In a phase III CABINET study, cabozantinib significantly improved progression-free survival (PFS) as compared with placebo in patients with previously treated, progressive extrapancreatic or pancreatic neuroendocrine tumours. No overall survival (OS) difference between the study groups has been observed; however, OS data were not mature at the time of the analyses.
Most patients treated with cabozantinib had dose modifications or reductions to manage adverse events. The findings are reported at the ESMO Congress 2024 along with a simultaneous publication by Dr. Jennifer A. Chan of the Dana–Farber Cancer Institute in Boston, MA, US, and colleagues in the NEJM on 16 September 2024.
Neuroendocrine tumours are a heterogeneous group of neoplasms. Treatment of advanced neuroendocrine tumours is guided by features including the primary tumour location, pathological differentiation and grade, presence of symptoms related to hormone secretion or extent of disease, and somatostatin-receptor expression.
Depending on these factors, treatment options for extrapancreatic neuroendocrine tumours include somatostatin analogues, lutetium Lu-177 dotatate, or everolimus. For pancreatic neuroendocrine tumours, sunitinib or alkylating agent chemotherapy also can be considered.
The authors wrote in the background that angiogenesis plays a key role in the pathogenesis of neuroendocrine tumours. Antiangiogenic agents targeting VEGF and its receptors have shown activity in the treatment of neuroendocrine tumours. Cabozantinib is an oral small-molecule inhibitor of multiple tyrosine kinases including VEGF receptors, MET, AXL, and RET.
Clinical activity of cabozantinib was shown in a phase II study involving patients with advanced extrapancreatic or pancreatic neuroendocrine tumours. Based on these results, the CABINET investigators conducted the double-blind, randomised, controlled study to evaluate the efficacy of cabozantinib in patients with previously treated, progressive extrapancreatic or pancreatic neuroendocrine tumours.
The study team enrolled two independent cohorts of patients, those with extrapancreatic and those with pancreatic neuroendocrine tumours, 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 endpoint was PFS as assessed by blinded independent central review (BICR). Key secondary endpoints included objective response rate (ORR), OS, and safety.
The study was stopped early and unblinded based on the interim results showing improvement in PFS by local radiology assessment, presented at the ESMO Congress 2023. Updated and final results of PFS by BICR, ORR, subgroup analyses, and safety are presented at the ESMO Congress 2024.
In the cohort of 203 patients with extrapancreatic neuroendocrine tumours, the median PFS with cabozantinib was 8.4 months, as compared with 3.9 months with placebo (stratified hazard ratio [HR] 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 tumours, the median PFS with cabozantinib was 13.8 months, as compared with 4.4 months with placebo (stratified HR 0.23, 95% CI, 0.12 to 0.42; p < 0.001).
Across clinical subgroups, including primary tumour site and prior anticancer therapy, PFS favoured cabozantinib. The incidence of confirmed objective response with cabozantinib was 5% and 19% among patients with extrapancreatic and pancreatic neuroendocrine tumours, as compared with 0% with placebo.
Grade 3 or higher adverse events were noted in 62-65% of the patients treated with cabozantinib, as compared with 23-27% of the patients who received placebo. Common treatment-related adverse events of grade 3 or higher included hypertension, fatigue, diarrhoea, and thromboembolic events. Adverse events, which were managed with dose reduction in most of the patients, were consistent with the known safety profile of cabozantinib.
The authors commented that the treatment landscape in neuroendocrine tumours has evolved over the last 15 years with the addition of molecularly targeted agents, Lu-177 dotatate for patients with gastrointestinal neuroendocrine tumours and pancreatic neuroendocrine tumours, and alkylating agent chemotherapy with temozolomide-based regimens for patients with pancreatic neuroendocrine tumours. The use of these agents in clinical practice can be extended to neuroendocrine tumours arising in other locations. Because disease ultimately will progress during or after treatment with these agents, additional therapies are needed.
The results from the CABINET study support the use of cabozantinib as a new treatment option for patients with advanced extrapancreatic or pancreatic neuroendocrine tumours whose disease has progressed after at least one other line of treatment, not including somatostatin analogues, or in whom unacceptable side effects have developed after such treatment. The choice of therapy should be individualised and based on the characteristics of the patient and the tumour. Future clinical trials evaluating the appropriate sequencing of treatment are needed.
The study was supported by grants from the US National Cancer Institute of the National Institutes of Health to the Alliance for Clinical Trials in Oncology, ECOG-ACRIN Cancer Research Group, NRG Oncology, SWOG Cancer Research Network, and by Exelixis.
References
- Chan JA, Geyer S, Zemla T, et al. Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors. NEJM; Published online 16 September 2024. DOI: 10.1056/NEJMoa2403991
- 1141O - Chan J, Geyer S, Zemla T, et al. Cabozantinib versus placebo for advanced neuroendocrine tumors (NET) after progression on prior therapy (CABINET Trial/Alliance A021602): Updated results including progression free-survival (PFS) by blinded independent central review (BICR) and subgroup analyses. Annals of Oncology 2024;35(Suppl 2):S749.