Chandrikha Chandrasekharan, MBBS

The panel focuses on the use of cabozantinib in grade 3 neuroendocrine tumors, a population increasingly encountered in clinical practice, possibly reflecting more standardized Ki-67 testing across community settings.

Faculty review the key safety findings from CABINET, emphasizing that no unexpected signals emerged relative to prior experience with cabozantinib in other malignancies.

The panel interprets the overall survival data from CABINET and the implications of the trial's early termination. Faculty note that overall survival remains immature and is confounded by permitted placebo crossover, emphasizing that the study was not powered for this endpoint and that progression-free survival was the primary measure.

Faculty present the progression-free survival findings from CABINET across both cohorts, emphasizing the encouraging and practice-changing results in a heavily pretreated population. In the pancreatic neuroendocrine tumor cohort, median progression-free survival exceeded 13 months with cabozantinib versus roughly 4 months with placebo.

The panel reviews the design of the CABINET trial, a large phase 3, randomized, double-blind, placebo-controlled study evaluating cabozantinib in advanced neuroendocrine tumors. Faculty describe the trial's ambitious and inclusive structure, enrolling both pancreatic and extra-pancreatic cohorts, with the extra-pancreatic group encompassing lung, thymic, gastrointestinal, small bowel, and unknown primary tumors. Patients were randomized 2:1 to cabozantinib 60 mg daily versus placebo. The discussion notes that the protocol was modified after launch to require progression on at least one prior approved therapy, reflecting the evolving treatment landscape. Faculty emphasize the broad eligibility, including grades 1 through 3 well-differentiated disease, and compare baseline characteristics with landmark neuroendocrine trials. They highlight that this was a modern-era study, with many patients having received prior radioligand therapy, everolimus, sunitinib, or capecitabine, underscoring how the heavily pretreated population reflects contemporary real-world sequencing and sets the trial apart from earlier studies.

Learn how NET therapy is tailored—surgery when curable, somatostatin analogs first, then PRRT, targeted drugs, and liver-directed options.

The panel examines how treatment is selected across the disease course in neuroendocrine tumors, beginning with the distinction between early-stage and advanced disease.

A multidisciplinary panel of oncologists opens this OncLive Peer Exchange on evolving strategies in neuroendocrine tumor management, introducing the faculty and framing the discussion around CABINET trial data and current clinical practice.

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.

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 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 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 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 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 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 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 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 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 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 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 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 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.