What’s new in NETs?

Lucy WallConsultant Medical Oncologist

Ann Edgar Patient Forum10th May 2013

What’s new in NETs?

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:

Promid Study Sunitinib Study in pancreatic NETs Everolimus study in pancreatic NETs

Promid Study

People with inoperable small intestinal NETs

Didn’t need somatostatin analogues for symptom control

Octreoscan positive Received either injections of

sandostatin or placebo

Slide showing graph of time to treatment progression removed due to copyright issues.

Sunitnib in pancreatic NETs

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

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

Slide showing difference in time to disease progression removed due to copyright issues

Everolimus in pancreatic NETs

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

Slide showing difference in time to disease progression removed due to copyright issues

Update from ENETs 2013

Treatments to control hormone symptoms

Brand new treatment options Trials to compare and assess new

and existing treatment options

Hormone symptoms

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

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

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)

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?

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

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

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 options2 - 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

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

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 options3 – 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

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

Patients with GI or pulmonary NETs Exploring the role of pasireotide and

everolimus in disease control

Co-operate-1Arms Assigned Interventions

Experimental: Functional tumors, pre-treated

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

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 options4 – sunitnib in non-pancreatic tumours?

• 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

New treatment options5 – pazopanib

Grande et al 2012

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

New treatment options6 – temsirolimus + bevacizumab ?

Hobday et al 2012

Patients had progressive disease in the 7 months before study entry

13 of the first 25 patients had disease shrinkage on the treatment (52%)

New treatment options6 – temsirolimus + bevacizumab ?

Hobday et al 2012

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

New treatment options7 – BEZ235 ??

NETTER-1 trial Patients with inoperable or

metastatic progressive SS receptor positive tumours

Treatments • 4 treatments with 177Lu-DOTA0-Tyr3-

Octreotate• 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?

How/ when to use current treatment options?

Where are we at

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