Tag: Neuroendocrine Tumors

Expanding systemic treatment options in neuroendocrine tumors

RR

Insights from the Phase 3 CABINET trial of CABOMETYX® (cabozantinib) including lung and thymic NET

Written by Munveer Bhangoo, MD
Sponsored by Exelixis, Inc.

Neuroendocrine tumors (NETs) are often characterized as a diverse category of diseases that often have widely differing clinical behavior and outcomes.  This behavior is at least in part a reflection of the fact that neuroendocrine cells are scattered through the body. Tumors evolving from neuroendocrine cells vary considerably in terms of location, biological aggressiveness, hormone status, and somatostatin receptor status.1 Taken together, patients with this disease exhibit highly variable clinical outcomes.2  Furthermore, the varied clinical and pathologic features of NETs impact the landscape of clinical trials in this space, with a longstanding need for trials to include a population representative of the disease.3,4

Metastatic neuroendocrine tumors have historically represented an unmet need, particularly for patients experiencing disease progression. In March 2025, the FDA approval of cabozantinib (CABOMETYX®) for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET) or extrapancreatic neuroendocrine tumors (epNET) marked a meaningful advancement in addressing this gap.3,5  As the only FDA-approved option for patients with previously treated NET, regardless of primary site, tumor grade, SSTR expression, or functional disease, CABOMETYX offers an approved treatment option for patients whose disease progresses on an initial therapy.5-11

Let’s review the pivotal trial data from CABINET, a Phase 3 trial enrolling a heterogeneous population with both pancreatic and extrapancreatic NET, which spanned gastrointestinal, lung, thymus, and unknown and other sites of origin.3

CABINET trial design

CABINET was a randomized (2:1), double-blind, placebo-controlled, Phase 3, National Cancer Institute-sponsored trial of CABOMETYX vs placebo in advanced NET patients previously treated with ≥1 FDA-approved systemic therapy, not including an SSA. CABINET enrolled 2 independent cohorts that evaluated patients with pNET (N=99) or epNET (N=199). The starting dose for CABOMETYX was 60 mg, administered orally once daily. The primary endpoint was PFS; ORR and OS were secondary endpoints.3,5

 

Study-Design-Exelixis-NET

*Unblinding and crossover to open-label CABOMETYX allowed after confirmation of progressive disease by real-time central radiology review.5


Primary efficacy results in CABINET

CABOMETYX quadrupled median PFS in pNET and doubled median PFS in epNET5

  • pNET: median PFS was 13.8 months (95% CI: 8.9-17.0; n=66) vs 3.3 months with placebo (95% CI: 2.8-5.7; n=33); HR=0.22 (95% CI: 0.12-0.41); P<0.0001
  • epNET: median PFS was 8.5 months (95% CI: 6.8-12.5; n=132) vs 4.2 months with placebo (95% CI: 3.0-5.7; n=67); HR=0.40 (95% CI: 0.26-0.61); P<0.0001

pNET-PFS-CABOMETYX

 

epNET-PFS-CABOMETYX


Exploratory subgroup analysis: PFS results in patients with lung/thymus site origin15

  • In the lung /thymus subgroup, median PFS was 8.2 months (95% CI: 6.0-NE; n=33) vs 2.7 months (95% CI: 1.9-NE; n=16) with placebo; HR=0.19 (95% CI: 0.06-0.54)

Lung-Thymus-Subgroup-PFS-CABOMETYX

 

Observed outcomes should be interpreted with caution because of the relatively small subgroup size. Subgroups were not powered to show differences between treatment arms, and results should be considered hypothesis generating.

CABINET safety results

The safety profile observed in CABINET was consistent with the known CABOMETYX safety profile, and no new safety signals were identified in the trial.3

AE-CABOMETYX

  • Commonly occurring treatment-related Grade 3 and 4 adverse events in the lung/thymus subgroup included fatigue, hypertension, diarrhea, and PPE15

*These ARs are grouped terms.5 For details, please see full Prescribing Information.
†NCI CTCAE Version 5.0.

CABOMETYX dosing for NET

The recommended starting dose of CABOMETYX for adult and pediatric patients 12 years of age and older and ≥40 kg is 60 mg once daily until disease progression or unacceptable toxicity (with dose reductions to 40 mg and 20 mg once daily). The recommended starting dose for pediatric patients 12 years of age and older and <40 kg is 40 mg (with dose reductions to 20 mg daily and 20 mg every other day). If previously receiving lowest dose, resume at same dose. If lowest dose not tolerated, discontinue CABOMETYX. The median average daily dose of CABOMETYX treatment was 41 mg in the pNET cohort and 43 mg in the epNET cohort.5

It is important to note that the overall efficacy results of the CABINET trial were achieved in the context of dose modifications.16

  • pNET: AR-related dose reductions occurred in 49% of patients receiving CABOMETYX vs 16% with placebo. Discontinuation due to ARs occurred in 19% of patients receiving CABOMETYX vs 10% with placebo
  • epNET: AR-related dose reductions occurred in 38% of patients receiving CABOMETYX vs 6% with placebo. Discontinuation due to ARs occurred in 28% of patients receiving CABOMETYX vs 19% receiving placebo

In summary, based on the CABINET data:

Cabozantinib became the first systemic therapy indicated for previously treated NETs regardless of origin based on the landmark Phase 3 CABINET trial.3,5,7-11 Furthermore, the broad eligibility criteria for CABINET allowed for the inclusion of patients irrespective of functional status or expression of somatostatin receptors.3

Taken together, the approval of cabozantinib represents an important advancement in the management of previously treated patients with advanced NETs across diverse sites of origin, including those with lung and thymic origin.3,5,17


Dr Bhangoo received a fee for participating in the development of this article, and his comments reflect his opinions and are not intended to constitute medical advice for individual patients

AR=adverse reaction; CI=confidence interval; DCR=disease control rate; ECOG PS=Eastern Cooperative Oncology Group performance status; epNET=extrapancreatic neuroendocrine tumor; HR=hazard ratio; NET=neuroendocrine tumor; ORR=overall response rate; OS=overall survival; NE=not estimable; PET=positron emission tomography; PFS=progression-free survival; pNET=pancreatic neuroendocrine tumor; PPE=palmar-plantar erythrodysesthesia; PRRT=peptide receptor radionuclide therapy.

INDICATIONS

CABOMETYX® (cabozantinib) is indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET).

CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated extrapancreatic neuroendocrine tumors (epNET).

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: CABOMETYX can cause severe and fatal hemorrhages. The incidence of Grade 3-5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3-4 hemorrhage and before surgery. Do not administer to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, and gastrointestinal (GI) perforations, including fatal cases, each occurred in 1% of CABOMETYX patients. Monitor for signs and symptoms, and discontinue CABOMETYX in patients with Grade 4 fistulas or GI perforation.

Thromboembolic Events: CABOMETYX can cause arterial or venous thromboembolic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events have occurred. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. In CABINET (n=195), hypertension occurred in 65% (26% Grade 3) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with antihypertensive therapy or for hypertensive crisis.

Cardiac Failure: CABOMETYX can cause severe and fatal cardiac failure. Cardiac failure occurred in 0.5% of patients treated with CABOMETYX as a single agent, including fatal cardiac failure in 0.1% of patients. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Withhold and resume at a reduced dose upon recovery or permanently discontinue depending on the severity.

Diarrhea: CABOMETYX can cause diarrhea and it occurred in 62% (10% Grade 3) of treated patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1; resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): CABOMETYX can cause PPE and it occurred in 45% of treated patients (13% Grade 3). Withhold CABOMETYX until PPE resolves or decreases to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): CABOMETYX can cause ONJ and it occurred in <1% of treated patients. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures. Withhold CABOMETYX for development of ONJ until complete resolution; resume at a reduced dose.

Impaired Wound Healing: CABOMETYX can cause impaired wound healing. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): CABOMETYX can cause RPLS. Perform evaluation for RPLS and diagnose by characteristic finding on MRI any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: CABOMETYX can cause thyroid dysfunction, primarily hypothyroidism, and it occurred in 19% of treated patients (0.4% Grade 3). Assess for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitor for signs and symptoms during treatment.

Hypocalcemia: CABOMETYX can cause hypocalcemia, with the highest incidence in DTC patients. Based on the safety population, hypocalcemia occurred in 13% of CABOMETYX patients (2% Grade 3 and 1% Grade 4). Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume CABOMETYX at a reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.

ADVERSE REACTIONS The most common (≥20%) adverse reactions are: CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong or Moderate CYP3A4 Inducers: If coadministration with strong or moderate CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Pediatric Use: Physeal widening has been observed in children with open growth plates when treated with CABOMETYX. Physeal and longitudinal growth monitoring is recommended in children (12 years and older) with open growth plates. Consider interrupting or discontinuing CABOMETYX if abnormalities occur. The safety and effectiveness of CABOMETYX in pediatric patients less than 12 years of age have not been established.

Please see accompanying full Prescribing Information by clicking here.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

References:
1. Sultana Q, Kar J, Verma A, et al. A comprehensive review on neuroendocrine neoplasms: presentation, pathophysiology and management. J Clin Med. 2023;12(15):5138
2. Dasari A, Wallace K, Halperin DM, et al. Epidemiology of neuroendocrine neoplasms in the US. JAMA Netw Open. 2025;8(6):e2515798. doi:10.1001/jamanetworkopen.2025.15798.
3. Chan JA, Geyer S, Zemla T, et al. Phase 3 trial of cabozantinib to treat advanced neuroendocrine tumors. N Engl J Med. 2024; Published online September 16, 2024. doi:10.1056/NEJMoa2403991.
4. Yang K, Li J, Cheng Y, Bai C. Evolving landscape of clinical trials in gastroenteropancreatic neuroendocrine neoplasms in the past two decades. Endocr Connect. 2023;12(4): e220441. doi:10.1530/EC-22-0441.
5. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc.
6. Bidani K, Marinovic AG, Moond V, Harne P, Broder A, Thosani N. Treatment of pancreatic neuroendocrine tumors: beyond traditional surgery and targeted therapy. J Clin Med. 2025;14(10):3389. doi:10.3390/jcm14103389.
7. LUTATHERA® (lutetium Lu-177 dotatate) Prescribing Information. Novartis Pharmaceuticals Corporation.
8. AFINITOR® (everolimus) Prescribing Information. Novartis Pharmaceuticals Corporation.
9. SUTENT® (sunitinib malate) Prescribing Information. Pfizer, Inc.
10. SOMATULINE® DEPOT (lanreotide) Prescribing Information. Ipsen Pharma Biotech.
11. SANDOSTATIN® LAR DEPOT (octreotide acetate) Prescribing Information. Novartis Pharmaceuticals Corporation.
12. Chan JA, Geyer S, Zemla T, et al. Phase 3 trial of cabozantinib in previously treated advanced neuroendocrine tumors [supplementary appendix]. N Engl J Med. 2024; Published online September 16, 2024. doi:10.1056/ NEJMoa2403991.
13. US Food and Drug Administration. FDA approves new treatment for certain digestive tract cancers. January 26, 2018. Accessed September 5, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-certain-digestive-tract-cancers. 14. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514-523.
15. Wolin EM, Zemla T, Strosberg JR, et al. Efficacy and safety of cabozantinib for advanced lung and thymus neuroendocrine tumors after progression on prior therapy: subgroup analysis of phase 3 CABINET trial (Alliance A021602). Poster presented at European Society for Medical Oncology Congress; October 17-21, 2025.
16. Data on file. Exelixis, Inc.
17. Oronsky N, Ma PC, Morgensztern D, Carter CA. Nothing but NET: a review of neuroendocrine tumors and carcinomas. Neoplasia. 2017;19(12):991-1002.

©2026 Exelixis, Inc.      CA‐3900     04/26

Extrapulmonary Neuroendocrine Carcinoma: Clinical Overview and Advances in DLL3 Targeted Therapy

RR

Written by: Dr. Eric Lander
Sponsored by Boehringer Ingelheim

Extrapulmonary neuroendocrine carcinomas (EP-NECs) are rare and phenotypically aggressive malignancies arising from neuroendocrine cells. While EP-NECs are currently managed with conventional chemotherapy in most cases, numerous therapies are in development which may show promise to improve disease management and prognosis for patients.

EP-NECs originate from neuroendocrine cells located in many different organs, most commonly arising from the GI tract or pancreas, followed by genitourinary tract and gynecologic organs [1]. NECs are often confused with neuroendocrine tumors (NETs). Though both NETs and NECs arise from epithelial neuroendocrine cells expressing pan-cytokeratin, synaptophysin, and Chromogranin A, by definition NETs are well-differentiated while NECs are poorly differentiated. Though NETs can be defined as grades 1-3, they are more commonly grade 1-2 (Ki-67 <20%); NECs must be grade 3 (Ki-67 ≥20% and/or mitotic count >20 per mm2), and the Ki-67 usually exceeds 50%. The remainder of this article will focus on EP-NECs and will not include discussion about grade 3 NETs. Please reference the NCCN Guidelines or the Expert Consensus Practice Recommendations of the North American Neuroendocrine Tumor Society (NANETS) to learn about management strategies for G3 NETs [2].

EP-NECs most commonly result from TP53 and RB1 inactivation, similar to small cell lung neuroendocrine carcinoma (SCLC), though EP-NECs often contribute their own unique genetic mutational background (e.g. BRAF, KRAS, PIK3CA, APC, etc.) based on their site of origin, unlike most SCLC cases. If the primary site of EP-NEC origin is unknown, as occurs in up to one third of cases, encouraging pathology to perform transcription factor IHC can facilitate a site of origin assignment. Certain transcription factors (in parentheses) are unique to each organ: midgut (CDX2); pancreas (PAX6, PAX8, islet 1, or PR); rectum (SATB2); lung (OTP, TTF-1). Delineating site of origin is of particular importance as EP-NEC may be treated according to its primary site of origin at time of relapse following platinum-based chemotherapy.

Since EP-NECs are aggressive, high-grade carcinomas, patients most commonly have metastatic disease at the time of presentation. Many patients initially present for the first time to the hospital because some symptom of their disease, such as severe pain or fracture in the case of bone metastases, necessitated their presentation to the emergency room. Initial workup following tissue diagnosis should consist of imaging of the chest/abdomen/pelvis with CT or FDG-PET/CT imaging. Notably, high grade NECs have lower somatostatin receptor (SSTR) expression than NETs; therefore, FDG is preferred over SSTR-PET radiotracers [3, 4]. For EP-NECs, the incidence of brain metastases is less than 2%; thus, brain MRI should only be considered at time of diagnosis in cases of high disease burden or in symptomatic patients [5].

For molecular workup, since many EP-NECs can harbor mutations in BRAF (particularly in colorectal EP-NECs) and tumor agnostic indications for other therapies exist, NGS testing may be considered. Mismatch repair (MMR) testing or MSI testing is also recommended since 10% of NECs are deficient MMR, opening the door to immunotherapies as therapeutic options. Delta-like ligand 3 (DLL3) is an emerging target in EP-NEC; reserving tissue for DLL3 IHC is recommended in cases where patients may enroll in a clinical trial investigating a drug targeting DLL3 – which will be discussed later.

For the management of localized EP-NEC, discussion at tumor board is recommended to provide a multidisciplinary treatment approach. Data surrounding the long-term curative potential of surgery is mixed based on the tumor site of origin when surgery is often invasive, and patients remain at high risk of metastatic disease recurrence. For this reason, neoadjuvant or adjuvant platinum-based chemotherapy may be paired with surgery. Many experts will favor neoadjuvant platinum/etoposide chemotherapy to test the biology of the disease and decrease theoretical risk of micro-metastasis prior to surgery. However, many patients will present to medical oncology following tumor resection, in which case adjuvant chemotherapy may be discussed with eligible patients. Otherwise, definitive chemoradiation for organ preservation may be considered with platinum plus etoposide as the recommended radiosensitizing agents. The accruing French NEONEC trial will prospectively test neoadjuvant chemotherapy followed by surgery or chemoradiation in patients to hopefully offer clarity regarding the optimal multidisciplinary approach [6].

In the case of metastatic EP-NECs, the treatment paradigm initially parallels that of SCLC. Enrollment in clinical trial when available or platinum plus etoposide for four to six cycles remains the current first-line standard-of-care. Unlike SCLC, atezolizumab is not written into the NCCN guidelines for EP-NEC. EP-NEC patients were not included in the IMpower133 trial, and a subsequent retrospective study of a small EP-NEC patient cohort did not demonstrate a PFS or OS benefit of adding atezolizumab to platinum-based chemotherapy [7]. Larger patient numbers in a prospective trial are likely required to detect a benefit of atezolizumab—an ongoing phase II/III SWOG trial is investigating platinum/etoposide with or without atezolizumab to address this evidence gap [8].

Most patients will achieve significant initial tumor shrinkage or disease control in response to carboplatin or cisplatin plus etoposide, especially if Ki-67 ≥ 55%, but the tumor response is not durable in most cases, and tumors are less responsive to chemotherapy upon disease progression. There is currently no standard second- or third-line treatment option for EP-NEC. When assessing patients’ treatment goals and performance status, best supportive care with hospice is a very reasonable approach in light of EP-NEC’s generally poor prognosis upon time of disease relapse.

When second-line and beyond therapy lines are being considered, enrollment in clinical trial is the preferred option for eligible patients. If patients experienced a durable response lasting at least 6 months following first-line platinum/etoposide, rechallenge may be considered. Among patients with gastrointestinal and pancreatic EP-NECs, second-line treatment with FOLFIRI has the most prospective data and lends a 6-month overall survival rate of 60% [9], while gynecologic EP-NEC has data for topotecan, taxanes, single agent irinotecan, or the combination of topotecan, paclitaxel, and bevacizumab that provided an 8-month median PFS in a small retrospective cohort [10]. For patients with dMMR/MSI-H or TMB-High disease, ipilimumab/nivolumab or pembrolizumab may be considered where dual checkpoint inhibition potentially yields a higher response rate [11]. For patients with BRAF V600E mutations, a STAR trial through SCRI is available to open at most US Oncology practices employing BRAF/MEK inhibition with dabrafenib/trametinib and includes patients with EP-NEC [12].

The most promising emerging therapies for EP-NEC remain those in clinical trials targeting DLL3—this assertion is based on extrapolation of promising data from the DeLLphi trials using tarlatamab in SCLC, and initial results investigating obrixtamig in SCLC and EP-NEC. Both tarlatamab and obrixtamig are DLL3/CD3 bispecific T-cell engagers. While DLL3 is expressed in approximately 90% of SCLC, rates of DLL3 expression in EP-NEC are lower [13]. Despite this, most patients with negative DLL3 expression in the DeLLphi-301 trial employing tarlatamab in refractory SCLC still experienced disease control with tarlatamab monotherapy [14]. Emerging therapeutics targeting DLL3 are mostly either DLL3/CD3 bispecific T-cell engagers or DLL3-targeting antibody-drug conjugates.

There are several clinical trials investigating DLL3/CD3 bispecific T-cell engagers and DLL3 antibody-drug conjugates in EP-NEC patients. At the time of writing, three different phase I studies are open and actively recruiting through US Oncology Network practices that include patients with EP-NEC, all of which require tissue for DLL3 IHC testing [15, 16, 17]. Among investigational DLL3/CD3 bispecific agents, Boehringer Ingelheim’s obrixtamig has shown promising results.  Data presented in 2025 from the phase I dose-escalation trial of obrixtamig showed that heavily-pretreated EP-NEC patients with high DLL3 expression had an overall response rate of 40% and duration of response of 7.9 months [18]. While not open in the US Oncology Network, the phase II DAREON-5 trial with obrixtamig is testing two different doses and includes patients with relapsed EP-NEC [19]. The results of ongoing obrixtamig trials will be important to follow and could potentially alter our future therapeutic approach to EP-NEC.

Standard-of-care options in EP-NEC do not yield survival much past one year in most patients. However, for the first time in decades, numerous emerging therapeutic options afford hope to significantly improve the treatment tolerability and prognosis for patients with this aggressive disease.

References:

  1. Dasari A, Mehta K, Byers LA, Sorbye H, Yao JC. Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: A SEER database analysis of 162,983 cases. Cancer. 2018;124(4):807-815. doi:10.1002/cncr.31124.
  2. Eads JR, Halfdanarson TR, Asmis T, et al. Expert Consensus Practice Recommendations of the North American Neuroendocrine Tumor Society for the management of high grade gastroenteropancreatic and gynecologic neuroendocrine neoplasms. Endocr Relat Cancer. 2023;30(8):e220206. Published 2023 Jul 11. doi:10.1530/ERC-22-0206.
  3. Tomimaru Y, Eguchi H, Tatsumi M, et al. Clinical utility of 2-[(18)F] fluoro-2-deoxy-D-glucose positron emission tomography in predicting World Health Organization grade in pancreatic neuroendocrine tumors. Surgery. 2015;157(2):269-276. doi:10.1016/j.surg.2014.09.011.
  4. Majala S, Seppänen H, Kemppainen J, et al. Prediction of the aggressiveness of non-functional pancreatic neuroendocrine tumors based on the dual-tracer PET/CT. EJNMMI Res. 2019;9(1):116. Published 2019 Dec 23. doi:10.1186/s13550-019-0585-7.
  5. Alese OB, Jiang R, Shaib W, et al. High-Grade Gastrointestinal Neuroendocrine Carcinoma Management and Outcomes: A National Cancer Database Study. Oncologist. 2019;24(7):911-920. doi:10.1634/theoncologist.2018-0382.
  6. Efficacy of neoadjuvant chemotherapy in terms of DFS in patients with locally advanced, poorly differentiated digestive neuroendocrine carcinomas (NEONEC). ClinicalTrials.gov identifier NCT04268121. Updated 2025. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT04268121
  7. Ho IW, Chiang NJ, Lai JI, et al. Efficacy of atezolizumab combined with platinum and etoposide in the treatment of extrapulmonary neuroendocrine carcinoma. Oncologist. 2025;30(3):oyae372. doi:10.1093/oncolo/oyae372.
  8. Evaluating the addition of the immunotherapy drug atezolizumab to standard chemotherapy treatment for advanced or metastatic neuroendocrine carcinomas that originate outside the lung (SWOG S2012). ClinicalTrials.gov identifier NCT05058651. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05058651
  9. Walter T, Lievre A, Coriat R, et al. Bevacizumab plus FOLFIRI after failure of platinum-etoposide first-line chemotherapy in patients with advanced neuroendocrine carcinoma (PRODIGE 41-BEVANEC): a randomised, multicentre, non-comparative, open-label, phase 2 trial. Lancet Oncol. 2023;24(3):297-306. doi:10.1016/S1470-2045(23)00001-3.
  10. Frumovitz M, Munsell MF, Burzawa JK, et al. Combination therapy with topotecan, paclitaxel, and bevacizumab improves progression-free survival in recurrent small cell neuroendocrine carcinoma of the cervix. Gynecol Oncol. 2017;144(1):46-50. doi:10.1016/j.ygyno.2016.10.040.
  11. Patel SP, Mayerson E, Chae YK, et al. A phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609: High-grade neuroendocrine neoplasm cohort. Cancer. 2021;127(17):3194-3201. doi:10.1002/cncr.33591.
  12. ClinicalTrials.gov. Clinical study to further evaluate the efficacy of dabrafenib plus trametinib in patients with rare BRAF V600E mutation-positive unresectable or metastatic solid tumors. Identifier NCT05868629. Updated 2025. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05868629
  13. Serrano AG, Rocha P, Freitas Lima C, et al. Delta-like ligand 3 (DLL3) landscape in pulmonary and extra-pulmonary neuroendocrine neoplasms. NPJ Precis Oncol. 2024;8(1):268. Published 2024 Nov 19. doi:10.1038/s41698-024-00739-y.
  14. Ahn MJ, Cho BC, Felip E, et al. Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer. N Engl J Med. 2023;389(22):2063-2075. doi:10.1056/NEJMoa2307980.
  15. ClinicalTrials.gov. A study of Peluntamig (PT217) in patients with neuroendocrine carcinomas expressing DLL3 (the SKYBRIDGE study). Identifier NCT05652686. Updated 2025. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05652686
  16. ClinicalTrials.gov. A study of IDE849 in patients with DLL3 expressing tumors including small cell lung cancer. Identifier NCT07174583. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT07174583
  17. ClinicalTrials.gov. A Phase Ib/II, open-label, multi-center study of ZL-1310 in participants with selected solid tumors. Identifier NCT06885281. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT06885281
  18. Capdevila J, Gambardella V, Kuboki Y, et al. Efficacy and safety of the DLL3/CD3 T-cell engager obrixtamig in patients with extrapulmonary neuroendocrine carcinomas with high or low DLL3 expression: Results from an ongoing phase I trial. J Clin Oncol. 2025;43(16_suppl):3004. doi: 10.1200/JCO.2025.43.16_suppl.3004.
  19. ClinicalTrials.gov. DAREON-5: A study to test whether different doses of BI 764532 help people with small cell lung cancer or other neuroendocrine cancers. Identifier NCT05882058. Updated 2026. Accessed March 9, 2026. https://clinicaltrials.gov/study/NCT05882058

CABOMETYX® (Cabozantinib)

RR

The FDA on March 26, 2025, approved CABOMETYX® for adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic NeuroEndocrine Tumors (pNET) and well-differentiated extra-pancreatic NeuroEndocrine Tumors (epNET). CABOMETYX® is a product of Exelixis, Inc.