Targeted Therapies and Immunotherapy have fundamentally changed the treatment of
metastatic non-small cell lung cancer (NSCLC).

There is an increasing interest in the use of stereotactic ablative radiotherapy (SABR)
for oligo-metastatic (oligo-M) NSCLC patients. It is postulated that definitive treatment
of the primary as well as regional node/s and oligo-M in these patients may improve their
overall survival (OS). Oligo-M is considered an intermediate state between local and
poly-metastatic disease and is commonly defined as 1-5 metastatic lesions, in keeping
with the recent European Society of Radiotherapy and Oncology (ESTRO) and American
Society for Radiation Oncology (ASTRO) consensus.

If discovered within 4-6months of diagnosis, they are termed synchronous oligo-M.
Alternatively, should oligo-M develop following definitive treatment of the primary
tumour, this is termed metachronous oligo-M.

Multiple clinical trials have demonstrated prolonged survival following SABR treatment to
all sites of oligo-M, particularly in NSCLC.

Targeted therapies (TT) and Immunotherapy (IT) have transformed the landscape of NSCLC
treatment by improving OS in metastatic setting. However, most SABR trials for oligo-M
patients were conducted in the pre-TT and pre-IT era. How SABR and TT or IT should be
integrated in the treatment of oligo-M NSCLC therefore remains an active area of
investigation.

Oligo-M is considered a clinically distinct from poly-metastatic disease, presenting a
unique therapeutic window during which the treatment of all oligo-M may result in
long-term disease control and possibly cure in select cases.

SABR offers the advantages of being non-invasive, safe, and well-tolerated, even by frail
patients. It ablates multiple targets simultaneously achieving good rates of local
control. The objectives of treating oligo-M using SABR include:

1. ablating all sites of visible disease to reduce tumor burden

2. preventing progression to a poly-metastatic disease state

3. relieving morbidity associated with metastases without a decline in quality of life
(QoL)

4. delaying the start of systemic therapy

Reasons to support SABR in oligo-M NSCLC:

1. Systemic treatment alone does not eradicate the presence of all oligo-M disease.
SABR may improve local control at the sites of oligo-M decreasing the risk of
poly-metastatic widespread by reducing the burden of proliferative malignant cells

2. SABR is a histology-agnostic ablative technique which can eradicate systemic
therapy-resistant disease. So, SABR optimizes local control at the sites of oligo-M,
thereby delaying the need to start a new systemic therapy or eliminating the
morbidity and potential mortality associated with local and eventually distant
progression of disease.

- Targeted therapies (TT) or Immunotherapy (IT) (chemotherapy) will be combined
with early SABR of all cancer sites in patients with synchronous oligo-M NSCLC:
primary tumour (T), regional node/s (N) and oligo-metastases (M). Eradication
of all macroscopic cancer sites at the time of primary diagnosis by combined
modality treatment is expected to decrease the risk of resistance development
with only microscopic disease potentially remaining. This will result in
improvement of progression free survival (PFS), QoL, delayed change of therapy
and OS without added high-grade (>G3) toxicity. Synchronous oligo-M NSCLC
patients will be enrolled to SABR and TT or IT.

- Targeted therapies or Immunotherapy (chemotherapy) will be combined with SABR
of all cancer residual sites in patients with oligo-persistence,
oligo-progressive or oligo- induced oligo-M NSCLC: primary tumour (T), regional
node/s (N) and oligo-M. Eradication of all macroscopic cancer sites at the time
of oligo-persistence or oligo- progression by combined modality treatment is
expected to delay the initiation of a new systemic therapy. This will result in
improvement of PFS and QoL, delayed change of therapy and OS without added
high-grade (>G3) toxicity. Metachronous oligo-M NSCLC patients will be enrolled
to SABR including maintenance TT or IT.

- Patients unfit for systemic therapy with synchronous or metachronous oligo-M
NSCLC will be enrolled to receive SABR alone in all sites of disease.
Eradication of all macroscopic cancer sites is expected to delay the widespread
and/or symptomatic disease. This will result in improvement of OS and QoL
without added high-grade (>G3) toxicity.