Biologically targeted therapies for PNETs

Pancreatic neuroendocrine tumours (PNETs) are a rare type of pancreatic cancer,1 typically diagnosed at the advanced, metastatic stage.2 Prognosis at this stage of the disease is poor and until recently only palliative treatments for metastatic PNETs were available.3 Targeted biological therapies are gaining an increasingly prominent role in anti-cancer therapy4 and have recently been trialled in the treatment of PNETs.3 Promising results from these trials offer new therapeutic options and new hope for patients with this rare type of cancer.3

Pancreatic neuroendocrine tumours

PNETs are a group of rare neoplasms that develop from neuroendocrine cells within the pancreas,¹ a gland which fulfils endocrine and exocrine functions.⁵ Pancreatic acinar cells fulfil exocrine functions, specifically the secretion of digestive enzymes which target the duodenum.⁵ Several types of endocrine cells, referred to collectively as islets of Langerhans, secrete pancreatic hormones, including insulin, glucagon, somatostatin and pancreatic polypeptide, into the bloodstream.^5,6

PNETs arise in the endocrine or islets of Langerhans cells, and are classified as either functioning or non-functioning depending on whether or not they actively secrete hormones. Functioning tumours are further classified depending on the type of hormone they secrete. For example, glucagon-secreting PNETs are referred to as glucagonoma, while those that secrete insulin are termed insulinoma.³

Age is the key risk factor for PNETs and incidence peaks in the 6th or 7th decade of life.² PNETs are rare tumours; incidence estimates vary from 1 in 100,000^2,7 for symptomatic diagnosis to 5.25 in 100,000 with other diagnostic techniques.⁸ For tumours not amenable to surgical excision, there has been a distinct lack of other curative treatments and subsequently, prognosis is poor.⁶ Although these tumours are thought to be slow-growing,¹ non-functioning PNETs (which comprise approximately 91% of all PNETs²) are typically asymptomatic until advanced tumour growth and/or metastasis has occurred.⁶ The majority of all PNETs (60%) have metastasised at the time of diagnosis, and a further 21% have spread locally.²

Prognosis following metastasis or local spread is poor. Recent advances in surgical management of PNETs have improved 5-year survival rates to as high as 80% in patients with non-metastatic PNETs. However, patients with localised metastasis to the liver have a considerably lower 5-year survival rate of 29%,⁶ while in patients with distant metastasis, median survival is just 24 months.⁹

Traditional therapies for PNET and their efficacy

Surgery has traditionally been the mainstay of PNET therapy,³ but it is not curative in all instances.⁶ Despite surgical advances improving the safety of this therapy (mortality rates have reduced from 25% in the 1960s to approximately 3% more recently)¹⁰and 5-year survival rates as high as 80%, surgery is not indicated as curative therapy in all patients.⁶

In patients with metastatic PNET (60% at the time of diagnosis), debulking surgery may have some benefit in controlling tumour growth and reducing symptoms, but is not curative.⁶ Historically, patients with advanced or metastatic cancers have had limited therapeutic options and proportionally poor prognosis.³

Biologically targeted therapies

In light of the limited pool of therapeutic options available for patients with advanced or metastatic PNETs, it is significant that biologically targeted therapies – those that target the biological pathways that drive disease progression – are receiving increasing attention in anti-cancer therapy.⁴ Advances in the understanding of signalling pathways that regulate cellular functions and the epigenetic and genetic events implicated in cancer pathogenesis have enabled the development of therapies that target pathways implicated in cancerous growth.⁴

For example, pharmaceuticals targeting cancer pathogenesis pathways regulated by epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) have been targeted in the treatment of head and neck squamous cell carcinoma.⁴

Recently, this knowledge of signalling pathways has led to biologically targeted therapies being trialled in the treatment of PNETs.³ PNET pathways targeted with biological therapies include those involving the mammalian target of rapamycin (mTOR), a serine–threonine kinase implicated in cell growth, proliferation and angiogenesis (everolimus, marketed as Certican, which is not currently approved for PNET treatment in Australia¹¹),⁹ and several growth factor receptors (sunitinib malate, marketed as Sutent, recently approved for PNET treatment in Australia¹²).³

Sunitinib malate

Sunitinib malate simultaneously inhibits numerous kinases and has particularly potent inhibitory action against platelet-derived growth factor β and VEGF receptors and stem cell factor receptor,¹² which are implicated in the pathogenesis of PNETs.³ Malignant PNET tissues widely express VEGF and platelet-derived growth factor receptors. Inhibition of these factors with sunitinib malate had been shown in laboratory and phase 1 and 2 trials to induce anti-tumour activity.³

Evidence from phase 3 trial of sunitinib malate provides new hope

A recent multi-country phase 3 randomised, double-blind, placebo-controlled trial comparing sunitinib malate and placebo in the treatment of advanced, well differentiated PNETs provided further evidence supporting the drug’s safety and efficacy. Involving 171 patients, the trial used progression-free survival as the primary endpoint, and showed clinically and statistically significant benefits with sunitinib malate.³

The trial was halted prematurely by the independent data and safety monitoring committee due to higher rates of mortality and some serious adverse events in the placebo group and increased progression-free survival in the sunitinib group. Progression-free survival was 11.4 months in the sunitinib group compared to 5.5 months in the placebo group. Likelihood of progression-free survival at 6 months was 71.3% in the sunitinib group compared to 43.2% in the placebo group.³

Benefits for sunitinib were also noted for secondary endpoints examined in the trial: overall survival, objective response rate, and safety. A statistically significant reduction in overall mortality rate (10% in the treatment group compared to 25% in the placebo group) and a significantly superior hazard ratio for death with sunitinib malate treatment were reported. In the sunitinib treatment group, either partial (6/8) or complete (2/8) tumour response was observed in 9.3% (8) of patients compared to 0% in the placebo group. Seven of the eight responsive tumours were non-functioning; the other was unknown.³

Although sunitinib malate treatment caused a clinically and statistically significant worsening of treatment-associated diarrhoea and nausea, adverse events were considered manageable. One patient in the sunitinib group died of treatment-related cardiac failure, while one patient in the placebo group died from treatment-related dehydration. Other serious adverse events occurred at a lower rate in the sunitinib (26%) compared to the placebo (41%) group.³

Further analysis of study data, including reassessment of tumour images for progression, was undertaken by a blinded independent data and safety monitoring committee. Based on that analysis, a statistically significant difference in median progression-free survival time of 12.6 months in the sunitinib group compared to 5.8 months for the placebo group was reported, confirming the magnitude of the treatment effect initially reported. Following closure of the trial, or disease progression, placebo patients were offered open-label sunitinib and 69% crossed over to the sunitinib group for further follow up. Data analysis by the independent committee showed that despite crossover, patients in the sunitinib group survived for an average of > 6 months longer than those in the placebo group. The median survival time was 30.5 months for the sunitinib group (including crossover patients), compared to 24.4 months in the placebo group.¹⁷

Implications for PNET therapy

The results of the trial provide new hope for patients with advanced PNETs.³ Although early cessation of the trial may have resulted in over-estimation of the drug’s efficacy,³ the evidence was considered sufficient that the Therapeutic Goods Administration approved sunitinib malate for the treatment of PNETs in Australia.¹² Similar approval was granted by the United States Food and Drug Administration.¹³

Questions still remain regarding the patients most likely to benefit or be at increased risk of adverse events from sunitinib malate treatment.¹⁴ Objective response in functioning tumours was not observed in the trial.³ As platelet-derived growth factor receptor inhibition has been shown to promote beta-cell survival in animal models, it has been suggested that the safety and efficacy of the drug may differ with various types of functional tumours (e.g. sunitinib may be particularly beneficial for patients with glucagonoma but potentially detrimental for those with insulinoma),¹⁴ and in patients with comorbid conditions that affect blood glucose such as diabetes mellitus.¹⁵ However, these remain hypothetical concerns.¹⁶

New option, new hope for PNET patients

Considering the particularly poor prognosis and limited therapeutic options for patients with metastatic PNET, these trial results are particularly important.³ The approval of sunitinib malate for treatment of PNETs in Australia¹² offers new hope to patients with this previously incurable disease.³

References

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Product Information: Certican. North Ryde, NSW: Novartis Pharmaceuticals Australia Pty Ltd; 30 March 2011.
Product Information: Sutent. West Ryde, NSW: Pfizer Australia Pty Ltd; 24 February 2011.
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