Maxwell, Fiona

4136 Background: NAPOLI 3 (NCT04083235, N = 770), a global, randomized, open-label phase 3 study, demonstrated that NALIRIFOX significantly improved overall survival (OS, primary endpoint) and progression-free survival compared with nab-paclitaxel and gemcitabine in patients with untreated mPDAC. Here, we report an updated analysis of OS. Methods: Eligible patients with histopathologically/cytologically confirmed untreated mPDAC were randomized (1:1) to receive liposomal irinotecan 50 mg/m2 + oxaliplatin 60 mg/m2 + leucovorin 400 mg/m2 + 5-fluorouracil 2400 mg/m2 (NALIRIFOX, n = 383) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 (Gem+NabP, n = 387) on days 1, 8 and 15 of a 28-day cycle. Randomization was stratified by ECOG performance status, geographic region and presence/absence of liver metastases. An updated OS analysis (data cutoff: 3 October 2023) was conducted. Kaplan–Meier methods were used to estimate median (95% confidence interval [CI]) OS and hazard ratios (HRs [95% CI]) were estimated using stratified Cox proportional hazard models. The difference between groups was tested using a stratified log-rank test. Results: The median follow-up for OS was 28.7 months in the NALIRIFOX arm and 29.7 months in the Gem+NabP arm. At data cutoff, 11 patients were still receiving study treatment, all of whom were in the NALIRIFOX arm. With a total of 673 OS events (NALIRIFOX, n = 328; Gem+NabP, n = 345), median OS was 11.1 months (95% CI 10.0–12.1) in the NALIRIFOX arm compared with 9.2 months (8.3–10.6) in the Gem+NabP arm (HR 0.84 [95% CI 0.72–0.98]; nominal p = 0.026). At 12 months and 18 months, survival rates were 45.6% (95% CI 40.5–50.5) and 26.6% (22.2–31.1), respectively, in the NALIRIFOX arm and 39.6% (34.7–44.5) and 20.0% (16.1–24.1), respectively, in the Gem+NabP arm. Conclusions: In this 29-month follow-up of NAPOLI 3, NALIRIFOX continued to demonstrate improved OS compared with Gem+NabP, with 11 patients still receiving the NALIRIFOX regimen. These data confirm NALIRIFOX as a new possible standard of care and reference regimen for the first-line treatment of patients with mPDAC. Clinical trial information: NCT04083235 .

AbstractLiposomal irinotecan is a liposomal formulation of irinotecan, which prolongs circulation of irinotecan and its active metabolite SN‐38. A population pharmacokinetic (PK) model was developed based on data from seven studies (N = 440). Adequacy of the model was assessed using multiple methods, including visual predictive check. Associations between PK exposure and the incidence of diarrhea (grade ≥3) and neutropenia adverse events (AEs) (grade ≥3) at first event in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) were investigated using logistic regression based on data from two studies (the phase III NAPOLI‐1 [N = 260] and phase I/II NCT02551991 [N = 56] trials). The PKs of total irinotecan was described by a two‐compartment model with first‐order elimination, with SN‐38 formed directly by a first‐order constant from the central compartment of irinotecan or after using a transit compartment. Clearance was 17.9 L/week (0.107 L/h) and 19,800 L/week (118 L/h) for total irinotecan and SN‐38, respectively. The UGT1A1*28 7/7 homozygous genotype had no significant impact on SN‐38 clearance. Model evaluation was satisfactory for both irinotecan and SN‐38. The incidence of diarrhea (grade ≥3) at first event was significantly higher with increasing average concentrations of total irinotecan and SN‐38; there was no significant association between an increased risk of neutropenia AEs (grade ≥3) at first event and average SN‐38 concentrations. In summary, the PKs of total irinotecan and SN‐38 after administration of liposomal irinotecan were well‐described by the model. The UGT1A1*28 status had no significant impact on the PKs of liposomal irinotecan.

TPS4661 Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA for metastatic pancreatic ductal adenocarcinoma (mPDAC) following progression with gemcitabine-based therapy. A phase 1/2 study in previously untreated locally advanced/metastatic PDAC showed promising anti-tumor activity with liposomal irinotecan 50 mg/m2 free base + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin (OX) 60 mg/m2 on days 1 and 15 of a 28-day cycle (Wainberg et al. Ann Oncol 2019;30 Suppl 4: SO-005). Herein, we present the design of the phase 3 NAPOLI-3 study investigating the efficacy and safety of this regimen as first-line therapy in patients with mPDAC. Methods: NAPOLI-3 (NCT04083235) is a phase 3, open-label, randomized, global study in adults with histologically/cytologically confirmed pancreatic adenocarcinoma not previously treated in the metastatic setting. Patients are required to have one or more metastatic tumors measurable with computed tomography/magnetic resonance imaging and an Eastern Cooperative Oncology Group performance status score of 0–1. Site activation began in Dec 2019 and enrollment is ongoing. Random allocation (1:1) of 750 patients is planned to liposomal irinotecan + 5-FU/LV + OX (regimen as per phase 1/2 study) or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 on days 1, 8 and 15 in a 28-day cycle. The primary endpoint is overall survival (OS). Secondary endpoints (progression-free survival [PFS] and overall response rate assessed with Response Evaluation Criteria in Solid Tumors v1.1 criteria) will be compared only if the primary endpoint shows superiority for liposomal irinotecan + 5-FU/ LV + OX over nab-paclitaxel + gemcitabine. Safety assessments include adverse-event monitoring. Patients will continue treatment until disease progression, unacceptable toxicity or study withdrawal, and will then be followed for survival every 2 months until death or study end (when all patients have died, withdrawn consent or are lost to follow-up). Clinical trial information: NCT04083235 .

Abstract BACKGROUND: nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor). Preclinical data show that nal-IRI accumulates in BMs and prolongs survival in animal models of BM. Findings from a phase 1 expansion study (NCT01770353), evaluating patients with mBC and active BM, are reported. METHODS: This phase 1 expansion study enrolled patients with mBC who received multiple prior lines of cytotoxic therapy in the metastatic setting, including one cohort with mBC and active BM, defined as radiographic evidence of new or progressive central nervous system (CNS) metastases after radiation therapy with ≥1 lesion of ≥1 cm in the longest dimension on gadolinium-enhanced magnetic resonance imaging. Patients received nal-IRI 50 mg/m2 (free-base equivalent; FBE) every two weeks (q2w) as an intravenous infusion over 90 minutes, escalating to 70 mg/m2 FBE q2w, if tolerated. RECIST v1.1 and modified RECIST criteria were used to assses non-CNS and CNS disease, respectively. RESULTS: In total, 30 patients were enrolled (10 with active BM). Median age was 53 years (range 29–70 years) and median number of prior cytotoxic anti-cancer regimens was 3 (range 0–6); 29 patients received ≥1 dose of nal-IRI 50 mg/m2 FBE. Overall, nal-IRI monotherapy appeared to be well tolerated, and achieved ≥30% objective response rates for both CNS and non-CNS disease. Among the 10 patients with active BM, 6 achieved CNS disease control (3 partial responses [PRs] and 3 stable disease [SD]), including one patient with durable CNS SD and non-CNS PR for 2 years. Among 7 patients with serial evaluation of CNS metastases posttreatment, 6 patients achieved a reduction in target CNS lesions compared with baseline. CONCLUSION: Treatment with nal-IRI resulted in CNS disease control among 6 of 10 heavily pretreated patients with mBC and active BM. Further exploration of nal-IRI in patients with mBC and active BM is warranted.

Abstract Background nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor), using intraliposomal stabilisation technology to enable high drug load and in-vivo stability. The expansion of Phase I NCT01770353 evaluated nal-IRI in patients (pts) with mBC. Methods This Phase I expansion study enrolled mBC pts (Cohort 1: ER+ and/or PR+ HER2 BC (C-1); Cohort 2: Triple Negative BC (TNBC, C-2); Cohort 3: BC with active Brain Metastasis (C-3)). Key inclusion criteria: ECOG ≤1; adequate organ function; received >1 to ≤5 prior lines of cytotoxic therapy in metastatic setting, except TNBC pts who could have progressed within 12 months of adjuvant therapy. Pts received nal-IRI 50 mg/m2 (Free-base equivalent, FBE) q2w iv infusion, escalating to 70 mg/m2 FBE q2w, if tolerated. Results 30 pts (10 per cohort) were enrolled: 29 received >1 dose nal-IRI 50 mg/m2 FBE (median age 53 yrs, range 29-70 yrs). Median number of cytotoxic therapies prior to study entry was 3. The most frequent treatment emergent adverse events (TEAEs) were gastrointestinal disorders (all cohorts, 100%), primarily diarrhea (C-1, 100% / C-2, 100% / C-3, 70%), nausea (C-1, 80% / C-2, 56% / C-3, 30%), and vomiting (C-1, 60% / C-2, 33% / C-3, 30%). The incidence of neutropenia was low (C-1, 10% / C-2, 0% / C-3, 10%), all grade 1 / 2. Most common grade 3 TEAEs were diarrhea (28%), nausea (17%), fatigue (14%), hypokalemia (10%) and asthenia (10%), with none reported as grade 4. No grade 5 TEAEs were reported. Partial response (per RECIST) was observed in 10 pts for an objective response rate (ORR) of 35% (C-1, 40% / C-2, 33%) / C-3, 30%). Stable disease was observed in 5 pts (17%). Duration of Response (median, months) was C-1, 7.5 (6.4-13.0) / C-2, 5.6 (3.7-7.4) / C-3, 4.1 (0.0-22.2, extracranial: RECIST) / C-3, 1.8 (0.0-1.9, intracranial: mRECIST). Table 1.Study Demographics, Adverse Events, and Best Overall ResponseDemographicsCohort 1ER+ and/or PR+ Breast Cancern=10Cohort 2Triple Negative Breast Cancern=10Cohort 3Breast Cancer with Active Brain Metastasisn=10Total PopulationN=30Gender, Female, n (%)10 (100%)10 (100%)10 (100%)30 (100%)Age, Years Median (range)56 (49-68)52.5 (37-70)45.5 (29-63)53 (29-70)Race, n (%)WhiteBlack/AfricanOther8 (80%)02 (20%)8 (80%)1 (10%)1 (10%)7 (70%)1 (10%)2 (20%)23(77%)2 (7%)5(16%)Months Since Metastatic diagnosis, Months Median (Range)63.7 (16-87)20.7 (0-34)32.4 (8-55)24.0 (0-87)Number of Prior Cytotoxic Anti-cancer Regimens Median (Range)3.0 (1-6)3.0 (0-5)32.4 (1-6)3.0 (0-6)Safety PopulationCohort 1ER+ and/or PR+ Breast Cancern=10Cohort 2Triple Negative Breast Cancern=9Cohort 3Breast Cancer with Active Brain Metastasisn=10Total PopulationN=29ExposureTreatment Duration, Weeks Median (range)6.1 (0-78)12.3 (0-49)13.9 (1-105)12.3 (0-105)Adverse EventsAny TEAE10 (100%)9 (100%)10 (100%)29 (100%)Grade 38 (80%)6 (67%)10 (100%)20 (69%)Grade 41 (10%)06 (60%)3 (10%)TEAE Related to nal-IRI10 (100%)8 (89%)10 (100%)28 (97%)Grade > 36 (60%)3 (33%)3 (30%)12 (41%)TEAE Related to nal-IRILeading to Dose Adjustment*7 (70%)3 (33%)4 (40%)14 (48%)SAEs6 (60%)4 (44%)7 (70%)17 (59%)SAE Related to nal-IRI4 (40%)1 (11%)1 (10%)6 (21%)Duration of Objective ResponseRECIST 1.1RECIST 1.1RECIST 1.1mRECISTMonths Median (Range)7.5 (6.4-13.0)5.6 (3.7-7.4)4.1 (0.0-22.2)1.84 (0.0-1.9)Best Overall ResponseRECISTRECISTRECISTmRECISTComplete Response (CR)0000Partial Response (PR)4 (40%)3 (33%)3 (30%)3 (30%)Stable Disease (SD)03 (33%)2 (20%)3 (30%)Progressive Disease (PD)5 (50%)2 (22%)3 (30%)2 (20%)Not Evaluable (NE)1 (10%)1 (11%)2 (20%)2 (20%)Objective Response RateCR+PR(95% CI)4 (40%)12.2 -73.83 (33%)7.5-70.73 (30%)6.7-65.33 (30%)(6.7-65.3)*n=1 patient in Cohort 1 discontinued treatment due to TEAE related to treatment with nal-IRI CI, Confidence Interval; nal-IRI, Irinotecan Liposome Injection; SAE, Serious Adverse Event; TEAE, Treatment Emergent Adverse EventSystemic tumor response was evaluated according to RECIST version 1.1CNS tumor response was evaluated according to mRECIST (Anders C. et al., Breast Cancer Res Treat, 2014: 146(3):557-66) Conclusion nal-IRI monotherapy 50g/m2 FBE Q2W appears well tolerated, and achieved >30% ORR for systemic and CNS disease among heavily pre-treated mBC pts regardless of receptor status. Citation Format: Jasgit Sachdev, Pamela Munster, Donald Northfelt, Hyo S. Han, Cynthia MA, Fiona Maxwell, Tiffany Wang, Bruce Belanger, Bin Zhang, Yan Moore, Carey Anders. Phase I expansion study of irinotecan liposome injection (nal-IRI) in patients with metastatic breast cancer (mBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT048.

e12003 Background: Irinotecan liposome injection (nal-IRI) uses intraliposomal stabilisation technology to enable high drug load and in-vivo stability. This analysis characterizes the PK profile of nal-IRI in pts with mBC. Methods: The expansion of NCT01770353 enrolled 30 pts with mBC over three cohorts (Cohort 1: ER+ and/or PR+ BC [C-1]; Cohort 2: Triple Negative BC [C-2]; and Cohort 3: BC with active Brain Metastasis [C-3]). Key inclusion criteria: ECOG ≤1; adequate organ function; and >1 and ≤5 prior lines of cytotoxic therapy in metastatic setting. Most pts received nal-IRI 60 mg/m2 salt-based equivalent (50 mg/m2 free base equivalent [FBE]) or 80 mg/m2 (70 mg/m2 FBE) q2w by iv infusion, based on tolerance; 2 pts were treated at 40 mg/m2 (35 mg/m2 FBE). Plasma samples were collected over 360h across cycles 1, 2 &3, and analysed using LC-MS/MS for total irinotecan. Data were analysed by a non-compartmental approach using Phoenix Winnonlin, and were compared with values from studies in other tumor types. Results: 21 patients were evaluable for PK analysis (C-1, n=6; C-2, n=7; and C-3, n=8). No trend for accumulation was observed in cycle 2 or 3, when comparing total irinotecan Cmax & exposure (area under the curve at 168 h [AUC168]) versus cycle 1. At 40-80 mg/m2 (35-70 mg/m2 FBE), Cmax of irinotecan tended to increase proportionally with total dose, and was comparable to studies in other tumour types (see Table). Among 29 pts who received nal-IRI, partial response (per RECIST) was observed in 10 pts. The most related TEAEs (≥ 25%) were diarrhea, nausea, vomiting, hypokalaemia, decreased appetite and fatigue. Stable disease was observed in 5 pts. Conclusions: PK parameters in patients with mBC were comparable to historical studies in patients with other tumour types. The safety profile of nal-IRI monotherapy appeared consistent with gastrointestinal and blood disorders. [Table: see text]