Molecular target therapy for gastroenteropancreatic endocrine tumours: Biological rationale and clinical perspectives

Gabriele Capursoaa,1, Nicola Faziobb,1, Stefano Festaaa, Francesco Panzutoaa, Filippo De Braudbb, Gianfranco Delle Faveaaa,*

a Digestive and Liver Disease Unit, S. Andrea Hospital, II Medical School, University “La Sapienza”, Via Di Grottarossa 1035-1039, 00189, Rome, Italy

 b Unit of Clinical Pharmacology and New Drugs, European Institute of Oncology, Milan, Italy

Critical Reviews in Oncology/Hematology. 2009; 72: 110-124

Abstract: Gastroenteropancreatic endocrine tumours (GEP ETs) represent a relatively rare and heterogeneous group of neoplasms whose therapy can be challenging. The poorly differentiated, fast-growing cases are treated with chemotherapy. In the slow-growing ones, biotherapy is usually performed. Several categories of targeted therapies have been studied for their treatment in vitro and in vivo. A critical review of molecular alterations suggests a rationale for targeting angiogenesis, and the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Accordingly, antiangiogenic agents and mTOR inhibitors are presently the most tested agents in phase II and III studies. Bevacizumab, some multitarget inhibitors, and mTOR inhibitors showed promising results in patients with advanced GEP ETs. A limited activity has been reported for imatinib and epidermal growth factor receptor (EGFR) inhibitors. Combinations of molecular targeted therapies with different sites of action, and somatostatin analogues may be relevant to avoid molecular escape pathways. Future trials should include more homogeneous groups of patients and pay more attention to the subgroup with progressive disease.

 

  • The following information was presented at the ASCO Gastrointestinal Cancers Symposium held in Orlando, Florida from January 22-24, 2010

Updated results of the phase III trial of sunitinib (SU) versus placebo (PBO) for treatment of advanced pancreatic neuroendocrine tumors (NET).

2010 Gastrointestinal Cancers Symposium Abstract 127

  1. Raymond, P. Niccoli-Sire, Y. Bang, I. Borbath, C. Lombard-Bohas, J. W. Valle, S. Patyna, D. Lu, R. C. Chao, J. Raoul

Authors’ Affiliations: Beaujon University Hospital, Clichy, France; Service d’Oncologie Medicale, CHU La Timone, Marseille, France; Seoul National University Hospital, Seoul, South Korea; Cliniques Universitaires Saint-Luc, Brussels, Belgium; Hopital Edouard Herriot, Lyon, France; The Christie NHS Foundation Trust, Manchester, United Kingdom; Pfizer Oncology, San Diego, CA; Pfizer Oncology, La Jolla, CA; Centre Eugene Marquis, Rennes, France

Background: The multitargeted tyrosine kinase receptor inhibitor sunitinib has shown activity against pancreatic NET in the RIP1-Tag2 mouse model and in phase I/II studies.

Methods: This phase III, multinational, randomized, double-blind trial (NCT00428597) investigated the efficacy and safety of SU vs PBO in patients (pts) with advanced pancreatic NET. Pts with well-differentiated pancreatic islet cell tumors and documented disease progression within the past 12 months were randomized (1:1) to SU 37.5 mg/day daily or PBO. All pts received best supportive care and somatostatin analogs, if indicated. The primary endpoint was progression-free survival (PFS) with target enrolment of 340 pts.

Results: This study was stopped early due to differences in efficacy, as recommended by the independent Data Monitoring Committee. Between Jun 2007 and Apr 2009, 171 pts were randomized to SU (n = 86) or PBO (n = 85); median age was 56 years, 52% were female, 50% had nonfunctional tumors, 95% had metastatic disease, and 71% had received various prior treatments. The most frequently reported adverse events (AEs) with SU were (SU vs PBO, all grades) fatigue/asthenia (60% vs 52%), diarrhea (59% vs 39%), nausea (45% vs 29%) and vomiting (34% vs 31%). Grade 3/4 AEs (SU vs PBO) included neutropenia (12% vs 0%), hypertension (9.6% vs 1.2%), fatigue/asthenia (8.4% vs 12.2%), palmar-plantar erythrodysesthesia (6.0% vs 0%) and abdominal pain (4.8% vs 9.8%). More serious AEs were reported in the PBO arm (26.5% in SU vs 41.5% in PBO). Final analysis of 81 events for PFS included 75 events of disease progression. Median PFS was 11.4 months in the SU arm vs 5.5 months in the PBO arm (p = 0.0001). The objective response rate (ORR) with SU was 9.3% (2 complete and 6 partial responses; 95% CI: 3.2-15.4%). There were 9 and 21 deaths in the SU and PBO arms, respectively.

Conclusions: Sunitinib prolonged PFS, increased ORR and OS, and displayed an acceptable safety profile in pts with advanced pancreatic NET.

SU (n = 86) PBO (n = 85) Hazard ratio (95% CI) p
Median PFS, months 11.4 5.5 0.418 (0.263, 0.662) 0.0001
ORR, n (%) 8 (9.3%) 0 0.0066
Median OS NR NR 0.404 (0.185, 0.882) 0.0186

Abbreviations: SU, sunitinib; PBO, placebo; CI, confidence interval; PFS, progression-free survival; ORR, objective response rate; OS, overall survival; NR, not reached.

(Please note: sunitinib is not yet FDA-approved for neuroendocrine tumors)

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