What’s new in NETs?
Lucy Wall
Consultant Medical Oncologist
Ann Edgar Patient Forum
10th May 2013
What’s new in NETs?
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What practice-changing studies have
recently been published?
What new treatments to control hormone
symptoms might be on the horizon?
What are the potential new treatment
options targeting disease control in NETs?
Update on trials to compare and assess
new and existing treatment options
In the last few years, 3 big randomised
studies have been published:
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Promid Study
Sunitinib Study in pancreatic NETs
Everolimus study in pancreatic NETs
Promid Study
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People with inoperable small
intestinal NETs
Didn’t need somatostatin analogues
for symptom control
Octreoscan positive
Received either injections of
sandostatin or placebo
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Slide showing graph of time to
treatment progression removed due
to copyright issues.
Sunitnib in pancreatic NETs
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Sunitinib is a tablet treatment that is
targeted to block certain molecular
processes within the cell
One of its effects is to block blood
vessel formation
On scans NETs are much richer in
blood vessels than some other
tumours
Does blocking blood vessels help to
control NET tumours?
Sunitnib in pancreatic NETs
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Sunitinib or placebo (dummy tablets)
given to people with pancreatic NETs
Disease followed very closely on scan
If disease got worse on scan and had been
taking dummy tablets, crossed over to
sunitinib
Study closed earlier than initially planned
(after recruitment of 171 patients) on
advice of data monitoring committee
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Slide showing difference in time to disease
progression removed due to copyright
issues
Everolimus in pancreatic NETs
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This is another targeted drug
It acts to inhibit the protein mTOR, which
is highly expressed in NET tumours
410 people with low or intermediate grade
pancreatic NETs randomised between
everolimus and placebo
At the time of progression, if people had
been on placebo, they could be crossed
over to active drug
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Slide showing difference in time to disease
progression removed due to copyright
issues
Update from ENETs 2013
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Treatments to control hormone
symptoms
Brand new treatment options
Trials to compare and assess new
and existing treatment options
Hormone symptoms
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Telotristat etiprate (LX1606) is a new
tablet treatment which acts by
inhibiting the enzyme tryptophan
hydroxylase.
This enzyme makes serotonin in the
body
Serotonin is (at least partly)
responsible for the hormonal symptoms
of carcinoid (the diarrhoea and flushing
that some people get)
Pavel et al 2013
Telestar
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When given to 15 people with
diarrhoea, the number of bowel
motions per day reduced, on average,
by 43%
Flushing was also reduced
The drug didn’t seem to have a lot of
side effects
There will be a randomised trial of this
compound opening soon - Telestar
Telestar
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People with small intestinal NETs whose
bowels are open more than 4x per day
will either get the real tablet (250mg or
500mg tid) or a dummy tablet over a 12
week period.
They’ll fill in questionnaires about
flushing, diarrhoea and abdominal pain.
After 12 weeks they will be able to
continue on the tablet if they are helped
by it
Pasireotide (SOM 230)
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This is a somatostatin analogue like
sandostatin and lanreotide, but is
thought to be more potent
In people whose symptoms were no
longer controlled by sandostatin,
pasiretode helped with hormonal
symptoms in about ¼
Kvols et al 2012
New treatment options
1 - SSA for disease control?
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For patients with small intestinal
NETs we know that sandostatin can
help to slow down tumour growth?
Do SSA stabilise non-SI NETs?
Clarinet study – in patients with
NETs but no syndrome, does
lanreotide control disease for longer
than placebo?
Clarinet
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Close radiological follow up for 2
years
On progression unblinded and
crossed over to drug if had been on
placebo
Due to report results this year
Co-operate-2
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In patients with pancreatic NETs on
everolimus will the addition of
pasireotide control the disease for
longer than everolimus alone?
The trial has completed recruitment,
but results not yet available
New treatment options
2 - anti-angiogenic therapy?
SWOG0518
 Patients with ‘poor prognosis
carcinoid’ – generally disease
growing although some other high
risk patient groups also included
 Randomized trial
• octreotide acetate + recombinant
interferon alfa-2b
• octreotide acetate + bevacizumab
SWOG0518
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Interferon alfa-2b has been used in
NETs for a long time with equivocal
evidence of efficacy. It is known to
inhibit the development of blood
vessels (amongst many other things)
Bevacizumab is an antibody that
blocks the formation of new blood
vessels. It is currently licensed for
the treatment of colorectal cancer
Everolimus and Octreotide With or
Without Bevacizumab
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This randomized phase II trial is
studying how well giving everolimus
and octreotide together with or
without bevacizumab works in
treating patients with locally
advanced or metastatic pancreatic
neuroendocrine tumors that cannot
be removed by surgery
It has completed recruitment, but no
results are available yet
New treatment options
3 – everolimus in non-pancreatic tumours?
Radiant 4
 Everolimus has been shown to control
pancreatic NETs for longer than placebo.
 A parallel trial in non-pancreatic NETs was
strongly suggestive of efficacy, but
unfortunately wasn’t considered strong
enough evidence to give everolimus to
other NET patients
Radiant-4
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People with NETs of lung or GI origin
which have progressed within the
previous 6 months will either receive
everolimus or placebo
Their disease will be closely
monitored so they can be switched to
an alternative treatment if the
tumour progresses
Co-operate-1
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Patients with GI or pulmonary NETs
Exploring the role of pasireotide and
everolimus in disease control
Co-operate-1
Arms
Assigned Interventions
Experimental: Functional tumors, pretreated
Drug: Pasireotide LAR followed by Pasireotide
LAR + Everolimus
Experimental: Functional tumors,
treatment naïve
Drug: Pasireotide LAR followed by Pasireotide
LAR + Everolimus
Experimental: Nonfunctional tumors,
pretreated 1
Drug: Pasireotide LAR followed by Pasireotide
LAR + Everolimus
Experimental: Nonfunctional tumors,
pretreated 2
Drug: Everolimus followed by Pasireotide LAR +
Everolimus
Experimental: Nonfunctional tumors,
treatment-naïve 1
Drug: Pasireotide LAR followed by Pasireotide
LAR + Everolimus
Experimental: Nonfunctional tumors,
treatment-naïve 2
Drug: Everolimus followed by Pasireotide LAR +
Everolimus
New treatment options
4 – sunitnib in non-pancreatic tumours?
Sunland Study
 A randomised, placebo-controlled
trial to see if the addition of sunitinib
to lanreotide therapy in patients with
progressing midgut NETs can be
associated with longer disease
control than lanreotide alone
New treatment options
5 – pazopanib
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• Pazopanib is a multi-targeted agent that has
already shown clinical activity in patients with
advanced NETs and also decreases blood flow
and permeability surface on functional CT scans.
Phase II trial of small intestinal and pancreatic
NETs which had progressed within the last 12
months
44 patients treated
At 6 months 85.7% of people hadn’t progressed
On average 10 months until disease did progress
Grande et al 2012
New treatment options
6 – temsirolimus + bevacizumab ?
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Trial of chemotherapy in pancreatic
NETs
Temsirolimus is an mTOR inhibitor
(grandfather of everolimus)
Bevacizumab is an anti-angiogenic
antibody used in the treatment of
colorectal cancer
This is a phase II (no comparison)
trial of 50 people
Hobday et al 2012
New treatment options
6 – temsirolimus + bevacizumab ?
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Patients had progressive disease in
the 7 months before study entry
13 of the first 25 patients had
disease shrinkage on the treatment
(52%)
Hobday et al 2012
New treatment options
7 – BEZ235 ??
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Currently under development as an
anti-cancer treatment in a number of
tumour types
Being used to treat pancreatic NETs
that have progressed after
everolimus
No results available at present
How/ when to use current
treatment options?
NETTER-1 trial
 Patients with inoperable or
metastatic progressive SS receptor
positive tumours
 Treatments
• 4 treatments with 177Lu-DOTA0-Tyr3Octreotate
• Octreotide LAR 60mg every 4 weeks
How/ when to use current
treatment options?
Seqtor study
 Patients with inoperable or
metastatic pancreatic NETs
 Is disease control better with
chemotherapy followed by
everolimus or the reverse sequence?
Where are we at
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Significant increase in trials in NETs over
the last 5 years
Many trials underway with results awaited
within the next couple of years
The hope is that people will be able to
have several new therapies consecutively
Unfortunately Scottish government
doesn’t fund cancer trials networks to the
same level as English government so
difficult to support all trials locally