STZ–5FU First Approach May Improve ORR For Advanced Pancreatic NETs

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Sequencing streptozotocin-fluorouracil (STZ–5FU) first and everolimus second may improve the likelihood of an objective response in patients with advanced pancreatic neuroendocrine tumours (NETs), phase III trial findings indicate. 

Ramόn Salazar, from L’Hospitalet de Llobregat in Barcelona, Spain, told delegates at the ESMO Congress 2022 in Paris, France, that although the treatments achieved “similar efficacy” in terms of time to the first progression event, prioritising STZ–5FU appeared to significantly improve the objective response rate (ORR). 

This suggests that “STZ–5FU should be the first treatment option when tumour shrinkage is a priority”, the presenter said. 

However, he added that “the differences in safety profile may also inform treatment choice for selected patients.” 

For the study, 141 patients with unresectable or metastatic G1–G2 pancreatic NETs were randomly assigned to receive everolimus 10 mg/day until first progression, at which point they switched to a Moertel or Uppsala regimen of STZ–5FU therapy, or to receive the same agents in the opposite sequence. 

Participants were permitted to have previously received somatostatin analogues for advanced disease, but all were naïve to chemotherapy, mTOR inhibitors and tyrosine kinase inhibitors, Ramόn Salazar said. 

The ORR to everolimus as the first treatment was 11% for the 68 patients who received treatment in this arm, with complete responses in 4%, partial responses in 7% and stable disease in 80%.  

The ORR for the 67 patients who received STZ–5FU as the first treatment was significantly superior to those given first-line everolimus, at 30%. However, the corresponding rates for complete, partial and stable disease responses with first-line STZ–5FU were 4%, 26% and 50%, and therefore the disease control rate was numerically lower with STZ–5FU than everolimus. 

After a median follow-up of 35.7 months, the time to first progression was a comparable 21.5 months with everolimus as the first agent and 23.6 months with STZ–5FU as the first agent. 

The primary endpoint of 12-month PFS did not significantly differ between first-line everolimus and first-line STZ–5FU, at 69.3% versus 63.5%. The 24- and 36-month rates were also similar between the groups, at 45.2% versus 48.5% and 34.3% versus 31.5%, respectively.  

Patients given first-line treatment with everolimus or STZ–5FU had comparable rates of any-grade (100 vs 97%) and grade 3 and more severe (66 vs 61%) adverse events.  

However, Ramόn Salazar noted that patients given everolimus first were more likely than those given STZ–5FU to experience any hyperglycaemia, rash, pneumonitis and lung infections, and less likely to have nausea, but grade 3–4 pneumonitis occurred in 1.5% of both arms.  

He concluded: “Final analysis on secondary objectives, predictive translational transcriptomic and pharmacoeconomic studies, [quality of life] and central tumour imaging review are underway.” 

Invited discussant Jonathan Strosberg, from the H Lee Moffitt Cancer Center in Tampa, Florida, USA, noted that the median 21.5-month PFS duration was longer than would be expected from a previous trial. 

He proposed this duration might be attributable to the study design not requiring patients to have evidence of disease progression at baseline, with over 50% of participants being treatment-naïve.  

Jonathan Strosberg therefore commented that the trial “does not provide answer on choice of treatment for progressive disease” and questioned whether ST–5FU is the “optimal chemo”, observing that “capecitabine-temozolomide may be more effective, tolerable and convenient.” 

References  

LBA45 - Salazar R, Tafuto S, Krogh M et al. Randomized open label phase III study comparing the efficacy and safety of everolimus followed by chemotherapy with streptozotocin-5FU upon progression or the reverse sequence, in advanced progressive panNETs: The SEQTOR study (GETNE 1206). Ann Oncol 2022; 33 (suppl_7): S808–S869. Doi: 10.1016/annonc/annonc1089