Streptozotocin-Based Regimen Enhances Responses in Pancreatic NETs

Receipt of streptozotocin (Zanosar) with 5-fluorouracil prior to everolimus (Afinitor) was associated with comparable survival and enhanced response rates among patients with pancreatic neuroendocrine tumors (NETs) vs everolimus prior to the streptozotocin-based regimen, according to findings from the phase 3 SEQTOR study (NCT02246127) published in ESMO Open.

Efficacy data revealed that the 12-month progression-free survival (PFS) rates were 71.4% (95% CI, 59.4%-81.6%) for the everolimus-first group and 61.8% (95% CI, 49.2%-73.3%) for the streptozotocin-first group (OR, 0.65; 95% CI, 0.32-1.32; P = .229). Additionally, the rates per blinded independent review committee (BIRC) assessment were 69.5% (95% CI, 58.9%-82.0%) vs 63.6% (95% CI, 52.7%-76.6%) in each respective arm (OR, 1.05; 95% CI, 0.53-2.08; P = .677).

Furthermore, the Kaplan-Meier–estimated median PFSfollowing the first line of treatment was 19.4 months (95% CI, 16.8-27.6) vs 22.7 months (95% CI, 13.3-28.6) in the respective arms (HR, 1.16; 95% CI, 0.77-1.75; P = .474). Following the second line of treatment, the investigator- and BIRC-assessed median PFS in each arm was 8.8 months (95% CI, 5.2-30.2) vs 9.5 months (95% CI, 6.6-19.3; HR, 1.6; 95% CI, 0.94-2.73; P = .082) and 8.8 months (95% CI, 5.2-27.7) vs 10.7 months (95% CI, 6.6-19.3; HR, 1.5; 95% CI, 0.88-2.61; P = .132), respectively.

Regarding responses, the streptozotocin regimen exhibited a statistically significant benefit at 11.6% with everolimus first vs 30.3% with the combination first (P = .012). Per BIRC evaluation, the objective response rate (ORR) was 10.3% (95% CI, 4.2%-20.1%) vs 30.2% (95% CI, 19.2%-43.0%) in the respective arms (P = .004). Furthermore, the median duration of response (DOR) in each respective arm was 4.5 months (95% CI, 0-35.2) vs 25.2 months (95% CI, 22.3-35.1).

“[A]lthough the assessment of sequentiality was not feasible, both strategies provide comparable 12-month PFS1 rates, disease control, and OS, indicating that neither is superior as an initial option. [Streptozotocin plus 5-fluorouracil] achieves higher response rates regardless of treatment sequence, suggesting its selection as the preferred therapy when cytoreduction is necessary,” lead author Jaume Capdevila, MD, PhD, senior medical oncologist at Vall d’Hebron University Hospital and senior clinical and translational researcher at Vall d’Hebron Institute of Oncology in Barcelona, Spain, wrote in the publication with study coinvestigators. “However, differences observed in [an] exploratory subgroup analysis suggest individualizing treatment based on patient characteristics, considering tumor grade, expected treatment effect, safety profile, and comorbidities.”

The international, open-label phase 3 trial enrolled patients with pancreatic NETs in several sites across Europe and randomly assigned them 1:1 to receive everolimus followed by streptozotocin/5-fluorouracil in the event of disease progression (n = 72) or the reverse sequence (n = 69). Assignment was stratified by ECOG performance status.

Everolimus was given at a dose of 10 mg once daily. Multiple schemes for streptozotocin/5-fluorouracil were employed: streptozotocin at 500 mg/m² plus 5-fluorouracil at 400 mg/m² on days 1 to 5 of every 6-week cycle; or 500 mg/m² of streptozotocin given on days 1 to 5 of each 6-week cycle plus 5-fluorouracil given at 400 mg/m² on days 1 to 3 followed by streptozotocin at 1 g/m² and 5-fluorouracil at 400 mg/m² once every 3 weeks. Treatment persisted in the absence of disease progression, unacceptable toxicity, withdrawal of consent, or death.

Among patients in the everolimus-first and streptozotocin-first arms, the median age was 59 years (range, 33-83) vs 58 years (range, 33-80), and 56.9% vs 63.8% of each were male. A total of 69.4% vs 68.1% had an ECOG performance status of 0, 87.5% vs 79.7% had WHO grade 2 tumors, and 95.8% vs 89.9% had baseline M1 disease. Most patients did not receive previous therapy (50.0% vs 62.3%), and the most common type of previous therapy were somatostatin analogues.

The primary end point of the study was originally 35-month PFS rate up to second documented disease progression but was revised due to slow patient accrual. The updated primary end point was 12-month PFS rate to the first treatment received. Secondary end points included ORR to both first and second treatments, DOR, PFS to the first and second treatments, patient-reported quality of life, and safety.

Among patients treated with everolimus first, oral mucositis, skin disorders, hyperglycemia, and edema occurred at a significantly higher frequency, whereas gastrointestinal toxicities were more common with streptozotocin/5-fluorouracil first. Pneumonitis was reported in 7% vs 21% of patients treated with everolimus as first- or second-line therapy.

For each first-line approach, the incidence of grade 3 or greater toxicities was 55.1% vs 43.9%, and 30.3% of patients treated with everolimus vs 27.8% of those treated with streptozotocin/5-fluorouracil in the second line experienced grade 3 or greater events. The most common everolimus-associated grade 3 or higher toxicities included hyperglycemia (5.8%), oral mucositis (4.3%), and pneumonitis (1.5%); with streptozotocin/5-fluorouracil, it was 1 case of high-grade hyperglycemia.

Reference

Capdevila J, Tafuto S, Krogh M, et al. 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. ESMO Open. 2025;10(12):105922. doi:10.1016/j.esmoop.2025.105922