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

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.

Inclusion Criteria:

1. An Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0, 1 or 2.

2. A confirmed diagnosis of neuro-endocrine carcinoma of the gynecological tract including small cell cervical cancer or other high-grade neuro-endocrine carcinoma from the vulva or vagina. Mixed histologies are allowed only if the neuro-endocrine carcinoma component is predominant

3. Previously been treated with platinum-based doublet chemotherapy, either in the locally-advanced or recurrent or metastatic setting. Prior treatment with an immune-checkpoint inhibitor is allowed.

4. Progressed radiographically on or after their most recent line of anticancer therapy

5. At least 1 lesion that meets the definition of measurable disease by RECIST v1.1 (radiologically measured by the Investigator)

6. Patients must be willing to provide an archival tumor tissue block or slides, or undergo a procedure to obtain a new biopsy using a low-risk, medically routine procedure for translational analysis only (including DLL3 expression determination). Subjects who do not have archived tumor tissue available and who are unable to undergo a pretreatment tumor biopsy (e.g. cannot be performed safely or if the tumor is inaccessible, as determined by the study investigator) may be allowed to enroll without a tumor biopsy upon agreement between the local investigator and the coordinating investigator.

7. Completed prior therapy within the specified times below:

   • Systemic antineoplastic therapy within 2 weeks prior to first dose of Tarlatamab
   • Focal radiation completed at least 1 week prior to first dose of Tarlatamab

8. Stabilized or recovered (Grade 1 or baseline) from all prior therapy-related toxicities (except alopecia and neuropathy)

9. Adequate hematologic, liver and kidney functions defined as:

   • Absolute neutrophil count (ANC) ≥ 1.0 x 109/L (1000/μL)
   • Platelet count ≥ 75 x 109/L (75 000/μL)
   • Hemoglobin ≥ 9.0 g/dL
   • Estimated glomerular filtration rate (eGFR) based on CKD-EPI calculation ≥ 30 mL/min/1.73 m2
   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN
   • Serum bilirubin ≤ 1.5 x ULN (patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin < 3.0 x ULN)
   • Serum albumin ≥ 25 g/L

10. No significant pleural effusion

11. Cardiac ejection fraction ≥ 50% as determined by an echocardiogram (ECHO) or multigated acquisition (MUGA) scan, no clinically significant pericardial, and no clinically significant electrocardiogram (ECG) findings (including but not limited to: signs of recent ischemia, high grade conduction abnormalities, QTcF>500ms)

12. Patients must be willing and able to sign the informed consent form (ICF) and to adhere to the protocol requirements

13. Women of childbearing potential (WCBP) must agree to use highly effective contraceptive method(s) while on Tarlatamab and for at least 2 months after the last dose

14. WCBP must have a negative pregnancy test within the 4 days prior to the first dose of Tarlatamab

15. Affiliated to a social health insurance plan

Exclusion Criteria:

• 1. Non-neuroendocrine histologies (e.g. adenocarcinoma, epidermoid carcinoma). 2. Well-differentiated NETs, especially NET G1 (typical carcinoid) and NET G2 (atypical carcinoid) 3. Neuro-endocrine carcinoma arising from the endometrium or ovaries or fallopian tubes.

  4. Treated with more than 2 previous lines of systemic therapy for the metastatic disease.

  5. Prior ICI-treatment is allowed, but patients who experienced severe, life-threatening immune-mediated adverse events or infusion-related reactions, including those that lead to permanent discontinuation while on treatment, are excluded.

  6. Untreated or symptomatic brain metastases and leptomeningeal disease. 7. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.

  8. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of Tarlatamab.

  9. Has a serious concurrent illness or clinically relevant active infection, including, but not limited to the following:

  • Active hepatitis B or C infection (whether or not on active antiviral therapy)
  • HIV infection
  • Presence of fungal, bacterial, viral, or other infection requiring oral or IV antimicrobials for management within 7 days of first dose of Tarlatamab.

NOTE: Simple urinary tract infection and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with the coordinating investigator. Subjects requiring oral antibiotics who have been afebrile > 24 hours, have no leukocytosis or have any clinical signs of infection are eligible.

10. History of other malignancy within the past 3 years, unless it will not interfere with the disease under study.

11. Myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association > class II) within 12 months of first dose of Tarlatamab 12. History of hypophysitis or pituitary dysfunction 13. Major surgery within 28 days of first dose Tarlatamab 14. Has a history of hemorrhagic or ischemic stroke within 6 months prior to enrollment 15. Has a history of cirrhotic liver disease (Child-Pugh Class B or C) 16. Has a history of prior hypersensitivity to monoclonal antibodies (mAb) 17. Women who are pregnant or breastfeeding 18. Who received prior treatment with Tarlatamab or other DLL3-targeting agents 19. Has known sensitivity to any of the products or components to be administered during dosing. (i.e allergy to Tarlatamab or any ingredient used in the formulation of the products) 20. History or evidence of any other clinically significant disorder, condition or disease that, in the opinion of the investigator would be a risk to the subject's safety or interfere with the study evaluation, procedures, or completion.

21. Treatment with live virus, including live-attenuated vaccination, within 4 weeks prior to the first dose of study treatment. Inactive vaccines and live viral non-replicating vaccines within 4 weeks prior to first dose of study treatment 22. Receiving government medical aid (Aide Médicale de l'Etat - AME) 23. Subject unable to give informed consent (e.g subject to a legal protection measure: curatorship, guardianship, future protection mandate …)