Wang-Gillam A, et al. ASCO GI 2018:388

Impact of dose modifications of nanoliposomal irinotecan plus 5-fluorouracil/leucovorin on efficacy in NAPOLI-1

Background

Results from the phase III NAPOLI-1 trial demonstrated that the addition of nanoliposomal irinotecan (nal-IRI) to 5-fluorouracil and leucovorin (5-FU/LV) significantly improved median overall survival (OS; 6.1 months vs. 4.2 months; p = 0.0122) compared with 5-FU/LV alone in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who progressed following gemcitabine-based therapy.1 The NAPOLI-1 trial protocol allowed dose reductions and delays of nal-IRI and 5-FU/LV to allow for recovery from treatment-related adverse events (AEs). At ASCO GI 2018, an exploratory post hoc analysis of the NAPOLI-1 trial which assessed the effect of dose modifications on OS 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 were initially randomized to receive 120 mg/m2 nal-IRI every three weeks (expressed as irinotecan hydrochloride salt, equivalent to 100 mg/m2 expressed as irinotecan free base) or 2,000/200 mg/m2 5-FU/LV weekly for four weeks of each 6-week cycle.
  • After 63 patients were enrolled, the protocol was amended to include a third treatment arm of 80 mg/m2 nal-IRI every two weeks (expressed as irinotecan hydrochloride salt, equivalent to 70 mg/m2 expressed as irinotecan free base) in combination with 2,400/400 mg/m2 5-FU/LV every two weeks.
  • The study protocol allowed for a maximum of two dose reductions for nal-IRI and 5-FU/LV, and for a dose delay of up to three weeks.
  • Treatment was continued until disease progression or unacceptable toxicity.
  • This post hoc analysis included patients in the nal-IRI plus 5-FU/LV arm who received study drug and required a dose reduction or dose delay for nal-IRI to manage AEs within the first six weeks of the study.
  • A dose reduction was defined as any reduction in the scheduled dose from the initial administered dose and a dose delay was defined as any delay in dosing greater than three days from the targeted dosing date.
  • To evaluate the impact of a dose modification on patient outcomes, OS was compared within the nal-IRI plus 5-FU/LV arm and with the 5-FU/LV arm using the cohort of patients enrolled after protocol amendment.

Study design

Key findings

  • AEs that required dose modification occurred more frequently in patients in the nal-IRI plus 5-FU/LV arm compared with patients in the 5-FU/LV arm (62% vs. 33%).
  • Of the 117 patients who received nal-IRI plus 5-FU/LV, 53 patients (45%) required a dose modification during the first six weeks of treatment.
  • A dose delay was required in 49 patients and a dose reduction was required in 34 patients (four patients who received a dose reduction did not require a dose delay).
  • The most common grade 3/4 AEs leading to nal-IRI dose delay in the first six weeks were white blood cell decrease (n = 11), neutrophil count decrease (n = 9), neutropenia (n = 8), diarrhea (n = 6), and platelet count decrease (n = 5).
  • The most common grade 3/4 AEs leading to nal-IRI dose reduction in the first six weeks were neutrophil count decrease (n = 7), neutropenia (n = 5), and white blood cell decrease (n = 5).
  • OS was greater in the nal-IRI plus 5-FU/LV treatment arm compared with the 5-FU/LV arm, regardless of whether patients received a dose delay or reduction. (Figure 1)
  • The median OS was numerically higher, but not significantly different, for patients who received a nal-IRI dose reduction within the first six weeks (n = 34) versus those who did not (n = 83) (9.4 months vs. 5.4 months; HR = 0.66, 95% CI: 0.43–1.02). (Figure 2)
  • The median OS was numerically higher, but not significantly different, for patients who received a nal-IRI dose delay within the first six weeks (n = 49) versus those who did not (n = 68) (8.4 months vs. 5.6 months; HR = 0.84, 95% CI: 0.57–1.23). (Figure 3)

Figure 1. Impact of nal-IRI dose reduction or dose delay on OS between treatment arms

Figure 2. Impact of nal-IRI dose reduction vs. no dose reduction on OS within the nal-IRI + 5-FU/LV arm

Figure 3. Impact of nal-IRI dose delay vs. no dose delay on OS within the nal-IRI + 5-FU/LV arm

Key conclusions

  • In this post hoc analysis of NAPOLI-1, OS was greater in patients who received nal-IRI plus 5-FU/LV but required a dose reduction or delay compared with those who received 5-FU/LV.
  • In the nal-IRI plus 5-FU/LV arm, the requirement of a dose reduction or delay in the first six weeks of treatment did not significantly impact OS compared with patients who did not have a dose modification.
  • This analysis suggests that an appropriate dose modification of nal-IRI plus 5-FU/LV during the first six weeks of treatment does not adversely affect the OS outcomes achieved with nal-IRI plus 5-FU/LV treatment.

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. Wang-Gillam A, Hubner R, Mirakhur B, et al. Dose modifications of nanoliposomal irinotecan (nal-IRI) + 5-fluorouracil/leucovorin (5-FU/LV) in NAPOLI-1: impact on efficacy. J Clin Oncol (ASCO GI Annual Meeting) 2018;36(Suppl):abstr 388.