Final results of the TALENT trial (GETNE1509): a prospective multicohort phase II study of lenvatinib in patients (pts) with G1/G2 advanced pancreatic (panNETs) and gastrointestinal (giNETs) neuroendocrine tumors (NETs).

Abstract

4106 Background: Approved systemic therapies for advanced NETs have showed limited tumor shrinkage and no data of activity after progression to prior targeted agents (TA) is available. Lenvatinib, a potent VEGFR1-3 & FGFR1-4 inhibitor may increase efficacy and revert primary and acquired resistance to TA. We report the final results of the TALENT trial. Methods: Two independent cohorts were included: panNETs and giNETs. All pts had baseline documented progression disease (PD) by RECIST. For panNETs, PD to TA was mandatory, regardless of prior therapy with somatostatin analogs (SSAs) or chemotherapy (CHT); and for giNETs, PD on SSAs. Pts were treated with lenvatinib at 24 mg qd until PD or intolerable toxicity. The primary endpoint was overall response rate (ORR) by central radiology review. Progression-free (PFS) and overall survival (OS) were assessed by investigator. With 55 pts per arm, our study was powered to identify an ORR ≥25% (90% power, 5% α-error). Results: We recruited 111 pts: 55 panNETs and 56 giNETs (78% from small intestine). Prior therapies were CHT 32%, SSAs 87%, everolimus 70% and sunitinib 30% for panNETs. ORR was 29%, 42.3% for panNETs and 16.3% for giNETs. With a median follow-up of 19 m, PFS and OS for panNETs were 15.5 m (95% CI 11.3-not reached (NR)) and 29.2 m (95% CI 23.2-NR); and 15.4 m (95% CI 11.5-19.4) and NR for giNETs, respectively. Pts who obtained a response by RECIST had a significantly better PFS compared with non-responders (NR vs 11.2 m in panNETs (p=0.004); 37.2 m vs 14.9 m in giNETs (p=0.005). In the subgroup analyses, all pts obtained the same benefit in PFS and ORR, including tumor grade, prior therapies, hormone release, primary location and tumor burden. The most frequent G3/4 adverse events were hypertension (22%), fatigue (11%) and diarrhea (11%). Dose reductions/interruptions were needed in 91.8% with a median dose of 20 mg qd. Conclusions: To our knowledge, we report the highest ORR by central radiology assessment with a TA in this setting. Lenvatinib showed a promising PFS and OS in a pretreated population with benefit across subgroups. Further development in advanced NETs is warranted. Clinical trial information: NCT02678780.

Systemic Treatment Selection for Patients with Advanced Pancreatic Neuroendocrine Tumours (PanNETs)

“…For many years targeted therapies achieved low RRs. However, lenvatinib has achieved a higher RR in patients with PanNETs, but the mechanism is still not clear [72]. Similarly, phase IV data from the use of sunitinib in PanNETs have also reported higher RRs than previous studies (9.3% in phase III study vs. 24.5% in phase IV study) [27,67].…”

“…The median PFS for patients with PanNETs ranged from 11.7 months for pazopanib [18] to 21.8 months for cabozantinib [71]. Among the expected moderate responses (between 15-19%) [18,71,73], there was a promising 42.3% response rate reported with lenvatinib [72]. With lenvatinib, the responding patients had a significantly better PFS compared to non-responders, a finding that is even more evident for the PanNET subgroup (median PFS in responders vs. non-responders: not reached (NR) vs. 11.2 months in PanNETs (p = 0.004).…”

“…Based on available data, targeted therapies are able to achieve prolonged disease control, despite low objective response rates. The only exception seems to be lenvatinib in the treatment of patients with advanced G1/G2 PanNETs and gastronintestinal NETs (achieved a high RR) [72], but its activity is still to be proven in the context of a phase III study.…”

“…These could be in the form of chemotherapy or PRRT, while SSAs and targeted therapies (reported to achieve lower response rate) may be reserved for patients with lower tumour burden. One of the exceptions may be lenvatinib, which leads to high response rates [72] and may change the management approach, if the results are confirmed in phase III studies. The type of distant metastases also represents the aggressiveness of the disease and it is also illustrated in a recently published analysis of SEER data from 2010 to 2014 [122].…”

“…Other antiangiogenic molecules have been tested in patients with PanNETs over the last 10 years in several phase II trials, such as pazopanib (targeting VEGFR, PDGFR, c-KIT, and fibroblast growth factor receptors (FGFR)); cabozantinib (targeting hepatocyte growth factor receptor protein (MET), VEGFR, RET, GAS6 receptor (AXL), KIT, Fms-like tyrosine kinase-3 (FLT3)); lenvatinib (targeting VEGFR, FGFR, PDGFR alpha, c-Kit, and the RET proto-oncogene); and surufatinib (targeting VEGFRs, FGFR, colony-stimulating factor 1 receptor) [ 18 , 70 , 71 , 72 , 73 ]. In all of these studies, mixed populations of patients with GEP-NETs were recruited, with limited numbers of patients with PanNETs (20–55).…”