Background: Patients with advanced lung neuroendocrine neoplasms (NENs) have few treatment options. Capecitabine and temozolomide have recently showed significant activity in patients with pancreatic neuroendocrine tumors (NETs), but data in lung NETs are limited. Methods: We retrospectively reviewed the records of patients treated at a large referral center to identify patients seen between January 2008 and September 2018 with metastatic lung NENs who received treatment with capecitabine and temozolomide (CAPTEM). Patients with small cell lung cancer were excluded. The primary endpoint was overall response rate per RECIST 1.1. Secondary endpoints included progression-free survival, overall survival, and toxicity. Results: Twenty patients were identified who received treatment with capecitabine and temozolomide. Fourteen (70%) had typical lung NETs, five had (25%) atypical carcinoids, and one (5%) had disease defined as a large-cell neuroendocrine carcinoma. Nineteen patients were evaluable for response. Six (30%) patients exhibited a best response of partial response per RECIST 1.1 criteria, 11 (55%) stable disease, and 2 (10%) progressive disease; objective response rate was 30%, and disease control rate was 85%. Eleven patients eventually progressed, only six of whom exhibited progression per RECIST 1.1 criteria. Median progression-free survival was 13 months (95% confidence interval [CI], 4.4–21.6 months). Median overall survival was 68 months (95% CI, 35.3–100.7 months). Toxicity profile was mild with mainly grade 1, expected toxicities. Six patients required dose reduction because of toxicity. Conclusion: The CAPTEM regimen is associated with a high response rate and a relatively tolerable toxicity profile in lung NENs. This regimen warrants further exploration in a prospective clinical trial.

Background: Although radiation-induced mesenteritis or peritonitis can potentially exacerbate the risk of bowel obstruction, there are no data in the literature on the incidence of intestinal obstruction related to peptide receptor radionuclide therapy (PRRT). Methods: Records of all patients treated with ¹⁷⁷Lu-Dotatate at Moffitt Cancer Center between 4/2018 and 10/2019 were evaluated. The number of patients who developed bowel obstruction within 3 months of a ¹⁷⁷Lu-Dotatate treatment was divided by the total number of patients with preexisting peritoneal or mesenteric disease. Management strategies and outcomes were evaluated. Results: Out of a total of 159 patients treated, 81 had baseline mesenteric and/or peritoneal disease, among whom 5 patients (6%) experienced at least one episode of bowel obstruction within 3 months of treatment. Two of the patients underwent surgical exploration during obstruction describing a ‘frozen abdomen’. All 5 responded at least temporarily to high-dose corticosteroid treatment and regained bowel function, but two patients eventually succumbed to progressive peritoneal disease. Conclusion: PRRT can lead to bowel obstruction in patients with mesenteric and/or peritoneal disease, likely by inducing inflammation. Corticosteroids can potentially play a role in treatment and prophylaxis.

Background: 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) has activity in pancreatic neuroendocrine tumors (pNETs), but its use is limited, partly because of toxicities. pNETs can often become aggressive over time. We evaluated the efficacy of FOLFOX in patients with aggressive pNETs who had progressed after capecitabine plus temozolomide (cap/tem) among other treatments. Materials and Methods: This was a retrospective study of all patients with well-differentiated metastatic pNETs, treated at an academic cancer center between January 2008 and June 2019, who received FOLFOX and had received cap/tem in the past. The primary endpoint was objective response rate. Results: Thirty-one patients met eligibility criteria. Twenty-five received FOLFOX, and six received FOLFOX with bevacizumab. Patients were heavily pretreated, having received a median of three prior lines of systemic therapy prior to FOLFOX (range, 1–8). Three (9.7%) patients had grade [G]1 tumors, 16 (51.6%) had G2, and 6 (19.4%) had G3, and grade was unspecified in 6 (19.4%) patients. Fourteen (45.2%) exhibited a best response of partial radiographic response per RECIST 1.1 criteria, 15 (48.4%) stable disease, and 2 (6.4%) progressive disease; overall response rate was 45.2% and disease control rate was 93.5%. Median progression-free survival was 6 months (95% confidence interval [CI], 5.0–7.0), and median overall survival was 16 months from onset of study treatment (95% CI, 11.3–20.7) and 67 months from date of diagnosis (95% CI, 49.8–84.2). Median duration of treatment was 3 months, and median duration of response was 2 months. Toxicity profile was consistent with known adverse events associated with this regimen. Conclusion: FOLFOX is active in aggressive, heavily pretreated pNETs that have progressed on prior cap/tem chemotherapy; response durations are relatively short. Implications for Practice: FOLFOX chemotherapy has robust activity in patients with rapidly progressive, heavily pretreated pancreatic neuroendocrine tumors (NETs), a setting in which few, if any, other options are likely to be effective. Durations of response, however, are relatively short, and new treatments are urgently needed for patients with aggressive transformation of pancreatic NETs.

The role for cytotoxic chemotherapy in patients with well-differentiated neuroendocrine tumors (NETs) remains debated. Compared to patients with poorly differentiated neuroendocrine carcinomas (NECs) where chemotherapy is utilized ubiquitously, chemotherapy may play a more select role in patients with certain types of NETs (e.g., pancreatic tumors, higher grade tumors, and tumors possessing DNA damage repair defects). The primary types of chemotherapy that have been tested in patients with NETs include alkylating agent- and platinum agent-based combinations. Across regimens, chemotherapy appears to elicit greater antitumor activity in patients with pancreatic or grade 3 NETs. The role for chemotherapy in lower grade extra-pancreatic NETs remains undefined. Furthermore, while chemotherapy has demonstrated clinically meaningful benefit for patients in the systemic setting, its role in the adjuvant or neoadjuvant setting is as-of-yet undetermined. Finally, efforts to combine chemotherapy with targeted therapy and peptide receptor radionuclide therapy are ongoing, in hopes of improving the cytoreductive treatment options for patients with NETs.

Background: Immune checkpoint inhibitors (CPIs) have not been shown to be active in well -differentiated neuroendocrine tumors (NETs), with response rates < 5%. Lenvatinib is a multitargeted tyrosine kinase inhibitor which binds to vascular endothelial growth factor and fi broblast growth factor receptors and has demonstrated ef fi cacy in pancreatic and gastrointestinal NETs [44% and 16% objective radiographic response rate (ORR), respectively]. The combination of antiangiogenic and CPI therapies can be synergistic. We therefore evaluated the combination of lenvatinib and pembrolizumab in well -differentiated gastrointestinal (GI) and thoracic NETs. Patients and methods: A prospective, phase II trial evaluated patients with advanced GI/thoracic NETs (pancreatic NETs were excluded due to high response rate of lenvatinib monotherapy in this patient population), with evidence of progression within 8 months of study entry and at least two prior lines of systemic therapy. Patients received lenvatinib 20 mg daily and pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or progression of disease. Primary endpoint was objective response rate, and an interim analysis was planned once 20 patients were enrolled. Four ORRs were required to continue enrollment. Results: Twenty patients were enrolled on protocol from April 2021 to January 2022 (nine small intestine, fi ve lung, two thymic, two unknown primary, one cecal, one presacral primaries). Two patients (10%) achieved a partial response (atypical lung and small intestinal primaries). Median progression -free survival (PFS) was 8 months (95% con fi dence interval 5.8-10.2 months). Twelve (60%) patients experienced probably or de fi nitely associated grade 3 adverse events (10 hypertension). Fourteen patients (70%) required dose reductions or discontinued one of the medications. Two patients discontinued treatment before radiographic assessment. Conclusions: The combination of pembrolizumab and lenvatinib did not show suf fi cient response in patients with NETs to warrant continued enrollment on trial.