Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms, mainly originating from the gastro-entero-pancreatic system and the lung. Molecular targeted therapy of NENs with the mTOR inhibitor everolimus is currently approved for GEP-Lung NENs and with the multi-tyrosine kinase inhibitor (multiTKI) sunitinib (VEGFR, PDGFR, KIT) for PAN-NENs. There is still an unmet need for further medical therapies including novel targeted therapies, the knowledge of the data on the role of the sequences of the therapies and the definition of new biological predictors of outcome and prognosis.~Cabozantinib targets VEGF receptors, MET, AXL, and RET. Cabozantinib is an oral, potent inhibitor of mesenchymal-epithelial transition factor (MET), VEGF receptor 2 (VEGFR2), and RET that produces robust antiangiogenic, antiproliferative, and antiinvasive effects in preclinical models. It has been shown to improve outcomes in advanced renal cell carcinoma patients in both the first-line and second-line settings and is also approved for progressive, metastatic medullary thyroid cancer.~Recent studies have suggested that activation of the MET signalling pathway may also play a role in the growth of neuroendocrine tumours. Increased expression of MET correlates with decreased overall survival in pancreatic neuroendocrine tumours. In preclinical pancreatic neuroendocrine tumour models, various multi-TKIs with combined anti-VEGF and anti-MET efficacy have shown enhanced angiogenesis inhibition, as well as suppression of tumour invasion and metastasis . Given the strong theoretical rationale for combining anti-VEGF and anti-MET activity in neuroendocrine tumours, in USA will start randomized, double-blinded phase III trial, named CABINET to evaluate the effects in terms of PFS in patients with advanced neuroendocrine tumours after progression on everolimus.~In an on-going clinical trial, Chan et al. showed, in patients with progressive, well differentiated, grade 1-2 carcinoid and treated with cabozantinib 60 mg po qd and without limit to prior therapy, 21.8 mo (95% CI, 8.5-32.0 mo) of mPFS in pts with pNET and 31.4 mo (95% CI, 8.5 mo-NR) in pts with carcinoid . In this study pNET achieved PR (ORR 15%, 95% CI 5-36%); 15/20 had SD. 6/41 pts with carcinoid achieved PR (ORR 15%, 95% CI 7-28%); 26/41 had SD.~The front-line treatment of advanced NENs depends on many clinical and pathological factors but there are no standard second-line therapies when the disease progress. Although data for temozolomide (TMZ)-based chemotherapy are still evolving, this treatment may replace STZ-based regimens in PAN-NENs due to its better tolerability and side effect profile. In addition, there is evidence that TMZ could also be used in the subgroup of well-differentiated G3 NETs. There is less clear-cut evidence of a benefit for chemotherapy in intestinal NETs, but still evolving data suggest that TMZ may be efficacious in particular patients. In our experiences, an intermittent schedule of metronomic TMZ is effective and safe in patients with advanced progressive G2-G3 NEN, showing to be a feasible second line treatment in this setting. This schedule has been also investigated by Chan et al. in 34 patients with advanced neuroendocrine tumors demonstrating a good safety profile. D.Shiff et al. demonstrated that cabozantinib at a dose of 40/60 mg daily plus TMZ for patients with newly diagnosed high-grade glioma was generally well tolerated even with the addition of radiotherapy, and also demonstrated no pharmacokinetic interactions with concurrent TMZ. Both mRNA and protein levels of c-Met were significantly associated with tumour grade progression and inversely correlated with overall and progression-free survival in high-grade gliomas. c-Met seems an independent prognostic marker in glioblastoma patients and further analysis in vitro revealed that downregulating the expression of c-Met dramatically inhibited cell migration and invasion capacities, enhanced sensitivity to TMZ chemotherapy . Cabozantinib downregulating c-MET pathway can induce, in addition to antiangiogenic and antiproliferative effects, also an increased sensitivity to Temozolomide.
The aim of CABOTEM study is to demonstrate the safety and activity of the Cabozantinib and Temozolomide combination in Lung and GEP-NENs patients, progressing after a first line therapy, including target therapies (everolimus, sunitinib) and / or chemotherapy, in the approved setting.