Introduction Recent classification of neuroendocrine neoplasms has defined well‐differentiated high‐grade neuroendocrine tumors (NET G3) as a distinct entity from poorly differentiated neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well‐described. This study aimed to evaluate metastatic NET G3 response to different treatment regimens. Materials and Methods This was a retrospective study of patients with NET G3 within the Mayo Clinic database. Patients’ demographics along with treatment characteristics, responses, and survival were assessed. Primary endpoints were progression‐free survival (PFS) and overall survival. Secondary endpoints were objective response rate (ORR) and disease control rate (DCR). Results Treatment data was available in 30 patients with median age of 59.5 years at diagnosis. The primary tumor was mostly pancreatic (73.3%). Ki‐67 index was ≥55% in 26.7% of cases. Treatments included capecitabine + temozolomide (CAPTEM) (n = 20), lutetium 177 DOTATATE (PRRT; n = 10), Platinum‐etoposide (EP; n = 8), FOLFOX (n = 7), and everolimus (n = 2). CAPTEM exhibited ORR 35%, DCR 65%, and median PFS 9.4 months (95% confidence interval, 2.96–16.07). Both EP and FOLFOX showed similar radiographic response rates with ORR 25.0% and 28.6%; however, median PFS durations were quite distinct at 2.94 and 13.04 months, respectively. PRRT had ORR of 20%, DCR of 70%, and median PFS of 9.13 months. Conclusion Among patients with NET G3, CAPTEM was the most commonly used treatment with clinically meaningful efficacy and disease control. FOLFOX or PRRT are other potentially active treatment options. EP has some activity in NET G3, but responses appear to be short‐lived. Prospective studies evaluating different treatments effects in patients with NET G3 are needed to determine an optimal treatment strategy. Implications for Practice High‐grade well‐differentiated neuroendocrine tumors (NET G3) are considered a different entity from low‐grade NET and neuroendocrine carcinoma in terms of prognosis and management. The oral combination of capecitabine and temozolomide is considered a good option in the management of metastatic NET G3 and may be preferred. FOLFOX is another systemic option with reasonable efficacy. Similar to other well‐differentiated neuroendocrine tumors, peptide receptor radionuclide therapy seems to have some efficacy in these tumors.

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Background. G3 GEPNENs are often aggressive, and the optimal treatment is unclear for this subgroup of NENs. Temozolomide (TEM)-based regimens have been increasingly used to treat grade 1-2 NENs, but their efficacy in G3 NENs remains undetermined. We aimed to assess the clinical efficacy of TEM-containing regimens in advanced grade 3 GEPNENs. Methods. A multicentre retrospective review (2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017)(2018) of patients with metastatic/unresectable G3 GEPNENs who received a TEM-containing regimen was undertaken within a North American partnership to pool data. The primary endpoint was time to treatment failure (TTF). Radiologic response was extracted from local reports. Results. One hundred and thirty patients in six high volume NEN centers were included (median age 55, 64% male, 18% functional, 67% pancreatic NEN). 49% were well-differentiated, 35% poorly-differentiated, and 15% unknown based on local pathology reports. The regimen used was capecitabine and temozolomide (CAP/TEM) in 92% and TEM alone in 8%. Radiological response by local assessment was seen in 36% of patients. Median TTF was 3.6 months and median overall survival (OS) 19.2 months. Six percent of patients required discontinuation of therapy due to adverse events. TTF was longer in first-line treatment (7.8mo vs 2.9mo, HR 1.62, 95% CI 1.11-2.36, p=0.015) and in patients with panNEN compared to GI NEN (5.8 months vs 1.8 months, p=0.04). The overall response rate was higher in the first-line setting (51% vs 29%, p=0.02) and in panNEN (41% vs 23%, p=0.04). Conclusion. This is the largest TEM treatment series in G3 NEN, involving collaboration of several major North American NEN centers as a partnership. Thirty-six percent of patients showed some degree of radiographic response, and treatment was generally well-tolerated, although the median duration of response was short. Response rates and time to treatment failure were superior in the first-line setting. CAPTEM should be considered a viable treatment option in this setting. Further randomized trials are warranted. The Oncologist 2021;9999:• •

617 Background: Currently, there is no published data on the efficacy of SSAs for well-differentiated G3 NETs. Randomized trials have demonstrated a progression-free survival (PFS) benefit and limited tumor response for lower grade 1-2 NETs, but the optimal systemic therapy for metastatic/unresectable G3 NETs is unknown. We sought to evaluate the efficacy of SSAs in G3 NETs. Methods: We performed a retrospective analysis of Mayo Clinic patients treated with SSAs for metastatic/unresectable G3 NETs, querying data from 1992 - present. Inclusion criteria were: centrally reviewed pathology confirming well-differentiated morphology, G3 based on WHO classification, SSA monotherapy, and radiological data available to assess response. Patients who had prior lines of treatment were included as long they subsequently were treated with single-agent SSA. Poorly-differentiated tumors were excluded. The primary endpoint was PFS. Best overall response was determined by radiographic regression, stabilization, or progression of tumor size. Results: Ninety patient records were reviewed, with 14 meeting inclusion criteria (diagnosed 2014 – 2018). Median Ki-67 proliferative index was 25%. Two patients (14%) had a partial response to SSA therapy, five (36%) had stable disease, and seven (50%) had progressive disease. The estimated median PFS was 4.4 months (95% CI 2.9 – 24). Of the 7 patients with stable disease or partial response, the median time to progression was 8.7 months. Three patients had stable disease for greater than 9 months (24, 29 and 42 months, respectively). Overall survival was not estimable. There was no association of Ki-67 index with PFS based on a proportional hazards model. Conclusions: This is the first report on the efficacy of SSAs for G3 NETs. Although half of the patients in our series had at least stable disease, the PFS was modest at only 4.4 months. Given their favorable side-effect profile compared to cytotoxic chemotherapy, SSAs may present an attractive option to be further explored in a prospective fashion. We are presently updating this data by reassessing response using RECIST criteria.

While cytochrome P450 (CYP)-mediated biosynthesis of arachidonic acid (AA) epoxides promotes tumor growth by driving angiogenesis, cancer cell intrinsic functions of CYPs are less understood. CYP-derived AA epoxides, called epoxyeicosatrienoic acids (EETs), also promote the growth of tumor epithelia. In cancer cells, CYP AA epoxygenase enzymes are associated with STAT3 and mTOR signaling, but also localize in mitochondria, where they promote the electron transport chain (ETC). Recently, the diabetes drug metformin was found to inhibit CYP AA epoxygenase activity, allowing the design of more potent biguanides to target tumor growth. Biguanide inhibition of EET synthesis suppresses STAT3 and mTOR pathways, as well as the ETC. Convergence of biguanide activity and eicosanoid biology in cancer has shown a new pathway to attack cancer metabolism and provides hope for improved treatments that target this vulnerability. Inhibition of EET-mediated cancer metabolism and angiogenesis therefore provides a dual approach for targeted cancer therapeutics.