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Clinical Trial
. 2025 Feb 13;392(7):653-665.
doi: 10.1056/NEJMoa2403991. Epub 2024 Sep 16.

Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors

Jennifer A Chan  1 , Susan Geyer  2 , Tyler Zemla  2 , Michael V Knopp  3 , Spencer Behr  4 , Sydney Pulsipher  2 , Fang-Shu Ou  2 , Amylou C Dueck  5 , Jared Acoba  6 , Ardaman Shergill  7 , Edward M Wolin  8 , Thorvardur R Halfdanarson  9 , Bhavana Konda  10 , Nikolaos A Trikalinos  11   12 , Bernard Tawfik  13 , Nitya Raj  14 , Shagufta Shaheen  15 , Namrata Vijayvergia  16 , Arvind Dasari  17 , Jonathan R Strosberg  18 , Elise C Kohn  19 , Matthew H Kulke  20   21 , Eileen M O'Reilly  13 , Jeffrey A Meyerhardt  1
Affiliations
Clinical Trial

Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors

Jennifer A Chan et al. N Engl J Med. .

Abstract

Background: Treatment options for patients with advanced neuroendocrine tumors are limited. The efficacy of cabozantinib in the treatment of previously treated, progressive extrapancreatic or pancreatic neuroendocrine tumors is unclear.

Methods: We enrolled two independent cohorts of patients - those with extrapancreatic neuroendocrine tumors and those with pancreatic neuroendocrine tumors - who had received peptide receptor radionuclide therapy or targeted therapy or both. Patients were randomly assigned in a 2:1 ratio to receive cabozantinib at a dose of 60 mg daily or placebo. The primary end point was progression-free survival as assessed by blinded independent central review. Key secondary end points included objective response, overall survival, and safety.

Results: In the cohort of 203 patients with extrapancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 8.4 months, as compared with 3.9 months with placebo (stratified hazard ratio for progression or death, 0.38; 95% confidence interval [CI], 0.25 to 0.59; P<0.001). In the cohort of 95 patients with pancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 13.8 months, as compared with 4.4 months with placebo (stratified hazard ratio, 0.23; 95% CI, 0.12 to 0.42; P<0.001). The incidence of confirmed objective response with cabozantinib was 5% and 19% among patients with extrapancreatic and pancreatic neuroendocrine tumors, respectively, as compared with 0% with placebo. Grade 3 or higher adverse events were noted in 62 to 65% of the patients treated with cabozantinib, as compared with 23 to 27% of the patients who received placebo. Common treatment-related adverse events of grade 3 or higher included hypertension, fatigue, diarrhea, and thromboembolic events.

Conclusions: Cabozantinib, as compared with placebo, significantly improved progression-free survival in patients with previously treated, progressive advanced extrapancreatic or pancreatic neuroendocrine tumors. Adverse events were consistent with the known safety profile of cabozantinib. (Funded by the National Cancer Institute and others; CABINET ClinicalTrials.gov number, NCT03375320.).

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Figures

Figure 1.
Figure 1.. Progression-free Survival by Blinded Independent Central Review and Overall Survival of Patients Enrolled in the Extra-pancreatic NET Cohort
Panel A demonstrates the results of progression-free survival (PFS), as assessed retrospectively per RECIST 1.1 criteria by blinded independent central review (BICR), for patients enrolled in the epNET cohort. For the comparison between treatment groups, two-sided stratified log-rank P-value <0.001. Panel B demonstrates the results of overall survival of patients enrolled in the epNET cohort. Panel C demonstrates the results of PFS according to stratification factors and selected clinical subgroups of patients enrolled in the epNET cohort. For the Tumor Grade subgroup analysis, the “Unknown” subgroup is not displayed in the figure due to having zero PFS events in at least one treatment arm.
Figure 1.
Figure 1.. Progression-free Survival by Blinded Independent Central Review and Overall Survival of Patients Enrolled in the Extra-pancreatic NET Cohort
Panel A demonstrates the results of progression-free survival (PFS), as assessed retrospectively per RECIST 1.1 criteria by blinded independent central review (BICR), for patients enrolled in the epNET cohort. For the comparison between treatment groups, two-sided stratified log-rank P-value <0.001. Panel B demonstrates the results of overall survival of patients enrolled in the epNET cohort. Panel C demonstrates the results of PFS according to stratification factors and selected clinical subgroups of patients enrolled in the epNET cohort. For the Tumor Grade subgroup analysis, the “Unknown” subgroup is not displayed in the figure due to having zero PFS events in at least one treatment arm.
Figure 1.
Figure 1.. Progression-free Survival by Blinded Independent Central Review and Overall Survival of Patients Enrolled in the Extra-pancreatic NET Cohort
Panel A demonstrates the results of progression-free survival (PFS), as assessed retrospectively per RECIST 1.1 criteria by blinded independent central review (BICR), for patients enrolled in the epNET cohort. For the comparison between treatment groups, two-sided stratified log-rank P-value <0.001. Panel B demonstrates the results of overall survival of patients enrolled in the epNET cohort. Panel C demonstrates the results of PFS according to stratification factors and selected clinical subgroups of patients enrolled in the epNET cohort. For the Tumor Grade subgroup analysis, the “Unknown” subgroup is not displayed in the figure due to having zero PFS events in at least one treatment arm.
Figure 2:
Figure 2:. Progression-free Survival According to Blinded Independent Central Review and Overall Survival of Patients Enrolled in the Pancreatic NET Cohort
Panel A demonstrates the results of progression-free survival (PFS), as assessed retrospectively per RECIST 1.1 criteria by blinded independent central review (BICR), for patients enrolled in the pNET cohort. For the comparison between treatment groups, two-sided stratified log-rank P-value <0.001. Panel B demonstrates the results of overall survival of patients enrolled in the pNET cohort. Panel C demonstrates the results of PFS according to stratification factors and selected clinical subgroups of patients enrolled in the pNET cohort. For the Histologic Differentiation subgroup analysis, “Moderately differentiated” and “Not specified” subgroups are not displayed in the figure due to having zero PFS events in at least one treatment arm.
Figure 2:
Figure 2:. Progression-free Survival According to Blinded Independent Central Review and Overall Survival of Patients Enrolled in the Pancreatic NET Cohort
Panel A demonstrates the results of progression-free survival (PFS), as assessed retrospectively per RECIST 1.1 criteria by blinded independent central review (BICR), for patients enrolled in the pNET cohort. For the comparison between treatment groups, two-sided stratified log-rank P-value <0.001. Panel B demonstrates the results of overall survival of patients enrolled in the pNET cohort. Panel C demonstrates the results of PFS according to stratification factors and selected clinical subgroups of patients enrolled in the pNET cohort. For the Histologic Differentiation subgroup analysis, “Moderately differentiated” and “Not specified” subgroups are not displayed in the figure due to having zero PFS events in at least one treatment arm.
Figure 2:
Figure 2:. Progression-free Survival According to Blinded Independent Central Review and Overall Survival of Patients Enrolled in the Pancreatic NET Cohort
Panel A demonstrates the results of progression-free survival (PFS), as assessed retrospectively per RECIST 1.1 criteria by blinded independent central review (BICR), for patients enrolled in the pNET cohort. For the comparison between treatment groups, two-sided stratified log-rank P-value <0.001. Panel B demonstrates the results of overall survival of patients enrolled in the pNET cohort. Panel C demonstrates the results of PFS according to stratification factors and selected clinical subgroups of patients enrolled in the pNET cohort. For the Histologic Differentiation subgroup analysis, “Moderately differentiated” and “Not specified” subgroups are not displayed in the figure due to having zero PFS events in at least one treatment arm.
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