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies. 
13.6 Multi-center Guidelines
N/A
13.7 Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA)
N/A

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14. STATISTICAL CONSIDERATIONS
Recent studies have explored the benefits of metastasis-directed SBRT in low metastatic 
burden or oligometastatic stage IV NSCLC. These studies have revealed that SBRT can 
achieve high rates of treated-metastasis control for patients with limited pulmonary, 
hepatic, adrenal, and spinal metastases. Local control of individual metastases in this 
setting may potentially result in longer PFS and better outcomes in patients with low 
burden metastatic NSCLC. 
Despite the overall theoretical benefits of SBRT in stage IV lung cancer, there has not been 
a prospective clinical trial of consolidative SBRT in oncogene-driven stage IV NSCLC. To 
assess the efficacy of integrating SBRT with targeted therapy and to establish a role for 
SBRT in the management of metastatic NSCLC, we will conduct phase II study of SBRT 
in 30 patients with low burden metastatic oncogene-driven NSCLC. 
We hypothesize that persistent tumor in sites of original disease can give rise to distant 
metastases and that localized SBRT to persistent sites of original disease may reduce the 
incidence of  DF occurring concurrently or in close temporal sequence with OF. The 
local control rate of metastases treated by SBRT is generally reported to be ~80%. We, 
therefore, hypothesize that we can reduce the frequency of combined OF and DF by 
~20%, thereby lowering the frequency of all DF (with or without OF) as first site of 
failure from ~40% to 20% (see also Figure 2).
14.1 Study Design/Endpoints
The main objective of this study is to evaluate the impact of SBRT on the frequency of 
patients with DF (with or without concurrent OF) in oncogene-driven NSCLC patients 
with residual oligometastatic disease at 12 months after initiation of SBRT, which on 
average will correspond to 18-24 months since TKI induction therapy.  
Secondary Endpoints 
1) To describe toxicities of treatment using CTCAE v4.0.
2) To determine median PFS time
3) To analyze the pattern of original and distant site failures (OF and DF)
4) To determine 2-year local control rate of treated lesions
5) To determine median overall survival time and 2-year overall survival rate
14.2 Sample Size/Accrual Rate
The target sample size will be 30 patients. We anticipate a very low drop out rate (<5%) 
since the target population will mainly consist of healthy patients who are relatively 
young and non-smokers, and death of non-cancer causes or loss to follow-up would be 
very unlikely. If we were to observe DF with or without concomitant OF in 8 or fewer of 
the 30 patients at their 12-month evaluation, 87% power is achieved to detect a 20% 
reduction in the rate of DF with concomitant OF, which would therefore drop from an 

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overall frequency of 40% DF (based on results from a review of EGFR-mutant NSCLC 
patients treated with TKI at MGH) to the hypothesized 20%. The decision rule is 
associated with 9% probability of accepting the efficacy of adjuvant SBRT if the 
underlying rate of DF were unchanged from 40%. As noted above, we do not anticipate 
that any subjects will have died of non-cancer-related causes (i.e., without any failure) 
before the primary study endpoint, 12 months after SBRT, is reached. We acknowledge 
that any deaths of other causes will reduce the statistical power. Lastly, any subjects 
developing failure prior to completion of SBRT (see section 5.5) will be removed from 
the study and replaced, i.e., will not count towards the target sample size of 30 patients.
At MGH, about 50-60 patients with EGFR/ALK/ROS positive NSCLC are started on 
selective TKI per year, per a recent re-review of clinical practice data. Data from us and 
other recent reports have indicated that 10-20% of such patients may be eligible for 
consolidation SBRT, and in our review of patients in our practice we currently estimate 
that about 9 patients per year are eligible for SBRT. Assuming a ~80% accrual rate 
from all eligible patients we now expect to accrue 7 participants per year (adjusted from 
a previous estimate of 10 subjects per year). We estimate that it will take an additional 2 
years to complete enrollment of 30 subjects and then complete follow-up to report 
results on the primary endpoint of frequency of DF at 1 yr post-SBRT.
Following the completion of planned SBRT treatments, patients will continue to receive 
standard of care therapy which would ordinarily involve continuation of maintenance 
TKI therapy until there is confirmed disease progression. Since the median PFS of TKI-
treated oncogene-driven NSCLC patients is approximately 12 months for traditional 
TKIs and approximately 18 months or longer for newer drugs such as osimertinib used 
in first line, an evaluation time point set at 12 months following  commencement of SBRT 
treatments, i.e., on average 18-24 months from TKI initiation will be sufficient to report 
the majority of failures.
Patients will be followed for 2 years after treatment or until death, whichever occurs 
first. Follow up examination and imaging studies will be scheduled as per standard 
clinical care for patients receiving TKI or other systemic therapy but intervals of 3 
months for two years is recommended. Upon each follow-up visit, patients will be 
assessed for disease control and treatment toxicity.
Accrual Targets
Sex/Gender
Ethnic Category
Females
Males
Total
Hispanic or Latino
1
+
0
=
1
Not Hispanic or Latino
14
+
15
=
29
Ethnic Category: Total of all subjects
15
+
15
=
30
Racial Category
American Indian or Alaskan Native
0
+
0
=
0
Asian
0
+
0
=
0

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Black or African American
1
+
1
=
2
Native Hawaiian or other Pacific 
Islander
0
+
0
=
0
White
14
+
14
=
28
Racial Category: Total of all subjects
15
+
15
=
30
14.3 Stratification Factors
N/A
14.4 Analysis of Secondary Endpoints
14.4.1 Adverse events
Subjects will be tabulated by adverse events and grade. The frequency of any 
adverse events, as well as Grade 2-5 adverse events will be reported by CTCAE 
v4.0 criteria. Frequencies of acute toxicities as well as crude and actuarial rates of 
late normal tissue reactions (> 90 days after completion of radiation) will be 
calculated.
14.4.2 Progression-free survival
Radiographic tumor response and progression will be described based on RECIST 
criteria as detailed in Section 10.1. Progression-Free Survival (PFS) is defined as 
the duration of time from documented start of TKI therapy to time of objective 
progressive disease. Death will also be regarded as a progression event. For the 
calculation of PFS times, the Kaplan-Meier estimate will be reported with 95% 
confidence intervals using Greenwood’s formula.
14.4.3 Assessment of pattern of failures
Progression will be divided into two categories: Original sites failure (OF) and 
distant failure (DF) (with and without concomitant OF). Crude frequencies and 
actuarial rates of original sites failure (OF) (primary or metastatic sites) as the first 
site of failure, as defined in Section 10.1, as well as crude frequencies and actuarial 
rates of distant failures (DF) as the first site of failure (with or without concomitant 
OF) will be calculated. OF is defined as disease progression in sites (primary and/or 
metastatic) that were present at diagnosis of metastatic NSCLC, prior to TKI 
initiation (includes both target and non-target lesions). DF are defined as 
development of new sites of metastases outside areas that originally contained 
disease. The diagnosis of OF with concomitant DF requires the detection of new 
sites of disease on the same follow up scan diagnosing progression in sites of 

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original disease (primary and metastatic sites). Original site and distant failures will 
be considered as individual events in the calculation of PFS. 
14.4.4 Local control of irradiated lesions
Local control (LC) is defined by the absence of progressive disease in target lesions 
treated with SBRT. The duration of LC is defined as the time period between the 
completion of SBRT to the time of objective progressive disease. 
14.4.5 Overall survival
Overall survival (OS) is defined as the duration of time from the start of 
documented TKI therapy to time of death. For the calculation of OS times, the 
Kaplan-Meier estimate will be reported with 95% confidence intervals using 
Greenwood’s formula
14.5 Reporting and Exclusions
14.5.1 Evaluation of toxicity
All participants will be evaluable for toxicity from the time of their first dose of 
radiation.  
14.5.2 Evaluation of response
Patients who received SBRT will be evaluated for response to treatment. Each 
participant should be assigned one of the following categories (based on the 
definitions of treatment outcome defined in Section 10.1):
1) Alive without evidence of OF or DF, 
2) Alive with OF as first failure only,
3) Alive with DF (with or without concurrent OF) as first failure only, 
5) Early death from malignancy, 
6) Early death from toxicity, 
7) Early death from other cause, 
8) Unknown (not assessable, insufficient data).
By arbitrary convention, category 8 usually designates the “unknown” status of 
any type of data in a clinical database.

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For each participant, the best clinical tumor response should be categorized as:
For lung primary and metastatic target lesions
a) complete response, or
b) partial response, or 
c) stable disease, or
d) local enlargement   
For metastatic target lesions within the liver, adrenals and spine
a) complete response, or
b) partial response, or
c) stable disease, or
d) local failure
15. PUBLICATION PLAN
The results will be made public within 24 months of the end of data collection. A report is 
planned to be published in a peer-reviewed journal and that initial release may be an abstract 
that meets the requirements of the International Committee of Medical Journal Editors. A 
full report of the outcomes will be made public no later than three years after the end of data 
collection. Authorship will be based on rules established in previously published guidelines 
(108). 

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Timmerman RD, Kavanagh BD, Cho LC, Papiez L, Xing L. Stereotactic body radiation 
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APPENDICES
Appendix A – AJCC 7th edition lung cancer staging 
17. Definition of TNM:
Primary tumor (T)
•
TX: Primary tumor cannot be assessed, or tumor proven by the presence of malignant 
cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy 
•
T0: No evidence of primary tumor 
•
Tis: Carcinoma in situ 
•
T1: Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without 
bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in 
the main bronchus). The uncommon superficial spreading tumor of any size is classified 
as T1 even when extending to the main bronchus, as long as the invasive component is 
limited to the bronchial wall. 

T1a: Tumor ≤2 cm in greatest dimension

T1b: Tumor >2 cm but ≤3 cm in greatest dimension
•
T2: Tumor >3 cm but ≤7 cm or tumor with any of the following features (T2 tumors with 
these features are classified T2a if ≤5 cm)
•
Involves the main bronchus, ≥2 cm or more distal to the carina 
•
Invades the visceral pleura 
•
Associated with atelectasis or obstructive pneumonitis that extends to the 
hilar region but does not involve the entire lung 

T2a: Tumor >3 cm but ≤5 cm in greatest dimension

T2b: Tumor >5 cm but ≤7 cm in greatest dimension
•
T3: >7 cm or one that directly invades any of the following: chest wall (including 
superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal 
pericardium; or tumor in the main bronchus <2 cm distal to the carina but without 
involvement of the carina; or associated atelectasis or obstructive pneumonitis of the 
entire lung or separate tumor nodule(s) in the same lobe
•
A tumor of any size that directly invades any of the following: chest wall (including 
superior sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; or tumor in 
the main bronchus less than 2 cm distal to the carina but without involvement of the 
carina; or associated atelectasis or obstructive pneumonitis of the entire lung 

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•
T4: Tumor of any size that invades any of the following: mediastinum, heart, great 
vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina; separate 
tumor nodule(s) in a different ipsilateral lobe
Regional lymph nodes (N) 
•
NX: Regional lymph nodes cannot be assessed 
•
N0: No regional lymph node metastasis 
•
N1: Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and 
intrapulmonary nodes including involvement by direct extension of the primary tumor 
•
N2: Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s) 
•
N3: Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral 
scalene, or supraclavicular lymph node(s) 
Distant metastasis (M)
•
MX: Distant metastasis cannot be assessed 
•
M0: No distant metastasis 
•
M1a: Separate tumor nodule(s) in a contralateral lobe, tumor with pleural nodules or 
malignant pleural or pericardial effusion
•
M1b: Distant metastasis
17.1 Stage Grouping
Occult Carcinoma
TX
N0
M0
Stage 0
Tis
N0
M0
Stage IA
T1a,b
N0
M0
Stage IB
T2a
N0
M0
Stage IIA
T1a,b 
N1
M0
T2a
N1
M0
T2b
N0
M0
Stage IIB
T2b
N1
M0
T3
N0
M0
Stage IIIA
T1, T2
N2
M0
T3
N1, N2
M0
T4
N0, N1
M0
Stage IIIB
T4
N2
M0
Any T
Any N
M0
Stage IV
Any T
Any N
M1a,b

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Appendix B: Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Description
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; 
some signs or symptoms of 
disease.
1
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
2
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, 
hospitalization indicated. Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair.
10
Moribund, fatal processes 
progressing rapidly. 
5
Dead.
0
Dead.