What’s new in NETs? Lucy Wall Consultant Medical Oncologist Ann Edgar Patient Forum 10 th May 2013

What’s new in NETs? What practice-changing studies have recently been published? What practice-changing studies have recently been published? What new treatments to control hormone symptoms might be on the horizon? What new treatments to control hormone symptoms might be on the horizon? What are the potential new treatment options targeting disease control in NETs? What are the potential new treatment options targeting disease control in NETs? Update on trials to compare and assess new and existing treatment options 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 Promid Study Sunitinib Study in pancreatic NETs Sunitinib Study in pancreatic NETs Everolimus study in pancreatic NETs Everolimus study in pancreatic NETs

Promid Study People with inoperable small intestinal NETs People with inoperable small intestinal NETs Didn’t need somatostatin analogues for symptom control Didn’t need somatostatin analogues for symptom control Octreoscan positive Octreoscan positive Received either injections of sandostatin or placebo Received either injections of sandostatin or placebo

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Sunitnib in pancreatic NETs Sunitinib is a tablet treatment that is targeted to block certain molecular processes within the cell 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 One of its effects is to block blood vessel formation On scans NETs are much richer in blood vessels than some other tumours On scans NETs are much richer in blood vessels than some other tumours Does blocking blood vessels help to control NET 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 Sunitinib or placebo (dummy tablets) given to people with pancreatic NETs Disease followed very closely on scan Disease followed very closely on scan If disease got worse on scan and had been taking dummy tablets, crossed over to sunitinib 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 Study closed earlier than initially planned (after recruitment of 171 patients) on advice of data monitoring committee

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Everolimus in pancreatic NETs This is another targeted drug This is another targeted drug It acts to inhibit the protein mTOR, which is highly expressed in NET tumours 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 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 At the time of progression, if people had been on placebo, they could be crossed over to active drug

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Update from ENETs 2013 Treatments to control hormone symptoms Treatments to control hormone symptoms Brand new treatment options Brand new treatment options Trials to compare and assess new and existing 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. Telotristat etiprate (LX1606) is a new tablet treatment which acts by inhibiting the enzyme tryptophan hydroxylase. This enzyme makes serotonin in the body 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) 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% When given to 15 people with diarrhoea, the number of bowel motions per day reduced, on average, by 43% Flushing was also reduced Flushing was also reduced The drug didn’t seem to have a lot of side effects The drug didn’t seem to have a lot of side effects There will be a randomised trial of this compound opening soon - Telestar 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. 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. 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 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 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 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? For patients with small intestinal NETs we know that sandostatin can help to slow down tumour growth? Do SSA stabilise non-SI NETs? Do SSA stabilise non-SI NETs? Clarinet study – in patients with NETs but no syndrome, does lanreotide control disease for longer than placebo? 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 Close radiological follow up for 2 years On progression unblinded and crossed over to drug if had been on placebo On progression unblinded and crossed over to drug if had been on placebo Due to report results this year 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? 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 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 Patients with ‘poor prognosis carcinoid’ – generally disease growing although some other high risk patient groups also included Randomized trial Randomized trial octreotide acetate + recombinant interferon alfa-2boctreotide acetate + recombinant interferon alfa-2b octreotide acetate + bevacizumaboctreotide 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) 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 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 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 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. 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 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 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 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 Patients with GI or pulmonary NETs Exploring the role of pasireotide and everolimus in disease control Exploring the role of pasireotide and everolimus in disease control

Co-operate-1 ArmsAssigned Interventions Experimental: Functional tumors, pre- treated Drug: Pasireotide LAR followed by Pasireotide LAR + Everolimus Experimental: Functional tumors, treatment na ï ve 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-na ï ve 1 Drug: Pasireotide LAR followed by Pasireotide LAR + Everolimus Experimental: Nonfunctional tumors, treatment-na ï ve 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 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 4 – 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. 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 Phase II trial of small intestinal and pancreatic NETs which had progressed within the last 12 months 44 patients treated 44 patients treated At 6 months 85.7% of people hadn’t progressed At 6 months 85.7% of people hadn’t progressed On average 10 months until disease did progress On average 10 months until disease did progress New treatment options 5 – pazopanib Grande et al 2012

Trial of chemotherapy in pancreatic NETs Trial of chemotherapy in pancreatic NETs Temsirolimus is an mTOR inhibitor (grandfather of everolimus) Temsirolimus is an mTOR inhibitor (grandfather of everolimus) Bevacizumab is an anti-angiogenic antibody used in the treatment of colorectal cancer Bevacizumab is an anti-angiogenic antibody used in the treatment of colorectal cancer This is a phase II (no comparison) trial of 50 people This is a phase II (no comparison) trial of 50 people New treatment options 6 – temsirolimus + bevacizumab ? Hobday et al 2012

Patients had progressive disease in the 7 months before study entry Patients had progressive disease in the 7 months before study entry 13 of the first 25 patients had disease shrinkage on the treatment (52%) 13 of the first 25 patients had disease shrinkage on the treatment (52%) New treatment options 6 – temsirolimus + bevacizumab ? Hobday et al 2012

Currently under development as an anti-cancer treatment in a number of tumour types 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 Being used to treat pancreatic NETs that have progressed after everolimus No results available at present No results available at present New treatment options 7 – BEZ235 ??

NETTER-1 trial Patients with inoperable or metastatic progressive SS receptor positive tumours Patients with inoperable or metastatic progressive SS receptor positive tumours Treatments Treatments 4 treatments with 177 Lu-DOTA 0 -Tyr 3 - Octreotate4 treatments with 177 Lu-DOTA 0 -Tyr 3 - Octreotate Octreotide LAR 60mg every 4 weeksOctreotide LAR 60mg every 4 weeks How/ when to use current treatment options?

Seqtor study Patients with inoperable or metastatic pancreatic NETs Patients with inoperable or metastatic pancreatic NETs Is disease control better with chemotherapy followed by everolimus or the reverse sequence? 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 Significant increase in trials in NETs over the last 5 years Many trials underway with results awaited within the next couple of 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 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 Unfortunately Scottish government doesn’t fund cancer trials networks to the same level as English government so difficult to support all trials locally