Targeted Agents and Combinations Being Studied in Pancreatic NETs

Selection of first-line treatments and the rational sequencing of therapies are the focus of current research in the treatment of pancreatic neuroendocrine tumors (NETs). Clinical trials are exploring the use of mTOR inhibitors, vascular endothelial growth factor (VEGF) inhibitors, cytotoxic chemotherapy, and somatostatin analogues as monotherapy, in various combinations, and as adjuvant therapy, according to Pamela L. Kunz, MD, at the 2014 North American Neuroendocrine Tumor Society (NANETS) Symposium.¹

Pamela L. Kunz, MD, on Sequencing Agents for the Treatment of pNETs

Kunz is a professor at the Stanford University School of Medicine.

The current treatment options include streptozocin, everolimus, and sunitinib—all of which are approved by the US Food and Drug Administration (FDA) for the treatment of pancreatic NETs (pNETs).In addition, the somatostatin analogue lanreotide has demonstrated a significant advantage in progression-free survival (PFS) over placebo in patients with advanced NETs.

Recent data show a trend toward an improvement in overall survival (OS) with the mTOR inhibitor everolimus compared with placebo in the treatment of pNETs. As presented at European Society for Medical Oncology (ESMO) 2014, median OS was 44.0 months in patients receiving everolimus compared with 37.7 months in placebo recipients, which did not achieve significance because of allowance of crossover from placebo to everolimus (hazard ratio [HR] = 0.94; P = .30).²

“This is encouraging because we saw not only a little bit of a signal, but also because in both the placebo and everolimus arms, PFS was quite long, demonstrating improvement over the past decade as far as how these patients are doing,” said Kunz, assistant professor of medicine at Stanford University in California. In another recent study, lanreotide was compared with placebo in 204 patients with metastatic enteropancreatic NETs of grade 1 or 2.³Patients were randomized to an extended-release aqueous gel formulation of lanreotide, 120 mg, or placebo once every 28 days for 96 weeks. Tumors originated in the pancreas in 45 patients. The study allowed for crossover from placebo to lanreotide in the case of progression.

Median PFS had not been reached in the lanreotide group at the time of the initial report and was 18 months in the placebo group (HR for progression or death = 0.47; P < .001). Among 88 patients enrolled in an extension study of lanreotide, median PFS is 32 months.

A study to examine sequencing of everolimus and streptozocin/5-fluorouracil in grade 1 or 2 progressive, metastatic pNETs as first-line therapy after a somatostatin analogue is anticipated to enroll its first patient this year, with an accrual goal of 180 patients. Lanreotide is being compared with placebo as maintenance therapy after first-line treatment in patients with duodeno-pancreatic grade 1 or 2 progressive, metastatic NETs, with an accrual goal of 118 patients and a primary endpoint of PFS.

The role of combination therapies is also under study. The combination of temsirolimus and bevacizumab was associated with a 6-month PFS of 79%, a 12-month PFS of 48%, and a median PFS of 11.7 months in a phase II trial of 55 patients with grade 1 or 2 advanced, progressive pNETs. These data were presented at American Society of Clinical Oncology (ASCO) 2013.

James C. Yao, MD, on Unanswered Questions Regarding the Treatment of pNETs

Yao is a professor at The University of Texas MD Anderson Cancer Center.

Biologics in combination are being assessed in 2 phase II trials of patients with advanced pNETs. CALGB 80701 is comparing everolimus plus octreotide LAR versus the same combination plus bevacizumab in 138 patients with PFS as the primary endpoint. Accrual is complete in COOPERATE-2, which is comparing everolimus plus pasireotide with everolimus alone on the primary endpoint of PFS in 160 patients. Results are expected to be presented at the ASCO Gastrointestinal Symposium early next year.

The cytotoxic combination of temozolomide and capecitabine is being compared with temozolomide alone in a phase II trial involving a planned 145 patients with grade 1 or 2 advanced pNETs. The primary endpoint is PFS; 45 patients have been enrolled as of October 2014. Ongoing phase I/II combination trials are exploring the utility of temozolomide plus pazopanib, capecitabine in combination with temozolomide and bevacizumab, and lanreotide plus temozolomide.

As adjuvant therapy, 12 months of everolimus is being examined in a planned 150 patients with low- or intermediate-grade pNETs following R0 or R1 resection of hepatic metastases.

Novel therapies being evaluated include the tyrosine kinase inhibitors cabozantanib, dovitinib, and regorafenib, and intratumoral immunotherapy with ipilimumab plus an anti-programmed death-ligand 1 (PD-L1) agent.

In other cancers such as melanoma, &ldquo;the new paradigm in clinical trials—targeted therapies given to biomarker-selected patients&mdash;have produced substantial improvements,&rdquo; said Kunz.

Clinical Pearls

• Selection of first-line treatments and the rational sequencing of therapies are the focus of current research in the treatment of pNETs.
• Data show a trend toward improved OS with the mTOR inhibitor everolimus compared with placebo in the treatment of pNETs.
• Among 88 patients enrolled in an extension study of lanreotide, median PFS is 32 months.
• A study to examine sequencing of everolimus and streptozocin/5-fluorouracil in grade 1 or 2 progressive, metastatic pNETs as first-line therapy after a somatostatin analogue is anticipated to enroll its first patient this year.
• CALGB 80701 is comparing everolimus plus octreotide LAR versus the same combination plus bevacizumab in 138 patients with PFS as the primary endpoint.
• Temozolomide plus capecitabine is being compared with temozolomide alone in a phase II trial.
• Ongoing phase I/II trials are exploring the utility of temozolomide plus pazopanib, capecitabine in combination with temozolomide and bevacizumab, and lanreotide plus temozolomide.
• Novel therapies being evaluated include the TKIs cabozantanib, dovitinib, and regorafenib, and intratumoral immunotherapy with ipilimumab plus an anti-PD-L1 agent.

Commonly mutated genes in pNETs are somatic inactivating mutations in the multiple endocrine neoplasia, type 1 (MEN1) gene, mutations in genes encoding either of the 2 subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain associated protein) and ATRX (&alpha; thalassemia/mental retardation syndrome X-linked), and mutations in genes in the mTOR pathway. In addition, a deficiency in levels of the DNA repair enzyme, O(6)-methylguanine DNA methyltransferase (MGMT, which is common in pNETs), has been hypothesized to predict response to temozolomide.⁴

References

1. Kunz P. Current treatment and clinical trial landscape in pancreatic NETs. Presented at North American Neuroendocrine Tumor Society (NANETS) Symposium; October 10-11, 2014; Nashville, Tennessee.
2. Oberg K, Yao J, Lam D H, et al. A randomized double-blind Phase III study of RAD001 10 milligrams per day (mg/d) plus best supportive care versus placebo plus best supportive care in the treatment of patients with advanced pancreatic neuroendocrine tumor (NET). Presented at the European Society for Medical Oncology (ESMO) Congress, September 26-30, 2014, Madrid, Spain (abstract #1132O).
3. Caplin ME, Pavel M, Ćwikła JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors.N Engl J Med. 2014;371(3):224-233.
4. Kulke MH, Hornick JL, Frauenhoffer C, et al. O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors.Clin Cancer Res. 2009;15(1):338-345.