Despite the rapid global advancement in anti-tumor drug development, most efforts have focused on high-incidence cancers such as lung, gastric, and colorectal cancer. In contrast, neuroendocrine neoplasms (NENs), which have a lower incidence rate, have received relatively less attention from drug developers. Fortunately, in China, dedicated clinicians specializing in NENs are actively advancing the field, bringing several investigational drugs into clinical trials for NEN treatment.

Professor Ming Lu, Chief Physician of the Department of Gastrointestinal Oncology at Peking University Cancer Hospital / Beijing GoBroad Hospital, shares key therapeutic developments in NENs expected in 2025, offering new hope and options for patients.

I. Current Status of Neuroendocrine Neoplasm Treatment

1. Neuroendocrine Tumors (NETs)

For gastroenteropancreatic neuroendocrine tumors (PanNETs), multiple treatment options are available, including octreotide, lanreotide, everolimus, and sunitinib. Additionally, surufatinib, capecitabine, temozolomide, and peptide receptor radionuclide therapy (PRRT) are also important therapeutic approaches. However, for pulmonary neuroendocrine tumors (LungNETs), available treatment options remain limited.

2. Neuroendocrine Carcinomas (NECs)

Treatment options for NECs are more limited. According to the Chinese Anti-Cancer Association (CACA) guidelines, platinum-based combination chemotherapy is recommended. First-line regimens include etoposide + cisplatin (EP), etoposide + carboplatin (EC), and irinotecan + cisplatin (IP).

II. Advances in Novel Therapies for NENs

1. Immunotherapy

Immunotherapy has become a cornerstone of treatment for several cancer types. However, its application in NENs remains complex due to the heterogeneity between well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Currently, immunotherapy is not a standard recommendation for either group. Monotherapy with immune checkpoint inhibitors typically shows a response rate of less than 5%. Even dual checkpoint blockade achieves only about 10% efficacy.

Nevertheless, in certain subgroups—such as well-differentiated pancreatic NETs—remarkable tumor regression has been observed with monotherapy, with some patients achieving disease control for over two years. The clinical challenge lies in identifying such responders. Based on prior trial data, we are currently exploring the use of new PD-L1 immunohistochemical testing kits to better screen potential candidates.

For non-pulmonary NECs, although agents like nivolumab and pembrolizumab are available, their monotherapy response rates remain low. Researchers are actively investigating combination strategies. While dual immunotherapy has shown efficacy in small-cell lung cancer, there is still a lack of phase III trial data to support its routine use in non-pulmonary NECs. Hence, immunotherapy is not yet widely recommended in this context.

2. Targeted Therapy: LBL-024 (PD-L1/4-1BB)

LBL-024 is a bispecific antibody that targets PD-L1 to block immune suppression and directs 4-1BB costimulation to the tumor microenvironment to enhance the antitumor immune response. In monotherapy trials for non-pulmonary NECs, LBL-024 demonstrated an objective response rate (ORR) of 33.3% and disease control rate (DCR) of 51.1%, surpassing current second-line treatments. It has received Orphan Drug Designation from the U.S. FDA and is undergoing registration and first-line combination trials with EP chemotherapy.

3. DLL3-Targeted Therapies

DLL3 has become a prominent target in NEC research, expressed in ~80% of small-cell lung cancers (SCLC) and other NENs, but rarely in normal tissues. Ongoing developments include agents such as BI 764532, HPN 328, and Tarlatamab.

• HPN 328: This investigational agent combines CD3 engagement with anti-albumin properties for extended half-life. In SCLC patients, HPN 328 achieved an ORR of 39% in active dose cohorts and up to 46% in other tumor types.
• Tarlatamab: A bispecific T-cell engager (BiTE) targeting DLL3 and CD3, with a phase I ORR of 23.4% and DCR of 51% in SCLC. Phase II trials identified a 10 mg dose as the recommended dose, achieving >30% ORR. It was approved by the FDA on May 16, 2024, for extensive-stage SCLC following platinum-based chemotherapy. Common adverse effects include cytokine release syndrome and neurotoxicity, both manageable.
• BI 764532: An IgG-like T-cell engaging bispecific antibody showing potential in DLL3-positive SCLC and NENs. It enrolled 150 SCLC and 66 non-pulmonary NEN patients in trials. For non-pulmonary NENs, ORR was 26% and DCR was 45%, indicating promising activity.

4. B7-H3-Targeted Therapies

B7-H3 is widely expressed in multiple cancers, especially SCLC, making it an attractive immunotherapeutic target. Therapeutic development includes bispecific antibodies, trispecific antibodies (TCEs), antibody-drug conjugates (ADCs), and CAR-T therapies.

• DS-7300: An ADC conjugated with camptothecin, demonstrated a 52.4% ORR, 12.2-month overall survival (OS), and 5.6-month progression-free survival (PFS) in 22 SCLC patients.
• MHB088C: A domestic Chinese ADC showing superior efficacy over DS-7300 with a 61.3% ORR and 93.5% DCR in SCLC.

5. SEZ6-Targeted Therapy

SEZ6 is a transmembrane protein expressed in SCLC, NENs, and CNS tumors.

• ABBV-706: A SEZ6-targeted agent in phase I/II trials abroad, showing an ORR of 43.8% in SCLC and 28% in non-pulmonary NENs. Although still in early clinical development, it demonstrates promising potential and may become a focal point for global development efforts.

6. Trop2 and Claudin 18.2 Targets

• Trop2 (Trophinin-associated protein): A transmembrane glycoprotein highly expressed in many tumors, including 37.1% of NECs and 15.3% of NETs. Expression rates in pancreatic and gastric NENs are 50% and 40%, respectively.

Given its widespread expression, Trop2-targeted ADCs have been approved, offering new options for patients with high Trop2 expression, especially when other treatments are limited.

• Claudin 18.2: A tight junction protein extensively studied in gastric and pancreatic cancers. While less researched in NENs, a subset of gastric and pancreatic NECs have shown Claudin 18.2 expression, prompting interest in future clinical trial development.

III. Conclusion

With the emergence of new drugs and therapeutic strategies, the outlook for neuroendocrine neoplasm (NEN) treatment is increasingly optimistic. We look forward to the timely completion of clinical trials and the translation of these innovative therapies into clinical practice, providing more effective treatment options for patients. Continued attention to ongoing research and a proactive approach to clinical application will be key to advancing NEN care.