CABINET (Alliance A021602) Trial

[Slide 1] The NEW ENGLAND JOURNAL of MEDICINE Cabozantinib for Advanced Neuroendocrine Tumors A Research Summary based on Chan JA et al. 10.1056/NEJMoa2403991 I Published on September 16, 2024 WHY WAS THE TRIAL DONE? Patients Most patients with extrapancreatic or pancreatic neuroen- 203 adults with extrapancreatic neuroendocrine tumors docrine tumors eventually have disease progression with 95 adults with pancreatic available therapies. A phase 2 trial of cabozantinib, a neuroendocrine tumors small-molecule inhibitor of multiple tyrosine kinases, Median age: 60 to 66 years showed clinical activity in these patient populations, but further study is needed. HOW WAS THE TRIAL CONDUCTED? Mil Patients with progressive, advanced neuroendocrine tumors who had received peptide receptor radionuclide therapy, targeted therapy, or both were grouped by tumor type (ex- trapancreatic or pancreatic), and each cohort was randomly Extrapancreatic NET Cohort Pancreatic NET Cohort assigned in a 2:1 ratio to receive oral cabozantinib or pla- Cabozantinib Placebo Cabozantinib Placebo cebo. The primary end point was progression-free survival. TRIAL DESIGN Phase 3 Placebo-controlled Double-blind Location: 62 sites in the Randomized United States RESULTS N=134 In both tumor-type cohorts, the median progression-free N=69 N=64 N=31 survival was significantly longer with cabozantinib than with placebo. The incidence of confirmed objective re- sponse (a secondary end point) with cabozantinib was 5% Progression-free Survival and 19% among patients with extrapancreatic and pancre- Extrapancreatic NET Cohort Pancreatic NET Cohort atic neuroendocrine tumors, respectively, as compared with 100 0% for placebo. Adverse events of grade 3 or higher oc- curred in nearly two thirds of patients in the cabozantinib 80 groups, as compared with about a quarter in the placebo 60 groups. The trial was stopped early after an interim analy- 4.4 13.8 sis showed superior efficacy with cabozantinib. 3.9 8.4 40 Placebo Cabozantinib LIMITATIONS AND REMAINING QUESTIONS 20 The early termination of the trial could lead to overesti- 0 mation of the treatment effect. 0 6 12 18 24 30 36 Placebo was used instead of an active comparator; how Months since Randomization cabozantinib would compare with an approved treatment is unclear. Clinical trials focusing on appropriate sequencing of Treatment-Related Adverse Events of Grade 3 or Higher therapy are needed. Cabozantinib Placebo 100 CONCLUSIONS 80 62 65 Among patients with previously treated, advanced, 60 progressive extrapancreatic neuroendocrine tumors or 40 pancreatic neuroendocrine tumors, treatment with 27 23 cabozantinib led to longer progression-free survival 20 than placebo. 0 Extrapancreatic Pancreatic NET Cohort NET Cohort NEJM QUICK TAKE Copyright © 2025 Massachusetts Medical Society.

[Slide 1] CABINET Trial Design * Unblinding and crossover allowed Extra-pancreatic R Cabozantinib PD after confirmation of PD by real-time 2:1 central radiology review NET (epNET) 60 mg daily Open-label Pancreatic R Placebo Cabozantinib NET (pNET) 2:1 daily PD* 60 mg daily Stratification factors: Study Endpoints: epNET: Concurrent SSA & Primary site Primary Endpoint per cohort: (midgut Gl/unknown VS. non-midgut - Progression-free survival (PFS) Gl/lung/other) by blinded independent central review (BICR) pNET: Concurrent SSA & Prior sunitinib . Secondary Endpoint per cohort: - Overall survival (OS) - Objective response rate (ORR) - Safety and tolerability ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY --- [Slide 2] pNET Cohort: Progression-Free Survival Blinded Independent Central Review 100 90 CABOZANTINIB Stratified HR = 0.23 PLACEBO 80 (95% CI: 0.12 - 0.42) 70 Median follow-up: 13.8 months log-rank p<0.0001 (95% CI: 10.1 - 19.7 months) 60 Median PFS 50 Cabozantinib = 13.8 months 40 (95% CI: 9.2 - 18.5 months) Placebo = 4.4 months 30 (95% CI: 3.0 - 5.9 months) 20 10 0 0 6 12 18 24 30 36 Time From Randomization (Months) congress BARCELONA 2024 ES MO Jennifer Chan, MD, MPH Content of this presentation is copyright and responsibility of the author Permission is required for re-use --- [Slide 3] CABINET Trial Design * Unblinding and crossover allowed Extra-pancreatic R Cabozantinib PD after confirmation of PD by real-time NET (epNET) 2:1 central radiology review 60 mg daily Open-label Pancreatic R Placebo Cabozantinib NET (pNET) 2:1 daily PD* 60 mg daily Stratification factors: Study Endpoints: epNET: Concurrent SSA & Primary site Primary Endpoint per cohort: (midgut Gl/unknown VS. non-midgut - Progression-free survival (PFS) Gl/lung/other) by blinded independent central review (BICR) pNET: Concurrent SSA & Prior sunitinib Secondary Endpoint per cohort: - Overall survival (OS) - Objective response rate (ORR) - Safety and tolerability ALLIANCE FOR CUNICAL TRIALS IN ONCOLOGY --- [Slide 4] epNET Cohort: Progression-Free Survival Blinded Independent Central Review 100 90 CABOZANTINIB Stratified HR = 0.38 80 PLACEBO (95% Cl: 0.25 — 0.59) 70 log-rank p<0.0001 Progression-Free Survival (%) Median follow-up: 10.2 months 60 (95% CI: 8.2 — 13.8 months) Median PFS 50 Cabozantinib = 8.4 months 40 (95% Cl: 7.6 - 12.7 months) Placebo = 3.9 months 30 (95% Cl: 3.0 — 5.7 months) 20 10 0 0 6 12 18 24 30 36 Time From Randomization (Months) BARCELONA congress 2024 ESMO Jennifer Chan, MD, MPH Content of this presentation is copyright and responsibility of the author. Permission is required for re-use. --- [Slide 5] pNET Cohort: Progression-Free Survival Blinded Independent Central Review 100 90 - CABOZANTINIB Stratified HR = 0.23 PLACEBO 80 (95% Cl: 0.12 - 0.42) 70 Median follow-up: 13.8 months log-rank p<0.0001 Progression-Free Survival (%) (95% Cl: 10.1 - 19.7 months) 60 Median PFS 50 Cabozantinib = 13.8 months 40 (95% Cl: 9.2 — 18.5 months) Placebo = 4.4 months 30 (95% Cl: 3.0 — 5.9 months) 20 10 0 0 6 12 18 24 30 36 Time From Randomization (Months) BARCELONA congress 2024 ESMO Jennifer Chan, MD, MPH Content of this presentation is copyright and responsibility of the author. Permission is required for re-use.

OCR text not available for this slide. View the original post on X for context.