Mercadé TM, et al. ASCO GI 2018:379

Subgroup analysis by baseline pain intensity and baseline analgesic use in NAPOLI-1, a study of nal-IRI ± 5-FU/LV in mPDAC patients previously treated with gemcitabine-based therapy

Background

The NAPOLI-1 study previously demonstrated that nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) improved median overall survival (OS) by 45% and doubled median progression-free survival (PFS) compared to 5-FU/LV alone in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy.1 At the 2018 ASCO GI Meeting, Mercadé and colleagues reported results from a post hoc subgroup analysis in the NAPOLI-1 study, in which patients with baseline pain intensity (BPI) and baseline analgesic use (BAU) received nal-IRI plus 5-FU/LV, nal-IRI, or 5-FU/LV.2

Study design

  • NAPOLI-1 was an international, open-label, randomized, phase III trial (NCT01494506).
  • In the NAPOLI-1 study, patients were randomized to nal-IRI or 5-FU/LV therapy alone; the protocol was later amended to add a third arm of nal-IRI plus 5-FU/LV.
  • The objective of this subgroup analysis was to assess the association of BPI or BAU with outcomes and efficacy within patient subgroups defined by BPI and BAU, including the overall intent-to-treat (ITT) population, the nal-IRI plus 5-FU/LV, and the 5-FU/LV treatment arms.
  • BPI and BAU were based on the average value over a seven-day period prior to the first dose of study drug; a minimum of three days of data were required.
    • Pain was evaluated daily, and patients were asked to record pain intensity on the 100-mm visual analogue scale.
      • Higher measurements were indicative of greater pain, with each daily score reflecting pain experienced in the past 24 hours.
    • Patients were required to keep a detailed analgesic medication diary to record actual analgesic consumption.
      • For those who were unable to complete the diary, consumption was tracked based on prescriptions and recorded in the patient medical records.
      • Patients’ analgesic needs were evaluated and converted to morphine equivalent (mg/day) for standardization.

Key findings

Baseline characteristics and disposition

  • Gender, ethnicity, and Karnofsky performance status (KPS) scores varied across BPI and BAU subgroups compared with the corresponding ITT population; there was a large variation in subgroup populations.
  • Of the 417 patients in the ITT population, 295 had BPI and 299 had BAU data.
  • Median BPI was 25.0 and median BAU was 8.1 mg/day.
  • In the ITT population, 88 patients received nal-IRI plus 5-FU/LV and 76 patients received 5-FU/LV only.
  • The number of patients in the BPI and BAU subgroups is shown in Table 1.
  • There was variability in KPS score across BPI and BAU subgroups compared to the corresponding overall ITT populations.
    • Patients with BPI = 0 or BPI ≤25 and those with BAU = 0 mg/day or BAU ≤8.1 mg/day had a better KPS score than patients with BPI >0 or BPI >25, and BAU >0 mg/day or BAU >8.1 mg/day.

Table 1. Patients in the BPI and BAU subgroups

Efficacy

  • Patient subgroups with higher BPI and BAU were generally at a greater risk for mortality than those with lower BPI and BAU.
  • The median OS was consistently lower in subgroups with higher BPI or BAU in the ITT population. (Figures 1 and 2)
    • The median OS for BPI >0 was 4.7 months, versus 8.9 months for BPI = 0 (HR = 2.01; 95% CI: 1.38–2.95; p = 0.0002).
    • The median OS for BPI >25 was 4.0 months, versus 6.3 months for BPI ≤25 (HR = 1.95; 95% CI: 1.49–2.53; p <0.00000x).
    • The median OS for BAU >0 mg/day was 4.3 months, versus 7.1 months for BAU = 0 mg/day (HR = 1.85; 95% CI: 1.42–2.43; p <0.00000x).
    • The median OS for BAU >8.1 mg/day was 4.4 months, versus 6.4 months for BAU ≤8.1 mg/day (HR = 1.67; 95% CI: 1.28–2.17; p = 0.0001).
  • Patients treated with nal-IRI plus 5-FU/LV had a greater median OS compared with those treated with 5-FU/LV alone across all subgroups except for the subgroup with BPI = 0. (Table 2)
    • The improvement in median OS was statistically significant in the subgroups with BPI >0, BPI >25, and BAU >8.1 mg/day.
  • Patients treated with nal-IRI plus 5-FU/LV had a greater median PFS compared with those treated with 5-FU/LV alone across all BPI and BAU subgroups. (Table 2)
    • The improvement in median PFS was statistically significant in subgroups with BPI >0, BPI >25, BAU >0 mg/day, and BAU >8.1 mg/day.
  • Patients receiving nal-IRI plus 5-FU/LV had a higher objective response rate (ORR) and carbohydrate antigen 19-9 (CA19-9) response rate compared with those receiving 5-FU/LV alone across all BPI and BAU subgroups. (Table 2)
    • The increase in ORR was statistically significant in subgroups with BPI >0, BPI >25, BAU >0 mg/day, and BAU >8.1 mg/day.

Figure 1. Increased mortality risk in patients with higher BPI (BPI ITT population*)

Figure 2. Increased mortality risk in patients with higher BAU (BAU ITT population*)

Table 2. Efficacy of nal-IRI + 5-FU/LV vs. 5-FU/LV in BPI and BAU subgroups (ITT population)

Safety

  • The safety profile in the overall BPI and BAU populations was similar across subgroups, except for abdominal pain. There were no new safety signals.
    • Grade 3/4 non-hematologic adverse events (AEs) in >5% of the overall safety population included late-onset diarrhea, vomiting, nausea, fatigue, asthenia, and abdominal pain.
      • More patients in the subgroups with higher BPI or BAU reported abdominal pain compared with those in subgroups with lower BPI or BAU.
    • The most common grade 3/4 hematologic AE based on laboratory values was drug-related AE.
  • The safety profile was similar across BPI and BAU subgroups when comparing nal-IRI plus 5-FU/LV with 5-FU/LV treatment arms.
  • Dose modifications based on treatment-emergent adverse events (TEAEs) were similar across BPI and BAU subgroups.
  • Patients in subgroups with higher BPI or BAU had a higher incidence of TEAEs leading to treatment discontinuation compared with those in subgroups with lower BPI or BAU.

Key conclusions

  • Higher BPI and BAU may be useful prognostic parameters for patients with mPDAC previously treated with gemcitabine-based therapy.
  • Treatment benefit was maintained in patients with high and low BPI and BAU across most subgroups that received nal-IRI plus 5-FU/LV versus 5-FU/LV alone.
  • The safety profile for nal-IRI plus 5-FU/LV in the BPI and BAU subgroups was consistent with the overall NAPOLI-1 population.
  • This post hoc analysis supports the use of nal-IRI plus 5-FU/LV in patients with mPDAC previously treated with gemcitabine-based therapy who have either high or low BPI and BAU.

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. Mercadé TM, Siveke JT, Dean A, et al. Subgroup analysis by baseline pain intensity (BPI) and baseline analgesic use (BAU) in NAPOLI-1, a phase 3 study of liposomal irinotecan (nal-IRI)±5-fluorouracil/leucovorin (5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy. J Clin Oncol (ASCO GI Meeting) 2018;36(Suppl):abstr 379.