Streptozotocin plus 5-fluorouracil followed by everolimus or the reverse sequence in patients with advanced pancreatic neuroendocrine tumors (SEQTOR-GETNE phase III study): a randomized clinical trial

Abstract

Background: Everolimus or streptozotocin plus 5-fluorouracil (STZ/5-FU) are approved treatments for patients with pancreatic neuroendocrine tumors (panNETs). The SEQTOR trial aimed to assess the optimal treatment sequence.

Patients and methods: SEQTOR was an international, open-label, randomized, crossover, phase III trial that recruited adults with unresectable or metastatic, advanced, well-differentiated panNET. Patients received 10 mg/day of everolimus followed upon progression by STZ/5-FU; or the reverse sequence. The primary endpoint was the 35-month progression-free survival (PFS) rate after first- and second-line treatment; however, due to slow accrual and longer survival, it was changed to the 12-month PFS rate following first-line treatment (12-mPFS₁).

Results: Patients were randomized to everolimus (n = 72) or STZ/5-FU (n = 69) first. The 12-mPFS₁ was 71.4% [95% confidence interval (CI) 59.4% to 81.6%] and 61.8% (95% CI 49.2% to 73.3%) (odds ratio 0.65, 95% CI 0.32-1.32) with a median PFS₁ of 19.4 versus 22.7 months for everolimus and STZ/5-FU, respectively. STZ/5-FU achieved a significantly higher overall response rate in first-line (11.6% versus 30.3%, P = 0.012) and second-line (30.6% versus 9.1%, P = 0.072) treatments. No differences were shown in overall survival (median 61.7 versus 50.6 months in everolimus first and STZ/5-FU first, respectively; hazard ratio 1.43, 95% CI 0.86-2.37). Discontinuations of everolimus were more frequent.

Conclusion: STZ/5-FU and everolimus were not statistically different in PFS rates, but STZ/5-FU achieved higher response rates.

Keywords: 5-fluorouracil; advanced pancreatic neuroendocrine neoplasm; everolimus; panNET; sequential strategy; streptozotocin.

Figure 1

CONSORT diagram showing patient allocation. 5-FU, 5-fluorouracil; ITT, intention-to-treat; pts, patients; SP, safety population; STZ, streptozotocin.

Figure 2

Survival outcomes in arm A (everolimus followed by STZ/5-FU) and arm B (STZ/5-FU followed by everolimus). (A) Kaplan–Meier analysis of progression-free survival (PFS) to first treatment (PFS₁). (B) Multivariable hazard analysis of PFS₁ to first treatment assigned in selected subgroups. (C) Kaplan–Meier analysis of PFS to second treatment (PFS₂). (D) Multivariable hazard analysis of PFS₂ to first treatment assigned in selected subgroups. (E) Kaplan–Meier analysis of overall survival. (F) Multivariable hazard analysis of OS in selected subgroups. The gold dots and error bars represent the HR and 95% CIs. 5-FU, 5-fluorouracil; CI, confidence interval; ECOG-PS, Eastern Cooperative Oncology Group performance status; Eve, everolimus; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; STZ, streptozotocin.

Figure 3

Objective response rate (ORR) in arm A (everolimus followed by STZ/5-FU) and arm B (STZ/5-FU followed by everolimus). (A) Waterfall plot for overall response rate (ORR) to everolimus and streptozotocin (STZ) plus 5-fluorouracil (5-FU) as first assigned treatment reporting the percentage change from baseline in the sum of the longest diameters of target lesions. (B) Multivariable analysis of ORR to first treatment assigned in selected subgroups. The gold dots and error bars represent the odds ratio and the 95% confidence interval. (C) Waterfall plot for ORR to everolimus and STZ plus 5-FU as second assigned treatment. (D) Multivariable analysis of ORR to the second treatment assigned in selected subgroups. Arm A (sequence everolimus/STZ and 5-FU) in blue and arm B (sequence STZ and 5-FU/Everolimus) in red. 5-FU, 5-fluorouracil; CBR, clinical benefit rate; CI, confidence interval; CR, complete response; ECOG-PS, Eastern Cooperative Oncology Group performance status; NE, not evaluable; OR, odds ratio; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease; STZ, streptozotocin.

Figure 4

Safety in arm A (everolimus followed by STZ/5-FU) and arm B (STZ/5-FU followed by everolimus). Treatment-related adverse events reported throughout the study period, including most frequent events (cut-off >5%) and those of special interest such as hematologic toxicities in first line (A) and second line (B). P value on the right of the events that had statistically significant differences in rates between study arms (Fisher’s exact test).