Nanoliposomal irinotecan (MM-398, nal-IRI) population pharmacokinetics (PK) and its association with efficacy and safety in patients with solid tumors based on the phase 3 study NAPOLI-1 and five phase 1 and 2 studies

Background: NAPOLI-1, a global, phase 3 randomized trial in 417 patients with metastatic pancreatic cancer previously treated with gemcitabine evaluating a nanoliposomal formulation of irinotecan (nal-IRI) with or without 5-fluorocuracil and leucovorin (5FU/LV). Nal-IRI+5FU/LV vs 5FU/LV, significantly improved OS (median 6.1m vs 4.2m; HR=0.57; P=0.0009). The most frequent grade 3+ AEs were neutropenia, fatigue, diarrhea, and vomiting. Mouse xenograft models have shown that unlike free irinotecan, nal-IRI prolonged circulation and increased intratumoral concentration of irinotecan (IRI) and SN-38 (active metabolite of irinotecan) corresponding with antitumor activity. We report population PK of total irinotecan (IRI) and SN-38 and their associations with safety in patients from 6 studies and with efficacy in patients from NAPOLI-1

Methods: PK analysis was performed for IRI and SN-38 in 353 patients from 6 studies of nal-IRI 60–80mg/m² and also administered alone (120mg/m² q3 weeks) or nal-IRI (80mg/m² q2 weeks) + 5FU/LV in NAPOLI-1. Covariates included body surface area (BSA), UGT1A1*28 7/7, bilirubin, liver metastasis, AST, ALT, albumin, CrCl, gender, ethnicity, age, and external factors (co-treatment with 5FU/LV, manufacturing site). Relationships of PK-efficacy (OS, PFS, ORR) were evaluated for each treatment arm in NAPOLI-1 and PK-safety (neutropenia, diarrhea, and anemia) were evaluated from all 6 studies.

Results: In NAPOLI-1, compared to patients treated with 120mg/m² q3 weeks, nal-IRI 80mg/m² q2 weeks had similar C_avg, but 1.5-fold lower C_max for both IRI and SN-38. In patients treated with nal-IRI+5FU/LV, higher SN-38 C_avg was associated with improved OS, PFS, and ORR. In a pooled analysis of 353 patients from 6 studies, SN-38 C_max was associated with grade 3+ neutropenia and IRI C_max was associated with grade 3+ diarrhea. Based on PK analysis of 353 patients, significant covariates to IRI were ethnicity and BSA and covariates to SN-38 were baseline bilirubin and BSA. No other covariates, including UGT1A1*28, were significant. When nal-IRI exposures and incidence rates of AEs were predicted from a dose of 80mg/m², Asians (43%) had a 0.5 x lower IRI C_max than Caucasians (5% lower predicted grade 3+ diarrhea), but a 1.5 x higher SN-38 C_max than Caucasians (7% higher predicted grade 3+ neutropenia). Patients with bilirubin 1.0–2.0mg/dL (n=20) had a 1.4 x higher SN-38 C_max vs patients with bilirubin <1.0mg/dL.

Conclusions: Lower-dose nal-IRI given more frequently was predicted to have similar C_avg and lower C_max. IRI C_max was associated with diarrhea and SN-38 C_max with neutropenia. Asians had lower IRI, but higher SN-38. Increasing baseline bilirubin was associated with higher SN-38 levels. Association between SN-38 and efficacy endpoints is consistent with the preclinical observation that nal-IRI increased prolonged intratumoral delivery.

Conflict of interest: Ownership: Merrimack employees (JK, BB, EB, BA). Advisory Board: JC (Eli Lilly). BM (Eli Lilly, Roche). Corporate-sponsored Research: WWM (Merrimack). JOP (GSK, Sanofi).