Cabozantinib In Advanced Neuroendocrine Tumors

1. Progression-free survival had a hazard ratio of 0.38 (extrapancreatic NETs) and 0.23 (pancreatic NETs) for those treated with cabozantinib compared to placebo.

2. Treatment-related adverse events grade 3 or higher occurred in 62-65% with cabozantinib vs 23-27% with placebo.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Neuroendocrine tumours (NETs) are a diverse group of neoplasms with therapies that eventually lead to disease progression. It was recently discovered that angiogenesis plays a key role in the pathogenesis of NETs, and thus a potential treatment target. This trial evaluated the efficacy of cabozantinib, an oral small-molecule tyrosine kinase inhibitor in patients with advanced NETs after progression on prior therapies. Patients were split among two cohorts, the extrapancreatic NETs cohort and the pancreatic NETs cohort. The primary endpoint was progression-free survival (PFS) and secondary endpoints included objective response rate (ORR), overall survival (OS), and safety. In the extrapancreatic NETs cohort, the median PFS was 8.4 months with cabozantinib and 3.9 months with placebo, with an HR of 0.38 (significant). In that cohort, the ORR was 5% (partial response) in the cabozantinib group vs 0% in the placebo group (significant). Median OS was 21.9 months with cabozantinib and 19.7 months with placebo, with HR 0.86 (non-significant). Quality of life remained stable and was similar in the two groups. In that cohort, treatment-related adverse events grade 3 or higher occurred in 62% with cabozantinib vs 27% with placebo with most common events with cabozantinib being hypertension (21%), fatigue (13%), and diarrhea (11%). Regarding the pancreatic NETs cohort, the median PFS was 13.8 months with cabozantinib and 4.4 months with placebo, with HR 0.23 (significant). In that cohort, the ORR was 19% (partial response) in the cabozantinib group vs 0% in the placebo group. Median OS was 40.0 months with cabozantinib and 31.1 months with placebo, with HR 0.95 (non-significant). Quality of life remained stable and was similar in the two groups. In that cohort, treatment-related adverse events grade 3 or higher occurred in 65% with cabozantinib vs 23% with placebo with the most common events with cabozantinib being hypertension (22%), fatigue (11%), and thromboembolic events (11%). The strengths of this study included its methodology, and the limitations included the sample size and the use of a placebo as the control as opposed to another active agent. Overall, this trial showed that cabozantinib, as compared with placebo, resulted in some improved outcome measures like PFS but no OS benefit in patients with NETs that progressed after previous therapy.

Click to read the study in NEJM

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In-Depth [randomized controlled trial]: This multicenter phase III trial enrolled adults with advanced METs who had disease progression after at least 1 line of approved therapy and randomized them (2:1) to receive cabozantinib or placebo. Patients were split among two cohorts, the extrapancreatic NETs cohort (n=203) and the pancreatic NETs cohort (n=95). Regarding the extrapancreatic NETs cohort, the median follow-up was 10.2 months (95%CI, 8.2-13.8). In that cohort, the median PFS was 8.4 months (95%CI, 7.6-12.7) with cabozantinib and 3.9 months (95%CI, 3.0-5.7) with placebo, with an HR 0.38 (95%CI, 0.25-0.59, p<0.001). In that cohort, the ORR was 5% (partial response) in the cabozantinib group (95%CI, 2-10) vs 0% (95%CI, 0-5) in the placebo group (p=0.05). Median OS was 21.9 months with cabozantinib and 19.7 months with placebo, with HR 0.86 (95%CI, 0.56-1.31). Quality of life remained stable and was similar in the two groups. In that cohort, treatment-related adverse events grade 3 or higher occurred in 62% with cabozantinib vs 27% with placebo with most common events with cabozantinib being hypertension (21%), fatigue (13%), and diarrhea (11%). Regarding the pancreatic NETs cohort, the median follow-up time was 13.8 months (95%CI, 10.1-19.7). In that cohort, median PFS was 13.8 months (95%CI, 9.2-18.5) with cabozantinib and 4.4 months (95%CI, 3.0-5.9) with placebo, with HR 0.23 (95%CI, 0.12-0.42, p<0.001). In that cohort, the ORR was 19% (partial response) in the cabozantinib group (95%CI, 10-30) vs 0% (95%CI, 0-11) in the placebo group. Median OS was 40.0 months with cabozantinib and 31.1 months with placebo, with HR 0.95 (95%CI, 0.45-2.00). Quality of life remained stable and was similar in the two groups. In that cohort, treatment-related adverse events grade 3 or higher occurred in 65% with cabozantinib vs 23% with placebo with the most common events with cabozantinib being hypertension (22%), fatigue (11%), and thromboembolic events (11%). Overall, this trial showed that cabozantinib, as compared with placebo, resulted in some improved outcome measures like PFS but no OS benefit in patients with NETs that progressed after previous therapy.

Image: PD

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