The PI3K-Akt-mTOR pathway is a key regulator pathway in the biology of NENs [28–35] and its constitutive activation has been described in many malignancies, including these tumors. Some genetic syndromes have evidenced the role of a loss or the down-regulation of tumor suppressor phosphatase and tensin homologue (PTEN) or tuberous sclerosis 2 (TSC-2) in the constitutive activation of the PI3K-Akt-mTOR pathway. These alterations have been frequently described also in NEN tumorigenesis; 85% of PanNENs show altered levels of TSC2 and/or PTEN and in both cases the degree of down-regulation inversely correlates with prognosis, as demonstrated in a series of 72 patients with PanNENs [36]. Furthermore genome sequencing together with expression profiling has identified somatic mutations implicated in the self-maintenance of activated signaling along this pathway.

Data from clinical trials have supported the central role of the PI3K-AktmTOR pathway in PanNEN tumorigenesis. In the RADIANT-1 study, everolimus was administered either alone or in combination with octreotide long-acting release (LAR), if such treatment was ongoing at baseline. The primary endpoint was RR in the largest stratum of everolimus monotherapy (n = 115 patients). In these patients, the RR was 9.6% vs. 4.4% for patients in the everolimus + octreotide stratum. No conclusions could be drawn regarding possible interactions between everolimus and SSA because: (a) it was not a randomized study; (b) the number of patients in the everolimus stratum greatly exceeded that in the combination arm; and (c) the biology of the patients enrolled in the two strata differed. Specifically, in the stratum with everolimus alone, 19% of SSA-naïve patients had a syndromic tumor, including those who might have benefited from inclusion in the stratum with everolimus and SSA. PFS in the SSA + everolimus stratum was longer than in the everolimus alone stratum (16.7 vs. 9.7 months) [37]. The antitumor activity and safety of everolimus in the treatment of NENs confirmed the conclusion of a previous phase II study. This trial similarly intended to evaluate the activity of everolimus in combination with octreotide LAR in patients with advanced PanNEN. The overall RR (ORR) was somewhat higher than in RADIANT-1 (30% in the arm comprising patients treated with the same everolimus dose). However, the population differed between the studies: in the first study, the percentage of patients (34%) enrolled with stable disease was higher and a minority of them (43%) were pretreated with chemotherapy [38].

The RADIANT-3 study further explored the role of everolimus in the management of 410 patients with advanced PanNENs, in a randomized fashion against placebo. Pretreatment with chemotherapy was a stratification criteria and SSA treatment was allowed in both arms during the trial. The trial design enabled cross-over at PD, with PFS as the only suitable primary endpoint in order to evaluate clinical benefit. PR, defined according to RECIST, was obtained in 5% of the patients in the everolimus arm but 64% of patients receiving the drug experienced some degree of tumor shrinkage, compared to 21% in the placebo arm. In addition, everolimus reduced tumor proliferation, as shown by a decreased in the Ki67 index on paired re-biopsies. However, the most striking benefit following everolimus treatment was longer time to disease progression. Specifically, the adjudicated central review PFS was 11.4 and 5.4 months for the everolimus and placebo arms, respectively, resulting in a reduction of the risk of progression for the experimental arm of nearly 65%. No subgroup was disadvantaged: neither chemotherapy-pretreated patients nor those with moderately differentiated tumors. The homogeneous selection of patients with PanNENs and progressive disease together with the adequate sample size enrolled renders the results of this trial essentially unquestionable. Nonetheless, some concerns remain regarding the biology of the tumors included in the study, since: (a) 70% of the patients had a diagnosis of PD within 3 months before enrollment and nothing is known about pre-progression disease behavior; (b) 17% of the patients had moderately differentiated tumors for which not even a median Ki67 was reported [39]. The lack of this information could make it difficult to compare this trial with others. The RR and PFS obtained with everolimus of 5% and 11.4 months, respectively, must be compared with those obtained with other strategies. PRRT with Lu-DOTAoctreotate on Octreoscan-positive PanNENs lead to RRs ranging from 36% for non-functioning pancreatic tumors to 60% for insulinomas, with a global PFS of nearly 40 months. STZ-based chemotherapy, according to a historical study, obtained an RR in 69% of PanNEN-bearing patients, with a median PFS of 22 months. Head-to-head comparisons, in the context of a phase III RCT, of the currently available therapeutic strategies are warranted.

NENs are highly vascularized tumors. High levels of VEGF expression by PanNENs is a negative prognostic factor related to higher microvessel density, a higher incidence of metastases, and a shorter PFS. Many different antiangiogenic drugs are now available for clinical use, both as specific target agents or as pleiotropic kinase inhibitors. Bevacizumab was tested in a phase II randomized study against pegylated interferon-α (PEG-IFNα) in a population of 44 patients with carcinoids (excluding pancreas primaries) who received a stable dose of octreotide. In the bevacizumab arm, 18% of patients achieved a PR, with 77% SD in contrast to the PEG-IFNα arm, in which no PR was documented and SD was obtained in 68% of patients [8]. The results of many trials, including bevacizumab in combination with either chemotherapy or other targeted agents, in patients with advanced, are awaited. A prospective randomized phase III trial testing bevacizumab + octreotide LAR vs. IFNα + octreotide LAR, as well as other phase II single-arm clinical studies (TMZ + bevacizumab, CAPOX + bevacizumab, FOLFOX + bevacizumab, everolimus + bevacizumab) are ongoing.

Sunitinib was also tested as anti-angiogenetic multi-target agent in NENs. The first experience, in a single-arm phase II trial, showed promising results. In that study, 109 patients with advanced NENs (66 PanNENs and 41 carcinoids) were evaluated. A PR was obtained in 16.7% of the PanNEN patients, with a median PFS of 7.7 months; among those with carcinoids, the RR was 2.4%, with a PFS of 10.2 months [40]. The assumed major clinical benefit of sunitinib in the subgroup of patients with PanNENs led to a phase III study in which only patients with advanced PanNENs were enrolled. The 171 patients were randomly assigned to receive sunitinib (37.5 mg/day) or placebo together with best supportive care. Patients with PD in the placebo arm were allowed to enter an open-label sunitinib extension protocol; thus, the primary end point was necessarily PFS, as in the everolimus registrative phase III study. Noteworthy baseline characteristics of the enrolled patients were: 22% with tumors having a Ki67 > 10% and 66% pretreated with chemotherapy in the experimental arm. Patients in both arms were allowed to receive SSAs according to the investigators’ discretion. Both these percentages were well-balanced in the placebo arm. After assessment of the data on 154 patients, the safety monitoring committee recommended discontinuation of the trial because of the large number of deaths and serious adverse events in the placebo group. At that time point, a RR of 9.3% and 0% were recorded in the experimental and placebo arms, respectively. A statistically significant difference in PFS between the two arms was also determined (11.4 vs. 5.5 months). Both subgroups of patients benefited from sunitinib but the hazard ratio for progression in the experimental arm compared to placebo seemed to favor patients with a Ki67 index ≤5 % [41].

The most relevant features of the main trials with target agents are summarized in Table 12.2.