Expert comment: Brain metastases in lung cancer | Lizza Hendriks

[MUSIC PLAYING] So this Friday, we had two very
interesting brain metastasis studies. The first study was a study
in non-small cell lung cancer patients with an ALK
translocation, the ASCEND-7 Study. This was with ceritinib. And interestingly, in the study,
only patients with active brain metastases were included, also
performance status 2 patients were eligible, patients with
stable neurological symptoms, and patients with
leptomeningeal metastases. And patients with
leptomeningeal metastases were discussed in
another session that day. Based on prior brain
radiotherapy and prior ALK inhibition, patients were
divided into four cohorts, and all these cohorts were
treated with ceritinib 750 mg fasted. Based on the cohorts, so
approximately 40 patients were included in each
cohort, except for one. The objective response rate
was around 30% in the brain in those that were pre-treated
with ALK inhibition, and around 50% in those that
were untreated with another ALK inhibitor. Disease control rate in
the brain was very high, it was above 80%. And duration of response
was 9 to 12 months. And if you compare that to the
ASCEND-4 and ASCEND-5 data, I think results are very
similar and very promising in this setting. So how to put this into context? Well, we also have
the ASCEND-8 data. So ceritinib 450
mg with food that results in less adverse events. But if you look at the
PK data of the ASCEND-8 compared to the ASCEND-7,
to the 750 mg without food, then PK data are similar. So you would expect that with
ceritinib 450 mg with food, you would have the same
brain results than 750 mg without food, but
it would be very interesting to see these
results from the ASCEND-8 trial. So how to move forward? I think, well, we
need to be aware that we need to
design clinical trials for this specific
patient population, so lung cancer patients
with brain metastases. We need to have by
bicompartmental endpoints, so you need to define
what to do with the brain and what to do with the
extracranial disease sites, as it is possible that
some patients respond in one compartment
and other patients only in the other compartment. We need to evaluate
whether TKI concurrent with cranial radiotherapy
are safe and effective, and whether it can
prevent a disease flare. And I think we should focus
on the next generation ALK inhibitors that have
high blood brain barrier concentration. But I think it’s very difficult
to compare all these trials because inclusion criteria
were very heterogeneous across all trials. But in general, they
are all very promising. So moving on to
the next abstract, we know that brain
metastases are associated with a lower quality of life. And it would be very
interesting whether we could predict which patients
have brain metastasis and which patients have not. So in a small Asian
series, patients with a synchronous brain
metastasis, 18 patients, and patients without brain
metastases, still that’s 31, were included. They had matched tissue of
the brain and the primary. And the authors evaluated
whether molecular alterations could predict which patients
had brain metastases. But they were not
able to do that. Interestingly, they did
also methylation analysis and with certain
methylation blocks they could fairly
accurately predict which patients had
brain metastases and which patients had not. So how to move forward? Well, I think they should be
validated in a larger series prospective with extensive
information on staging. But it would be the best
if this signature was also predictive for development of
brain metastasis in the future. So in the end that
you can design trials which really aim at
predicting brain metastasis development in
high risk patients, for example, the prophylactic
cranial irradiation or epigenetic drugs. [MUSIC PLAYING]