Refractory Advanced diGestive Neuroendocrine Carcinomas Treated With tARlatamab

1. RACIONAL Neuroendocrine carcinomas (NECs) are aggressive neoplasms located primarily in the gastroenteropancreatic (GEP) tract or of unknown origin. They are uncommon tumors with an estimated incidence per year that ranges from 5 to 7 cases per 100,000 people. The reported incidence has substantially increased over the last decades, at least partially due to improved diagnostic techniques and clinical awareness.

Treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NEC) is primarily based on chemotherapy regimens, primarily platinum-based, which achieve limited benefit and a median overall survival of approximately 12 months.

Dual blockade of PD-1 and CTLA-4 has demonstrated efficacy in several tumor types and achieved prolonged survival in a subset of pretreated patients with Grade 3 GEP-NEN. Therefore, activating the immune system to stimulate antitumor responses and prolong survival in patients with NECs is a feasible strategy to explore. Given the high levels of DLL3 expression on the cell surface of neuroendocrine tumor cells and its minimal, primarily cytoplasmic, localization in normal tissues, DLL3 is a promising target for the development of T-cell-directed therapies in NECs. Tarlatamab is a HLE BiTE molecule that combines the binding specificities for DLL3 and CD3, which could activate the immune system to fight NEC cells. Tarlatamab is currently approved for the treatment of patients with small cell lung cancer. 2. HYPOTHESIS The main hypothesis is that treatment with tarlatamab, a bispecific anti-DLL3 and anti-CD3 conjugate, either as a single agent or in combination with standard second-line chemotherapy (FOLFIRI) scheme could be an effective treatment option for patients with advanced neuroendocrine carcinomas of the digestive system or unknown primary origin. 3. OBJECTIVES

The main objectives:

1. To find the best tarlatamab-based treatment. 2. To evaluate the efficacy of tarlatamab, either as a single agent or in combination with the FOLFIRI regimen, in patients with NECs, assessed in terms of overall survival (OS).

Secondary objectives

1. To evaluate the clinical efficacy results of tarlatamab for patients with NEC. 2. To assess the correlation of risk factors with the efficacy of tarlatamab treatment. 3. To assess the quality of life (QoL) of patients with NEC treated with tarlatamab. 4. To assess the safety of the planned treatment regimen. 5. To determine molecular or clinical predictive biomarkers of response to tarlatamab