A real-world prospective analysis of the relationship between nanoliposomal irinotecan and fluorouracil with folinic acid and neutropenia in patients with pancreatic cancer (NAPOLEON-2 study, NN-2401).
Authors: Shirakawa Tsuyoshi , Araki Tomonori , Shimokawa Mototsugu , Otsuka Taiga , Nakazawa Junichi , Shimokawa Hozumi , Koga Futa , Oda Hisanobu , Takeshita Shigeyuki , Arima Shiho , Arita Shuji , Kawaguchi Yasunori , Nishikawa Kazuo , Taguchi Hiroki , Jikuya Kenichi , Sakai Tatsunori , Ueda Yujiro , Sakae Takahiro , Mizuta Toshihiko , Mitsugi Kenji 
Published: January 2025

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Background:
Nanoliposomal irinotecan and fluorouracil with folinic acid (NFF) is a standard regimen after gemcitabine-based chemotherapy (CTx) for unresectable or recurrent pancreatic cancer (urPC) patients. Neutropenia caused by systemic CTx has been reported to be a prognostic marker in several cancers, however, the relationship between neutropenia and efficacy of NFF in urPC patients is unknown. Therefore, we initiated a prospective observational study to investigate whether neutropenia can be a prognostic marker in the real-world (NN-2401), followed by a retrospective one (NN-2301).
Methods:
We collected the data of urPC patients treated with NFF who had received at least one previous CTx in 17 hospitals in Japan from June 2021 to October 2023. The primary endpoint was overall survival (OS). Secondary endpoints included the progression-free survival (PFS) and overall response rate (ORR). To analyze them, we divided urPC patients into three groups by the grade of the most severe neutropenia during NFF (Cutoff A, grade 0 vs 1-4; Cutoff B, grade 0-1 vs 2-4; Cutoff C, grade 0-2 vs 3-4). Besides that, we compared OS among the following three groups receiving NFF ≥4 cycles in Cutoff C; one showed neutropenia with NFF reduction after the 4th cycle (Cutoff C High-Late), another showed neutropenia with NFF reduction in the 2nd or 3rd cycle (Cutoff C High-Early), and the other did grade 0-2 neutropenia (Cutoff C Low).
Results:
Among the 150 patients, the number of patients with the most severe neutropenia of grade 0, 1, 2, 3, or 4 was 79, 7, 23, 34, and 7, respectively. The median OS of severe neutropenia group in Cutoff A, B, or C was 9.8, 9.8, and 10.6 months, respectively. Both OS and PFS were significantly better in all severe neutropenia groups; hazard ratio [HR] of OS for Cutoff A, B, or C was 0.58, 0.54, and 0.60, respectively; HR of PFS was 0.61, 0.56, and 0.56, respectively. Only Cutoff C showed a significant difference with an odds ratio of 3.06 (95% confidence interval [CI], 1.06-8.80; p=0.04) in ORR. Multivariate Cox regression analysis showed significant difference of OS in all Cutoffs; adjusted HR was 0.58 for Cutoff A, 0.53 for Cutoff B, and 0.52 for Cutoff C. Logistic regression analysis showed a significant difference in ORR of Cutoff C with an odds ratio of 4.02 (95%CI, 1.29-12.6; p=0.02). In addition, the numbers of patients were 73, 14, and 19 in Cutoff C Low, High-Late, and High-Early, respectively. The median OS of Cutoff C High-Late was significantly better than that of Cutoff C High-Early or Cutoff C Low (15.0 vs 10.4 or 9.1 months, p<0.05).
Conclusions:
In NFF treatment, neutropenia showed the usefulness as a prognostic marker for both OS and PFS, and also a predictive one for tumor response in urPC patients. The results are similar to our previous data, so we conclude that neutropenia can be a useful biomarker of NFF.
Clinical trial information: UMIN000043939
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