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

Abstract

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=66.50 mg '4-weeks on/2-weeks off' schedule; n=86 '37.5 mg 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).

Conclusions: A 10% reduction within marker lesions identifies pNET patients benefiting from sunitinib treatment with implications for maintenance of dose intensity and future trial design.

Conflict of interest statement

Angela Lamarca has received Travel and Educational Grants from Pfizer; she has also participated in Speakers' Bureaus for Pfizer. Jorge Barriuso has received Travel Grants, and Research funding from Pfizer, he has also participated in Speakers' Bureaus for Pfizer. Juan W Valle has participated in Consulting or Advisory Role and Speakers' Bureaus for Pfizer. Eric Raymond has received Consulting and Research Grants from Pfizer.

Figures

Figure 1

Outcome of patients treated with sunitib/placebo. Progression-free survival in patients with sunitinib and placebo (A); Waterfall-plot showing best changes in sum of marker lesions in patients treated with sunitinib (B) and placebo (C). HR, hazard ratio; 95% CI, 95% confidence interval; n, number of patients.

Figure 2

Progression free-survival in patients treated with 37.5 mg continuously of sunitinib (Phase III clinical trial), both cut-offs (classical 30% and our proposed alternative 10%) are tested. CI=confidence interval; HR=hazard ratio; 95% nr=not-reached.