Overexpression or amplification of cell cycle regulators like cyclin-dependent kinase-4 (Cdk-4), phospho-Rb1, or cyclin D1 are observed in 58%, 68%, and 68% pancreatic neuroendocrine tumors (pNETs), respectively. Moreover, these alterations correlate with a more aggressive behavior. Palbociclib targets Cdk-4/6 and has shown in vitro activity in pNETs cell lines overexpressing Cdk-4.
In this non-randomized, open-label, phase II study, patients (pts) with metastatic grade (G) 1/2 pNETs were recruited from 10 centres belonging to the Spanish Taskforce Group of NETS (GETNE). Palbociclib 125 mg was given once daily for 21 of 28 days until disease progression (DP) or unacceptable toxicity. The initial planned recruitment was 21 patients based on a 2-stage Simon’s phase II design, where palbociclib would be considered inactive if
21 pts were included. One pt withdrew from the study due to clinical deterioration after < 1 month (m). 54% were males, mean age was 54 years (range: 33-66), and 67% had received > 3 previous lines of therapy (23.8% pazopanib; 80.9% sunitinib; 47.6% everolimus) beside somatostatin analogs. 20 pts were evaluable for ORR with a median follow up of 10m (4.23-12.43). No responses (0%) were observed; 11 (55%) pts had stable disease and 6 of them lasted more than 6m; 7 (35%) pts had progression as best response. 1 pt had tumor shrinkage of 8%. Median PFS was 1.9m (IC95% 0 - 13). Median OS was 16.6m (IC95% 9.3 – 23.9). Most frequent toxicities of any grade were: asthenia (16.2%), diarrhea (6.4%), abdominal pain (4.7%), nausea (4.3%) and neutropenia (11.5%). 5 pts developed G3-4 neutropenia (1 case of febrile neutropenia) and 2 pts G3-4 thrombocitopenia.
Lack of activity was observed with palbociclib in 21 molecularly unselected and heavily pretreated patients with advanced G1/2 pNETs. Translational studies correlating activity with molecular tumor markers and Ki67 proliferation index are ongoing.
Clinical trial identification
Legal entity responsible for the study
GETNE (Spanish Taskforce Group for Neuroendorine Tumors)
E. Grande Pulido: Advisor for Ipsen, Pfizer, Lexicon. Scientific lectures for Pfizer and Ipsen. All other authors have declared no conflicts of interest.