Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response

Background: Sunitinib prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumours (pNET). Response Evaluation Criteria in Solid Tumors (RECIST)-defined partial responses (PR; classically defined as ≥30% size decrease from baseline) are infrequent. Methods: Individual data of pNET patients from the phase II [NCT00056693] and pivotal phase III [NCT00428597] trials of sunitinib were analysed in this investigator-initiated, post-hoc study. The primary objective was to determine the optimal RECIST (v.1.0) response cut-off value to identify patients who were progression-free at 11 months (median PFS in phase III trial); and the most informative time-point (highest area under the curve (AUC) by receiver operating characteristic (ROC) analysis and logistic regression) for prediction of benefit (PFS) from sunitinib. Results: Data for 237 patients (85 placebo; 152 sunitinib [n=66 50mg “4-weeks on/2-weeks off” schedule; n=86 “37.5mg continuous daily dosing (CDD)”]) and 788 scans were analysed. The median PFS for sunitinib and placebo were 9.3 months (95%-CI 7.6-12.2) and 5.4 months (95%-CI 3.5-6.01), respectively (Hazard Ratio (HR) 0.43 (95%-CI 0.29-0.62); p<0.001)). A PR was seen in 19 patients (13%) on sunitinib; the median change in the sum of the lesions (vs. baseline) was -12.8% (range - 100 to +36.4). Month 7 was the most informative time-point [AUC 0.78 (95%-CI 0.66-0.9); Odds Ratio 1.05 (95%-CI 1.01-1.08), p=0.002]. Reduction of 10% (vs. baseline) achieved the highest sensitivity (50%) and specificity (82%), amongst cut-offs tested. A 10%-reduction in marker lesions was associated with improved PFS in the whole sunitinib population (HR 0.55 (95%-CI 0.3-0.9); p=0.04); mostly in patients on sunitinib CDD (HR 0.33 (95%-CI 0.2-0.7); p=0.005). A 10%-reduction in marker lesions (p=0.034) and sunitinib treatment (p=0.012) independently impacted on PFS (multivariable analysis). Conclusion: A 10%-reduction within marker lesions identifies pNET patients benefiting from sunitinib treatment with implications for maintenance of dose intensity and future trial design