Clinical Perspectives on the Treatment of Neuroendocrine Tumors

Panelists discuss how the understanding and treatment of neuroendocrine tumors (NETs) has evolved dramatically over the past 3 to 4 decades, with incidence rising to nearly 200,000 in the population and survival extending from just a few years to 8 to 10-plus years through advances from single-agent somatostatin analogs to targeted therapies.

Panelists discuss how neuroendocrine tumors (NETs) are defined as cancers of neuroendocrine cells that can develop almost anywhere in the body, are classified as functional or nonfunctional, and are categorized as well-differentiated (graded by Ki-67 index) or poorly differentiated neuroendocrine carcinomas with very aggressive biology.

Panelists discuss how initial treatment recommendations require a comprehensive framework considering tumor site of origin, symptom burden, disease grade and distribution, somatostatin receptor status, and patient factors, with somatostatin analogs typically serving as first-line therapy for appropriate patients based on data from the PROMID and CLARINET trials.

Panelists discuss how treatment decisions after progression on first-line somatostatin analog therapy must consider disease location, symptom burden, quality of life impact, and patient comorbidities when choosing between options like peptide receptor radionuclide therapy (PRRT), targeted therapies (mTOR inhibitors, tyrosine kinase inhibitors), or local-regional treatments.

Panelists discuss how peptide receptor radionuclide therapy (PRRT) has traditionally been the go-to second-line treatment after somatostatin analog progression, though there’s hesitancy due to it being a “one-shot deal,” and growing interest in moving PRRT to earlier lines for patients with high disease burden.

Panelists discuss how the treatment landscape has been shaped by landmark trials including the RADIANT studies (everolimus for pancreatic and other neuroendocrine tumors [NETs]), sunitinib studies for pancreatic NETs, the NETTER-1 trial (lutetium-177 dotatate), and capecitabine/temozolomide data, providing multiple targeted therapy options that have dramatically improved patient outcomes.

Panelists discuss how cabozantinib approval helps fill treatment gaps for patients who have exhausted standard therapies like somatostatin analogs, peptide receptor radionuclide therapy (PRRT), and everolimus, providing a new option for healthy patients seeking additional treatment lines in this indolent but progressive disease.

Panelists discuss how the CABINET trial enrolled nearly 300 patients with well-differentiated neuroendocrine tumors (NETs) (mostly grade 1-2) who were heavily pretreated, demonstrating cabozantinib’s superiority over placebo with over 8 months progression-free survival vs 3 months, with manageable toxicity and effective dose reduction strategies.

Panelists discuss how the pancreatic neuroendocrine tumor (NET) cohort in CABINET showed particularly impressive results with 13.8 months median progression-free survival vs 4.4 months for placebo, an 18% to 19% response rate, and activity even in patients previously treated with sunitinib, though sequencing decisions remain complex.

Panelists discuss how cabozantinib showed promising activity in the challenging well-differentiated grade 3 neuroendocrine tumor (NET) population (around 25% response rate), offering a nonchemotherapy option for these aggressive tumors that often lack uniform somatostatin receptor expression.

Panelists discuss how recent trials like COMPETE (comparing peptide receptor radionuclide therapy [PRRT] vs everolimus) and other PRRT studies provide additional evidence supporting PRRT’s role, though questions about optimal sequencing with oral agents like cabozantinib remain unanswered and will require real-world experience to resolve.

Panelists discuss how cabozantinib’s flexible FDA label allows physician discretion in treatment sequencing after progression, potentially moving the drug to earlier lines when rapid response is needed, while considering patient-specific factors like hypertension and thromboembolic risk.

Panelists discuss how managing cabozantinib’s adverse effects requires proactive patient counseling about expected dose reductions, aggressive supportive care for manageable toxicities like hypertension and diarrhea, frequent early monitoring, and recognition that the median effective dose (40 mg) is lower than the starting dose (60 mg).

Panelists discuss how the future of neuroendocrine tumor (NET) treatment looks promising with new agents in development including nonpeptide drug conjugates, immune therapies, chimeric antigen receptor (CAR) T approaches, and improved tyrosine kinase inhibitors (TKIs), emphasizing the importance of thoughtful sequencing, patient access, and maintaining focus on the individual patient experience.