Neuroendocrine Tumour PFS Extended With Second-Line Or Later Cabozantinib

medwireNews: Cabozantinib significantly improves progression-free survival (PFS) versus placebo for patients with extra-pancreatic and pancreatic neuroendocrine tumours (epNETs and pNETs) who have progressed after at least one prior line of therapy, demonstrates research reported at the ESMO Congress 2023 in Madrid, Spain. 

Presenting author Jennifer Chan, from Dana-Farber Cancer Institute in Boston, Massachusetts, USA, told delegates at the meeting that the CABINET trial recruitment closed early following “compelling efficacy” at the first interim analysis for the pNET cohort and the second interim analysis for the epNET cohort. 

The study included patients with well-to-moderately differentiated, grade 1–3 NETs who had disease progression in the past year or intolerance to at least one treatment other than a somatostatin analogue (SSA). Prior agents included everolimus, sunitinib and/or Lu-177 dotatate depending on the specific form of NET, and participants were permitted to continue with a stable dose of SSA during the study. 

In the epNET cohort, PFS by local review at data cutoff in June 2023 was a median 8.3 months with cabozantinib 60 mg/day (n=129) and 3.2 months with placebo (n=68), giving a significant hazard ratio (HR) for progression or death of 0.45 in favour of the multikinase inhibitor after a median follow-up of 13.9 months. 

The predominant primary tumour site in this cohort was gastrointestinal (50–66%), followed by lung (18–21%), unknown (1–16%) or other (14–15%), with the majority of patients having well-differentiated (79–84%), grade 2 disease (63–66%). Most participants (62–65%) continued with an SSA.  

PFS was also significantly better for patients with pNET who were given cabozantinib (n=62) than those treated with placebo (n=31), at a median of 11.4 and 3.0 months, respectively, after a median follow-up of 16.7 months. The HR for progression or death was 0.27, the presenter said. 

Again, patients in this group generally had well-differentiated (90–97%), grade 2 (63%) disease and most had previously received an SSA (94–97%), with 44–45% continuing this treatment. 

Jennifer Chan reported that the PFS findings for both treatment groups were consistent with those determined at interim analysis by local review, as well as with the blinded independent central review at data cutoff. 

Overall survival was statistically comparable between the treatment arms among both the epNET and pNET cohorts, but the data are yet to mature, and the outcome will also likely be affected by crossover from placebo to cabozantinib when the study accrual ended, the investigator added.  

Adverse events (AEs) among the epNET cohort occurred at grade 3 for 59.7% of cabozantinib-treated patients and 33.3% of controls, at grade 4 for 7.3% and 1.6%, respectively, and at grade 5 for 8.9% and 7.9%, with three deaths possibly related to treatment. The most common AEs at grade 3 or higher were hypertension (27.4 vs 4.8%), fatigue (13.7 vs 7.9%) and diarrhoea (10.0 vs 3.0%). 

Similarly, among cabozantinib-treated patients with pNET, grade 3, 4 and 5 AEs occurred in 56.7%, 8.3% and 3.3%, respectively, with 43.3% of placebo-treated patients experiencing grade 3 AEs. There were no grade 4 or 5 AEs in the control arm. The most common grade 3 or more severe AEs were hypertension (26.7 vs 20.0%), fatigue (13.3 vs 3.3%), thromboembolism (11.7 vs 0.0%), hand–foot syndrome (10.0 vs 0.0%) and hyperglycaemia (8.3 vs 10.0%). 

Jennifer Chan concluded that the “statistically significant and clinically meaningful improvement in PFS” mean that “cabozantinib may be a new treatment option for patients with previously treated, progressive NET.” 

Session discussant Marianne Pavel, from the University of Erlangen in Germany, said the CABINET trial participants were generally “heavily pretreated”, with the epNET and pNET groups having received up to seven and nine lines of systemic therapy (median 2 and 3), respectively. 

She noted that the control arm for both tumour cohorts had a short PFS, perhaps reflecting “changes in tumor biology” over a median 7 years of treatment between diagnosis and enrolment in the study. 

The discussant summarised that cabozantinib offers an “additional therapy option” in the second- or later-line and will compete with other agents, such as peptide receptor radionuclide therapy, and rechallenge Lu-177-dotatate as well as novel ligands under investigation.  

However, Marianne Pavel cautioned that more research is required to understand differences in response by primary tumour site grade, and whether prior sunitinib has an impact on pNET response to cabozantinib.  

Reference 

LBA53 - Chan J, Geyer S, Ou F-S, et al. ALLIANCE A021602: Phase III, double-blinded study of cabozantinib versus placebo for advanced neuroendocrine tumors (NET) after progression on prior therapy (CABINET). Ann Oncol 2023;34(Suppl_2):S1254–S1335. DOI: 10.1016/j.annonc.2023.10.047