A multicentre randomised open-label phase III study of stereotactic radiosurgery, in addition to standard systemic therapy for patients with metastatic melanoma or newly diagnosed metastatic NSCLC and asymptomatic or oligosymptomatic brain metastases.

Central nervous system (CNS) metastases are a growing challenge in oncology,
due to
increasingly effective therapies at non-CNS sites and thus overall longer
survival. Brain
metastases may affect up to 30% of patients with metastatic cancer and are a
major cause
for morbidity (by reducing autonomy and quality of life) and mortality.
Brain metastases are most common in melanoma, lung cancer, breast cancer and
kidney
cancer. Treatment approaches include neurosurgical interventions, various
approaches of
radiotherapy, and systemic pharmacotherapy.
Surgery and radiotherapy have traditionally been the mainstay of treatment of
brain
metastasis. Stereotactic radiosurgery, often referred to as SRS and defined as
a single
fraction, or stereotactic radiotherapy (SRT, consisting of several fractions),
now assumes a
much more prominent role than whole brain radiotherapy for patients with brain
metastasis.
SRS alone has less acute and long-term side effects and notably causes less
neurocognitive
decline, compared to SRS given in combination with whole brain radiotherapy.
SRS alone
might be characterised by an improved therapeutic risk benefit ratio compared
with whole
brain radiotherapy, also for patients with a larger number of brain metastases.
Encouraging response rates and reasonable response duration in patients with
asymptomatic or oligo-symptomatic brain metastasis with low CNS burden treated
with novel
systemic therapies including immune-checkpoint inhibitors and targeted therapy
have been
reported in several cohorts of melanoma and non-small cell lung cancer (NSCLC).
With the increasing use of systemic immune-checkpoint inhibitor treatment or
targeted
therapy and their induction of durable responses, the question has been raised
whether
patients with brain metastases who are started on these treatments need
additional
immediate radiotherapy or whether radiotherapy can be safely delayed, without
compromising brain control and overall outcome. Thus, one of the major current
controversies centres on the optimal timing of SRS for patients with brain
metastasis: should
it be administered upfront to optimise local control and thereby prevent
neurological deficits,
with a risk of neurotoxicity in long-term surviving patients, or should
radiotherapy be delayed
until systemic therapy has failed, to avoid overtreatment in patients with good
response to
systemic therapy? The latter approach is increasingly preferred by medical
oncologists,
based e.g. on response rates with immune-checkpoint inhibition in the range of
46-55% in
melanoma and of 30% in NSCLC with PD-L1 expression in tumour cells of more than
1% and with targeted therapy of up to 60% in melanoma (BRAF-mutant) and up to
88% (gefitinib) in epidermal growth factor receptor (EGFR) mutant NSCLC, albeit
in
selected patient groups. Yet, the best approach remains controversial because
there are
concerns that at least a minority of patients may no longer be eligible for SRS
and may have fixed neurological deficits at the time of further progression.
Additionally, responses to systemic therapies are often limited in time and a
delay of radiotherapy therefore requires
frequent cranial MRI follow-up. Thus, a systematic meta-analysis of mostly
uncontrolled data
suggests improved overall survival after early combination of immune-checkpoint
inhibitors
and SRS compared to a sequential approach.

The primary objective of the study is to assess the efficacy in terms of
CNS-specific PFS of
the combination of standard systemic treatment plus SRS versus standard systemic
treatment alone in patients with newly diagnosed and untreated (except for
surgery)
asymptomatic or oligo-symptomatic brain metastases from melanoma or non-small
cell lung
cancer, with indication for systemic therapy.

Secondary objectives:
- To evaluate secondary measures of clinical efficacy, including OS,
CNS-response
rate, duration of CNS-response, pattern of CNS-progression and extra-CNS PFS
- To assess the safety and tolerability of SRS in combination with standard
systemic
treatment
- To evaluate changes in neurocognitive function
- To evaluate changes in quality of life and functional independence
- To assess the above measures of efficacy and safety in the overall study
population and within each tumour cohort

Prospective phase III, multicentre randomised (1:1) open label superiority
study

The treatment regimen within the ETOP 19-21 USZ-STRIKE study consists of
standard
systemic treatment with (Arm A) or without (Arm B) stereotactic radiosurgery.

Radiotherapy may cause side effects that include:
- Fatigue
- Seizures
- Hair loss
- Worsening of neurological symptoms such as headache, sensory problems (vision,
hearing, taste) or motor disturbances (coordination, balance)
- Worsening of mental functions (worsening of attention, memory or language).

A blood sample for laboratory tests can cause bruising at or near where the
needle
enters the vein and can increase the risk of infection.
For radiological tests requiring injection of contrast dye, there is a risk of
an allergic
reaction.