Tarlatamab in Recurrent Gynecological Neuroendocrine Carcinomas: A Phase II Proof-of-concept Study

Neuroendocrine carcinoma of the cervix (NECC) is an aggressive histological variant of cervical cancer accounting for about 1-1.5% of all cervical cancers. Small cell NEC is the most common type of NECC. This malignancy is induced by the human papillomavirus, like the other more common cervical cancers subtypes (i.e squamous cervical cancer and adenocarcinoma), but has a far worse prognosis. Local and distant relapses occur more often in NECC, and the 5-year overall survival (OS) is significantly poorer with around 30% (compared to \> 65% for the others). Thus, the aggressive nature of NECC resembles that of small cell lung cancer (SCLC), which, at the time of initial diagnosis, is mostly locally advanced or metastasized.

The Gynecologic Cancer InterGroup recommends a multimodal approach for advanced disease, with chemoradiation or systemic chemotherapy consisting of etoposide and cisplatin. There is no standard of care in case of recurrence after platinium-based chemotherapy. Retrospective data suggests the combination of Paclitaxel, Topotecan, and Bevacizumab1, but median progression-free-survival (PFS) was only 8,7 months and median OS 16.8 months with this regimen in the NECTuR retrospective register (starting from the initiation of therapy for recurrence).

Tarlatamab is a bispecific T-cell engager immunotherapy (BiTE). It binds to both DLL3 on cancer cells and to CD3 on T cells, leading to T-cell-mediated lysis of cancer cells. DLL3, a protein that inhibits Notch signaling, is overexpressed on the surface of SCLC. It is associated with OS benefit in pre-treated SCLC in the randomized phase 3 DeLLphi-304 trial (Mountzios et al). Recently, it has been confirmed that high DLL3 expression is associated with high-grade neuroendocrine features, making it a promising therapeutic target beyond SCLC. Interestingly, gynecological neuro-endocrine neoplasias were classified as DLL3-high expressing tumors with whole-transcriptome sequencing analysis (Lozano et al).

Given the biological similarities between SCLC and NECC, and the high expression of DLL3, Tarlatamab should also be evaluated in gynecological NEC.