麻豆传媒

The multitargeted tyrosine kinase inhibitor (TKI) lenvatinib induced a strong tumor response in patients with previously treated advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs), according to results from a phase II trial in Europe.

In this multicenter, open-label study involving 111 patients, treatment with lenvatinib (Lenvima) led to an overall response rate (ORR) of 29.9%, with a particularly high ORR -- 44.2% -- in patients with pancreatic NETs, reported Jaume Capdevila, MD, PhD, of Vall Hebron University Hospital in Barcelona, and colleagues.

"This study provides novel evidence for the efficacy of lenvatinib in patients with disease progression following treatment with other targeted agents, suggesting the potential value in the treatment of advanced GEP-NETs," they wrote in the .

It was a decade ago this month that the (Sutent), another multitargeted TKI, as the first anti-vascular endothelial growth factor (VEGF) therapy targeted to treat progressive well-differentiated pancreatic NETs in patients with unresectable locally advanced or metastatic disease. Since then, investigators have been evaluating newer-generation TKIs that target VEGF receptors (VEGFRs), among other receptors, both in pancreatic and non-pancreatic NETs.

Lenvatinib targets VEGFR 1-3, fibroblast growth factor receptors (FGFR) 1-4, and platelet-derived growth factor receptor alpha.

Capdevila and colleagues noted that studies have shown it is particularly potent against FGFR-1, which is a key driver of resistance to antiangiogenic drugs, "suggesting that it could potentially also reverse primary and acquired resistance to anti-VEGFR treatments or to other targeted agents."

From September 2015 to March 2017, 111 patients were enrolled in the study involving 21 centers in four European countries; 55 had histologically confirmed grade 1-2 pancreatic NETs, while 56 had gastrointestinal NETs. Patients were treated with 24-mg lenvatinib once daily until disease progression or treatment intolerance. Median follow-up was 23 months.

The ORR was 16.4% for patients with gastrointestinal NETs, Capdevila and team said. The median duration of response was 19.9 months for patients with pancreatic NETs and 33 months for gastrointestinal NETs. The median progression-free survival (PFS) for the full cohort was 15.7 months.

These results compare favorably to PFS outcomes reported in phase III trials, including those evaluating sunitinib and surufatinib, the authors noted.

"Interestingly, the ORR in pancreatic NETs was 44%, a rate not seen before with targeted agents," Jonathan Strosberg, MD, head of the neuroendocrine tumor division at Moffitt Cancer Center in Tampa, told 麻豆传媒.

Strosberg, who was not involved with this research, noted that the study population was comprised of heavily pretreated patients, and that 29% had received prior sunitinib. "In contrast, the response rates with other TKIs have been <20% in this population, even in less heavily treated populations. The ORR for gastrointestinal NETs was more modest, but still impressive," he added.

The most common grade 3/4 adverse events included hypertension (22.7%), fatigue (13.9%), and diarrhea (10.9%). In addition, 81% of patients required at least one dose reduction, while 92.8% required at least a temporary treatment interruption.

"This suggests that lower starting doses might be considered in this population, and that particularly close monitoring of blood pressure is necessary," said Strosberg.

The results of this study "suggest that lenvatinib is more than just a 'me-too' competitor to sunitinib," he noted. "It actually seems to have superior activity, potentially due to its ability to target both the VEGF and FGF receptors. Moreover, it appears to have activity in patients who have progressed on sunitinib. Randomized phase III studies with this drug are warranted, both for pancreatic and GI/lung NETs."

Comment