Similar Outcomes With Streptozotocin/5-FU and Everolimus Sequences in Pancreatic NETs

Data from the phase 3 SEQTOR trial (NCT02246127) suggest that streptozotocin plus 5-fluorouracil (STZ/5-FU) followed by everolimus (Afinitor) and its reverse sequence provide comparable clinical outcomes for patients with advanced pancreatic neuroendocrine tumors (NETs).¹

Findings from the trial were published in ESMO Open. Given that both STZ/5-FU and everolimus are approved treatments for pancreatic NETs, the study set out to investigate the optimal sequencing of the treatments.

The trial established no statistically significant difference in progression-free survival (PFS) between the 2 sequences. The 12-month PFS rate following first-line treatment reached 71.4% with everolimus and 61.8% with STZ/5-FU (OR, 0.65; 95% CI, 0.32-1.32). The median PFS was 19.4 months for everolimus and 22.7 months for the STZ/5-FU combination.

Notably, responses were significantly higher in those receiving STZ/5-FU first. The first-line overall response rate (ORR) for STZ/5-FU was 30.3%, compared with 11.6% for everolimus (P =.012). This trend continued into the second-line setting, where STZ/5-FU maintained a 30.6% ORR vs 9.1% for everolimus. While the higher response rates associated with STZ/5-FU provide a distinct clinical advantage in scenarios requiring rapid tumor shrinkage, the lack of a statistical difference in PFS suggests that both agents remain effective options for long-term disease control, according to investigators.

Secondary outcomes from the study showed that the sequence of treatment also did not have a significant impact on overall survival (OS). Patients in the everolimus-first arm experienced a median OS of 61.7 months, while those starting with STZ/5-FU had a median OS of 50.6 months (HR, 1.43; 95% CI, 0.86-2.37).

Regarding the safety and tolerability of the regimens, the researchers noted that discontinuations were more frequent among patients receiving everolimus first compared with those on the STZ/5-FU regimen.

“In conclusion, although the assessment of sequentiality was not feasible, both strategies provide comparable 12-month PFS rates, disease control, and OS, indicating that neither is superior as an initial option,” wrote authors Capdevila et al in the study.¹

SEQTOR Design and Methodology

The SEQTOR trial was a global, randomized, crossover study designed to compare the efficacy and safety of STZ/5-FU followed by everolimus vs the reverse sequence as first-line treatment for adult patients with unresectable or metastatic, advanced, well differentiated pancreatic NETs.²

The study accrued patients across several countries in Europe, including Spain, Germany, France, Denmark, the Netherlands, Sweden, Italy, and the United Kingdom. A total of 141 patients were randomized 1:1 to initially receive either 10 mg everolimus (n = 72) daily or STZ/5-FU (n = 69), followed by the other respective treatment upon progression.

The study’s primary end point underwent a notable modification during the trial period. While the investigators initially aimed to assess the 35-month PFS rate after both first- and second-line treatments, slow patient accrual and survival durations that exceeded initial projections led to the adoption of 12-month PFS following first-line treatment as the primary measure of efficacy.

Clinical Implications

The SEQTOR trial provides critical evidence for the management of advanced pancreatic NETs, where treatment sequencing has long been a matter of clinician preference. The findings suggest that while everolimus is a robust first-line option with a high 12-month PFS rate, STZ/5-FU should be considered when a higher likelihood of tumor response is necessary.

Ultimately, the trial concludes that while the 2 treatments are not statistically different in terms of PFS rates, the superior response rates of STZ/5-FU and the higher discontinuation rate of everolimus are vital factors for oncologists to consider when personalizing treatment plans for their patients.

REFERENCES

1. 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):105922-105922. doi:10.1016/j.esmoop.2025.105922

2. Sequentiality of everolimus and STZ-5FU in advanced pancreatic neuroendocrine tumor (SEQTOR). ClinicalTrials.gov. Updated May 11, 2025. Accessed January 23, 2026. https://clinicaltrials.gov/study/NCT02246127