Siveke JT, et al. ASCO GI 2018:460

Subgroup analysis by measurable metastatic lesion number and selected lesion locations at baseline in NAPOLI-1, a phase III study of nal-IRI ± 5-FU/LV in patients with mPDAC

Background

Results from the phase III NAPOLI-1 trial demonstrated that addition of nanoliposomal irinotecan (nal-IRI) to 5-fluorouracil and leucovorin (5-FU/LV) significantly improved median overall survival (6.1 months vs. 4.2 months; p = 0.0122) and median progression-free survival (3.1 months vs. 1.5 months; p = 0.0001) compared with 5-FU/LV alone in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who progressed following gemcitabine-based therapy.1 At the ASCO GI 2018 symposium, a post hoc subgroup analysis of outcomes in the NAPOLI-1 trial by measurable metastatic lesion (ML) number and selected lesion locations (LL) at baseline was presented.2

Study design

  • The NAPOLI-1 study was an international, open-label, randomized, phase III trial in patients with mPDAC who progressed after prior gemcitabine-based therapy.
  • Patients in this trial were initially randomized to nal-IRI monotherapy or 5-FU/LV; however, the protocol was amended to include nal-IRI plus 5-FU/LV combination therapy as a third arm once safety data for nal-IRI plus 5-FU/LV became available from a concurrent metastatic colorectal cancer trial.
  • The objective of this post hoc analysis was to assess the impact of baseline ML and selected baseline LL on efficacy outcomes within the overall intent-to-treat (ITT) population and the nal-IRI plus 5-FU/LV treatment arm.
  • Descriptive p-values were included in this analysis.
  • The number of measurable MLs was recorded at baseline in patients with measurable and non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
  • Primary and metastatic LL at baseline (measurable and non-measurable) was investigator-reported using RECIST version 1.1.
    • Patients with more than one lesion location were counted once for each lesion.
    • This analysis included data for liver, lung, and peritoneal locations only.

Key findings

  • Of the 417 patients in the ITT population, 354 patients had measurable MLs at baseline and 1,080 LLs were recorded.
  • Patient demographics and baseline characteristics differed between baseline ML and LL subgroups and the overall ITT population, likely due to the large variation in subgroup populations, which should be considered when interpreting results.
  • In the overall ITT population, a lower risk of mortality and a lower risk of disease progression were reported in patients with one ML at baseline versus patients with two, three, or greater than three MLs. (Table 1)
    • These trends were also observed in the nal-IRI plus 5-FU/LV treatment arm.
  • In both the overall ITT population and the nal-IRI plus 5-FU/LV arm, patients with a liver lesion at baseline had a significantly increased risk of mortality and of disease progression compared with patients without a liver lesion at baseline. (Table 2)
    • These trends were not observed in other LL subgroups.
  • A reduction in mortality risk was observed with nal-IRI plus 5-FU/LV compared with 5-FU/LV alone in the 2 and >3 ML subgroups (HR = 0.47 and 0.17, respectively) and for all LL subgroups (HR = 0.39–0.83). (Table 3 and 4)
  • The risk of disease progression was reduced in patients receiving nal-IRI plus 5-FU/LV compared with 5-FU/LV alone across all ML and LL subgroups (statistical significance reached in 2 ML and all LL subgroups). (Table 3 and 4)
  • Patients receiving nal-IRI plus 5-FU/LV had higher overall response rates compared with 5-FU/LV alone across all ML and LL subgroups (statistical significance reached in 2 and >3 ML subgroups and ‘any liver’, ‘no lung’, and ‘any peritoneal’ LL subgroups). (Table 3 and 4).

Table 1. Outcomes by number of selected measurable metastatic lesions at baseline (ITT population)

Table 2. Outcomes by selected lesion location at baseline (ITT population)

Table 3. Efficacy of nal-IRI + 5-FU/LV vs. 5-FU/LV in selected baseline ML number subgroups (ITT population)

Table 4. Efficacy of nal-IRI + 5-FU/LV vs. 5-FU/LV in selected baseline LL subgroups (ITT population)

Key conclusions

  • Results from this post hoc analysis of the NAPOLI-1 trial suggest that the presence of liver lesions, and to some degree, the number of measurable MLs at baseline may be useful prognostic indicators for survival and disease progression outcomes, regardless of treatment.
  • A treatment benefit for nal-IRI plus 5-FU/LV over 5-FU/LV alone was observed in most baseline ML number and all LL subgroups; however, statistical significance was not reached in all groups and small subgroup numbers preclude firm conclusions.
  • Overall, these data support the use of nal-IRI plus 5-FU/LV in patients with mPDAC previously treated with gemcitabine-based therapy, regardless of measurable MLs or LLs at baseline.

References: 1. 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. 2. Siveke JT, Hubner RA, Mercadé TM, et al. Subgroup analysis by measurable metastatic lesion (ML) number and selected lesion locations (LL) at baseline in NAPOLI-1, a phase 3 study of liposomal irinotecan (nal-IRI)±5-fluorouracil/leucovorin (FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy. J Clin Oncol (ASCO GI Annual Meeting) 2018;36(Suppl): abstr 460.