Hubner R, et al. ESMO 2017:741P

Prognostic value of baseline neutrophil-to-lymphocyte ratio for predicting clinical outcome in metastatic pancreatic ductal adenocarcinoma patients treated with liposomal irinotecan plus 5-fluorouracil and leucovorin (5-FU/LV) vs. 5-FU/LV alone

Background

Neutrophils have been shown to inhibit the activity of T cells, which is associated with a poor prognosis, while tumour-infiltrating lymphocytes are associated with better outcomes in a variety of cancers.1 High peripheral blood neutrophil-to-lymphocyte ratio (NLR) is associated with a poor outcome in patients with pancreatic cancer.1–5 An exploratory post hoc analysis of the NAPOLI-1 trial assessed the relationship between NLR and overall survival (OS) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with nanoliposomal irinotecan (nal-IRI) and/or 5-fluorouracil and leucovorin (5-FU/LV). Results were presented at the ESMO 2017 Congress.6

Study design

  • NAPOLI-1 was a large phase III trial that evaluated nal-IRI alone and in combination with 5-FU/LV compared with 5-FU/LV alone for patients with mPDAC previously treated with gemcitabine-based therapy.7
  • Patients were initially randomized to receive nal-IRI (120 mg/m2 every three weeks) or 5-FU/LV (2,000/200 mg/m2 weekly for four weeks of each six-week cycle).
    • After 63 patients were enrolled, a third arm, nal-IRI (80 mg/m2 every two weeks) plus 5-FU/LV (2,400/ 400 mg/m2 every two weeks) was added.
  • Treatment was continued until disease progression or unacceptable toxicity.
  • Primary endpoint was OS.
  • Key secondary endpoints included progression-free survival (PFS), objective response rate, and safety.
  • The exploratory post hoc analysis was performed on patients from NAPOLI-1 who were enrolled in the study after the addition of the third arm, who received nal-IRI plus 5-FU/LV or 5-FU/LV alone, and who had baseline NLR data available.
  • Data cutoff was November 16, 2015.
  • Hazard ratios for OS comparisons based on high (>5) or low (≤5) baseline NLR in individual and pooled treatment arms were estimated by Cox regression analysis, and Fisher’s exact test was used for comparisons; p-values were descriptive.

Key findings

Baseline characteristics and disposition

  • A total of 222 patients met the criteria of enrolling in the study after the third arm was added and received study drug; 221 (99%) of these had baseline NLR available.
  • Median age was 62.2 years in the pooled population (NLR ≤5 and NLR >5 groups pooled by treatment arm).
  • The majority of patients were male (56.1% in the pooled NLR ≤5 group and 59.1% in the pooled NLR >5 group), Caucasian (62.6% in the pooled NLR ≤5 group and 68.2% in the pooled NLR >5 group), and had received one prior line of metastatic therapy (56.1% in the pooled NLR ≤5 group and 54.5% in the pooled NLR >5 group).

Efficacy

  • After pooling treatment arms, the NLR ≤5 group had significantly increased OS compared with the NLR >5 group (p = 0.02). (Figure 1)
  • In the nal-IRI plus 5-FU/LV arm, the NLR ≤5 group had significantly increased OS compared with the NLR >5 group (p = 0.001). (Figure 2)
    • The difference in the 5-FU/LV arm was not significant (p = 0.6). (Figure 3)
  • PFS was significantly increased in patients with NLR ≤5 vs. NLR >5 in the pooled (2.7 vs. 1.4 months; HR = 0.7; p = 0.05) and nal-IRI plus 5-FU/LV (4.2 vs. 1.4 months; HR = 0.5; p = 0.002) treatment arms, but not the 5-FU/LV arm (1.5 vs. 1.4 months; HR = 1.1; p = 0.6).

Figure 1. OS by high vs. low NLR: pooled treatment arms

Figure 2. OS by high vs. low NLR: nal-IRI + 5-FU/LV arm

Figure 3. OS by high vs. low NLR: 5-FU/LV arm

Safety

  • Grade 3/4 adverse events in the post hoc analysis population were consistent with the overall population.

Key conclusions

  • nal-IRI plus 5-FU/LV significantly improved OS and PFS compared with 5-FU/LV alone in the NAPOLI-1 trial of patients with mPDAC following gemcitabine-based therapy.
  • Based on these post hoc analyses, median OS and PFS were significantly increased in patients with low (vs. high) baseline NLR in the nal-IRI plus 5-FU/LV arm, but not in the 5-FU/LV arm.
  • These data are consistent with previous reports suggesting the prognostic value of baseline NLR in mPDAC and extend it to the post-gemcitabine setting.
  • Adverse events in this population were consistent with the overall population.
  • These analyses may be limited by the small sample size of post hoc analysis subgroups.

References: 1. Faria SS, Fernandes PC Jr, Silva MJ, et al. The neutrophil-to-lymphocyte ratio: a narrative review. Ecancermedicalscience 2016;10:702. 2. Yang JJ, Hu ZG, Shi WX, et al. Prognostic significance of neutrophil to lymphocyte ratio in pancreatic cancer: a meta-analysis. World J Gastroenterol 2015;21(9):2807–15. 3. Luo G, Guo M, Liu Z, et al. Blood neutrophil-lymphocyte ratio predicts survival in patients with advanced pancreatic cancer treated with chemotherapy. Ann Surg Oncol 2015;22(2):670–6. 4. Goldstein D, El-Maraghi RH, Hammel P, et al. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst 2015;107(2). pii: dju413. doi: 10.1093/jnci/dju413. 5. An X, Ding PR, Li YH, et al. Elevated neutrophil to lymphocyte ratio predicts survival in advanced pancreatic cancer. Biomarkers 2010;15(6):516–22. 6. Hubner R, Chen L-T, Li C-P, et al. Prognostic value of baseline neutrophil-to-lymphocyte ratio for predicting clinical outcome in metastatic pancreatic ductal adenocarcinoma (mPDAC) patients treated with liposomal irinotecan (nal-IRI) + 5-fluorouracil and leucovorin (5-FU/LV) vs. 5-FU/LV alone. ESMO Annual Congress Abstracts 2017:741P. 7. Wang-Gillam A, Li C-P, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet 2016;387(10018):545–57.