Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors

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

Source: DOI: 10.1056/NEJMoa240399

Dr. Maen Hussein's Thoughts

This actually was mentioned during the Neil Love /FCS summit, it seems more tolerable than Afinitor, so is another option for relapsed refractory disease.

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.)

Author Affiliations

¹Dana–Farber Cancer Institute, Boston; ²Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN; ³Wright Center of Innovation and the Imaging and Radiation Oncology Core, University of Cincinnati, Cincinnati; ⁴University of California, San Francisco, San Francisco; ⁵Alliance Statistics and Data Management Center, Mayo Clinic, Scottsdale, AZ; ⁶University of Hawaii Cancer Center, Honolulu; ⁷Alliance Protocol Operations Office, University of Chicago, Chicago; ⁸Mount Sinai Medical Center, New York; ⁹Mayo Clinic Comprehensive Cancer Center, Rochester, MN; ¹⁰Ohio State University Comprehensive Cancer Center, Columbus; ¹¹Washington University School of Medicine, St. Louis; ¹²Siteman Cancer Center, St. Louis; ¹³University of New Mexico Comprehensive Cancer Center, Albuquerque; ¹⁴Memorial Sloan Kettering Cancer Center, New York; ¹⁵Stanford Cancer Center, Stanford, CA; ¹⁶Fox Chase Cancer Center, Philadelphia; ¹⁷M.D. Anderson Cancer Center, Houston; ¹⁸Moffitt Cancer Center, Tampa, FL; ¹⁹National Cancer Institute, Bethesda, MD; ²⁰Boston Medical Center, Boston; ²¹Boston University, Boston

NAPOLI-3: A randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).

The NAPOLI-3 study assessed FOLFOX+ liposomal irinotecan vs. gemcitabine + nab-paclitaxel. NALIRIFOX was superior, with an OS of 11.1 vs. 9.2 months. Criticisms of modern gem trials are often that of rigid dosing requirements that differ from modern clinical practice. Additionally, it is unclear whether NALIRIFOX provides any meaningful benefit over FOLFIRINOX, and the cost is always a consideration.