Health-related quality of life and performance status with NALIRIFOX versus nab-paclitaxel + gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma: results from the NAPOLI 3 trial

Abstract

Background

In NAPOLI 3 (NCT04083235), first-line (1L) liposomal irinotecan plus 5-fluorouracil/leucovorin plus oxaliplatin (NALIRIFOX) demonstrated statistically significant improvements in overall survival and progression-free survival compared with gemcitabine plus nab-paclitaxel (Gem + NabP) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). In this exploratory analysis, health-related quality of life (HRQoL) and performance status (PS) outcomes from NAPOLI 3 were evaluated.

Materials and methods

HRQoL was assessed at baseline, day 1 of each treatment cycle, and at end of treatment (EoT) using the European Organisation for Research and Treatment of Cancer Quality of Life core questionnaire (EORTC QLQ-C30). Analyses included patients who provided baseline and at least one subsequent assessment. A mixed model for repeated measures was used to describe score evolution over time between treatment arms. Eastern Cooperative Oncology Group (ECOG) PS was recorded in the intention-to-treat (ITT) population at baseline, days 1, 8, and 15 of each treatment cycle, and EoT. Time to deterioration (TTD) in EORTC QLQ-C30 and ECOG PS scores was estimated using the Kaplan–Meier methodology.

Results

Overall, 245 patients in the NALIRIFOX arm (ITT population, n = 383) and 232 patients in the Gem + NabP arm (n = 387) provided baseline and at least one subsequent EORTC QLQ-C30 assessment. There was an initial decline in global health status (GHS) from baseline to week 12 across both treatment arms [least-squares mean −2.4, 95% confidence interval (CI) −5.9 to 1.1; Gem + NabP: −0.7 (−4.2 to 2.9)], with no further deterioration from week 16 onwards. TTD in GHS (hazard ratio 0.74, 95% CI 0.53-1.04, nominal P = 0.08) and ECOG PS score (hazard ratio 0.72, 95% CI 0.55-0.92, nominal P = 0.009) was longer with NALIRIFOX than with Gem + NabP.

Conclusions

These data suggest that 1L NALIRIFOX provides efficacy benefits for patients with mPDAC without compromising HRQoL or PS compared with Gem + NabP.

Highlights

• •Patients with metastatic pancreatic cancer typically experience poor QoL and impaired day-to-day function.
• •All patients in NAPOLI 3 experienced an initial decline in EORTC QLQ-C30 GHS from baseline to week 12.
• •EORTC QLQ-C30 GHS stabilized at week 16 in both treatment arms, with no further deterioration.
• •NALIRIFOX was associated with longer TTD in GHS and PS than Gem + NabP.
• •First-line NALIRIFOX provides efficacy benefits without compromising QoL or PS compared with Gem + NabP.

Introduction

Pancreatic cancer is a highly aggressive disease¹ and a leading cause of cancer-related death worldwide.² Nearly half of patients present with metastatic disease at diagnosis,³ in part owing to a paucity of specific symptoms.⁴ These patients experience a considerable symptom burden, including pain, weight loss, and fatigue, which can affect daily function and compromise quality of life (QoL).¹ For patients with pancreatic cancer, health-related quality of life (HRQoL) is demonstrably worse than in the general population.⁵ Although HRQoL of patients with pancreatic cancer is generally similar to that of patients with other tumor types, patients with pancreatic cancer tend to report significantly more fatigue and score worse in psychological domains than those with other tumor types, which may relate to differences in tumor etiology.⁶ Differences in psychological domains may also relate to the poor prognosis of metastatic pancreatic cancer (5-year survival rate, 3.1%).³

Despite incremental advances, current treatments are associated with limited survival gains and toxicity that may negatively affect HRQoL. As such, there is an unmet need for new therapeutic strategies to improve survival and preserve QoL. Liposomal irinotecan (ONIVYDE, ONIVYDE pegylated liposomal; historical names include nal-IRI, MM 398, or PEP02; Ipsen, Cambridge, MA) is a liposomal formulation that encapsulates irinotecan, a topoisomerase inhibitor, in a lipid bilayer vesicle. Although non-liposomal irinotecan is used in combination therapies such as FOLFIRINOX, this formulation has a short plasma half-life and limited uptake into target tumors in animal models.^7,8 Encapsulation of irinotecan in a lipid bilayer vesicle (long-circulating liposomes) keeps irinotecan in circulation for longer before conversion to its active metabolite, SN-38, thereby protecting irinotecan from hydrolysis and rapid metabolic conversion.⁹ As a result of the difference in formulation, liposomal irinotecan demonstrates more potent antitumor activity and a higher therapeutic index (a qualitative assessment of the relative efficacy-to-safety ratio) in animal models than non-liposomal irinotecan.¹⁰

In the phase III NAPOLI 3 trial, liposomal irinotecan plus 5-fluorouracil/leucovorin plus oxaliplatin (NALIRIFOX) demonstrated significant and clinically meaningful improvements in overall survival (OS) and progression-free survival (PFS) compared with gemcitabine plus nab-paclitaxel (Gem + NabP) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).¹¹ The most frequently reported grade 3-4 treatment-emergent adverse events (TEAEs) by patients who received NALIRIFOX versus Gem + NabP in NAPOLI 3 were diarrhea (20% versus 5%), hypokalemia (15% versus 4%), and neutropenia (14% versus 25%).¹¹ Treatment-related TEAEs leading to treatment discontinuation or dose reduction occurred in 25% and 54% of patients who received NALIRIFOX and 23% and 49% who received Gem + NabP, respectively.¹¹ After 29 months of follow-up, NALIRIFOX continued to demonstrate improved median OS (11.1 months) compared with Gem + NabP (9.2 months, nominal P = 0.026), and 11 patients, all in the NALIRIFOX arm, were still receiving study treatment at data cut-off (3 October 2023).¹² NALIRIFOX has also demonstrated a median OS of 40.3 months when used as a perioperative strategy in patients with resectable PDAC.¹³

In early 2024, based on the results of NAPOLI 3,¹¹ the United States Food and Drug Administration and European Medicines Agency approved NALIRIFOX for the first-line (1L) treatment of adults (aged ≥18 years, no upper age limit) with mPDAC.14, 15, 16

In this exploratory analysis of data from NAPOLI 3, we evaluated the effects of NALIRIFOX and Gem + NabP on HRQoL [measured using the European Organisation for Research and Treatment of Cancer Quality of Life core questionnaire (EORTC QLQ-C30)] and Eastern Cooperative Oncology Group (ECOG) performance status (PS) in patients with previously untreated mPDAC.

Materials and methods

Study design and patients

Details of the NAPOLI 3 study design, inclusion criteria, and treatment have been published previously.¹¹ Briefly, NAPOLI 3 (ClinicalTrials.gov number, NCT04083235; EudraCT 2018-003585-14) was a randomized, open-label, phase III study conducted at 187 community and academic sites across Europe, North America, South America, Asia, and Australia. Adults aged 18 years or older with histologically or cytologically confirmed mPDAC previously untreated in the metastatic setting were randomized (1 : 1) to receive NALIRIFOX (liposomal irinotecan 50 mg/m², oxaliplatin 60 mg/m², leucovorin 400 mg/m², and fluorouracil 2400 mg/m²) on days 1 and 15 of a 28-day cycle, or nab-paclitaxel 125 mg/m² and gemcitabine 1000 mg/m² on days 1, 8, and 15 of a 28-day cycle. Randomization was stratified by geographical region (North America versus East Asia versus the rest of the world), PS (ECOG PS score 0 versus 1), and the presence of liver metastases (yes versus no) (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2025.105534). The study was carried out in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Consolidated Guideline on Good Clinical Practice and the requirements of the United States Food and Drug Administration or local regulatory authorities regarding the conduct of human clinical trials. The protocol was approved by the local institutional review board and independent ethics committees of the participating centers.¹¹ For a plain language summary of this manuscript, see Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2025.105534.

This QoL analysis was conducted with a cut-off date of 23 July 2022, which was the cut-off date for the original analysis of efficacy and safety.¹¹

Patient-reported outcomes

HRQoL, an exploratory outcome in NAPOLI 3, was measured using the EORTC QLQ-C30 questionnaire (v3.0), which is validated for the measurement of QoL in prospective clinical trials in patients with cancer.¹⁷ This questionnaire contains 30 items that evaluate physical (five items), role (four items), emotional (two items), cognitive (two items), and social (two items) functioning, as well as global health status (GHS; two items). High scores in the functional domains indicate high or healthy levels of functioning, and higher GHS scores indicate better QoL. There are also three symptom scales measuring nausea and vomiting (two items), fatigue (three items), and pain (two items), as well as six single items assessing other disease-related symptoms (dyspnea, insomnia, appetite loss, constipation, diarrhea) and financial impact. High scores in a symptom scale indicate a high symptom burden. Linear transformation is used to standardize raw scores, such that scores range from 0 to 100.

Patients were asked to complete questionnaires at baseline, day 1 of each treatment cycle, and at the end of treatment (30 days after the last dose). The baseline value was defined as the last observed measurement taken before first drug administration (day 1 of cycle 1).

Performance status outcomes

ECOG PS scores describe levels of functioning in patients with cancer in terms of ability to care for oneself, daily activity, and physical ability (e.g. walking or working). An ECOG PS score of 0 indicates that a patient is fully active and able to carry on all pre-disease performance without restriction, whereas higher scores indicate worsening function and reduced ability to carry out day-to-day tasks such as strenuous physical activity or work.¹⁸ In NAPOLI 3, ECOG PS score was recorded by the clinician at baseline, days 1, 8, and 15 of each treatment cycle, and at the end of treatment (30 days after last dose).

Statistical analysis

Patient-reported outcomes

Exploratory HRQoL analyses were carried out in the EORTC QLQ-C30 population, defined as all patients in the intention-to-treat (ITT) population who completed the baseline and at least one subsequent EORTC QLQ-C30 assessment.

EORTC QLQ-C30 results were summarized by treatment arm at each visit based on the number of patients with non-missing data. Change from baseline scores at each visit were compared using an analysis of covariance (ANCOVA) model with treatment as a fixed effect and baseline as a covariate adjusting by randomization stratification factors per the Interactive Web Response System. Least-squares (LS) mean changes from baseline in EORTC QLQ-C30 scores, including GHS, were evaluated. A mixed model for repeated measures was used to describe score evolution over time between treatment arms.

Time until definitive deterioration (TUDD) in EORTC QLQ-C30 score was estimated using the Kaplan–Meier methodology and defined as: the time between randomization and the first occurrence of a decrease of at least 10 points in the EORTC QLQ-C30 score compared with the baseline score, without a subsequent increase of at least 10 points or without further data due to discontinuation.¹⁹ Treatment arms were compared using a stratified log-rank test and the estimated hazard ratio (HR) from the stratified Cox regression analysis was used to summarize treatment effect.

Performance status outcomes

Post hoc ECOG PS analyses were conducted in the ITT population. Time to deterioration (TTD) in ECOG PS was defined as the time from randomization to the first observation of ECOG PS score ≥2. Data were censored at the date of the last ECOG PS assessment if no deterioration was observed. TTD in ECOG PS score was compared between treatment arms using an unstratified log-rank test and presented using Kaplan–Meier plots. HRs were estimated using the Cox proportional hazards model. Additional analyses were conducted using different definitions of deterioration, which included a change in ECOG PS score to ≥3 or a change of ≥1 or ≥2 levels from baseline.

Exploratory analyses of OS and PFS were also conducted in patients for whom an ECOG PS score of 0 or 1 at baseline was maintained at the end of treatment. This analysis included patients who were still receiving study treatment at the time of the primary analysis.

Results

Patient characteristics and EORTC QLQ-C30 completion

Overall, 245 patients (64.0% of the ITT population, n = 383) in the NALIRIFOX arm and 232 patients (59.9% of the ITT population, n = 387) in the Gem + NabP arm provided baseline and at least one subsequent EORTC QLQ-C30 assessment. Patient demographics and baseline characteristics were balanced between the treatment arms (Table 1) and were broadly similar to those of the overall study population,¹¹ except for a slightly higher proportion of patients with ECOG PS score 0 across both treatment arms.

Table 1.

Baseline characteristics of the EORTC QLQ-C30 population^a

Characteristic	NALIRIFOX (n = 245)	Gem + NabP (n = 232)
Age, years, median (range)	64.0 (20.0-85.0)	64.0 (36.0-80.0)
Men, %	54.3	59.5
White, %	82.0	88.4
ECOG PS score, %
0/1	46.5/53.5	50.4/49.6
Number of metastatic sites, %
1/2/≥3	27.8/30.6/41.6	35.3/28.0/36.6
Liver metastases, %	79.6	78.4
Geographic region, %
North America	29.0	29.3
East Asia	3.7	3.9
Rest of the world	67.3	66.8
Main pancreatic tumor location
Head	38.0	37.1
Otherb	62.0	62.9
Baseline CA 19-9, %c
<37 U/ml	15.9	19.0
≥37 U/ml	83.7	81.0
Time from metastatic diagnosis at study entry until randomization, weeks, median (range)	3.14 (0.6-8.9)	3.43 (0.4-10.9)

CA, carbohydrate antigen; ECOG PS, Eastern Cooperative Oncology Group performance status; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life core questionnaire; Gem, gemcitabine; ITT, intention-to-treat; NabP, nab-paclitaxel; NALIRIFOX, liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin.

^aThe ITT population in NAPOLI 3 included 383 patients in the NALIRIFOX arm and 387 patients in the Gem + NabP arm.

^bBody, tail, or unknown location.

^cOne patient (0.4%) from the NALIRIFOX arm had missing baseline CA 19-9 values.

At baseline, the EORTC QLQ-C30 questionnaire was completed by 74.4% and 71.6% of patients in the ITT population of the NALIRIFOX and Gem + NabP arms, respectively. There was a gradual week-on-week decline in questionnaire completion: at week 16, 42.8% and 36.7% of patients randomized to receive NALIRIFOX and Gem + NabP, respectively, had completed questionnaires (Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.105534).

Change from baseline in EORTC QLQ-C30 scores

Baseline GHS and functional and symptom scores were similar across treatment arms. At baseline, mean [± standard deviation (SD)] GHS score was 62.1 (±20.4) in patients receiving NALIRIFOX and 61.2 (±21.5) in those receiving Gem + NabP. Between baseline and week 12, GHS scores decreased in both treatment arms {NALIRIFOX LS mean −2.4 [95% confidence interval (CI) −5.9 to 1.1]; Gem + NabP: −0.7 [95% CI −4.2 to 2.9]}. From week 16 onwards, there was no worsening of GHS scores in the NALIRIFOX arm relative to the Gem + NabP arm (Figure 1). Over the duration of follow-up, there was a trend toward improvement in GHS scores for patients receiving NALIRIFOX compared with those receiving Gem + NabP.

Figure 1.

Least-squares mean change from baseline in EORTC QLQ-C30 global health status and functional scale scores^a over time (left) and symptom scale scores^b (right) over time (EORTC QLQ-C30 population). EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life core questionnaire; Gem, gemcitabine; GHS, global health status; NabP, nab-paclitaxel; NALIRIFOX, liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin. ^aHigher scores indicate improvement. ^bLower scores indicate improvement. ^cValues obtained every 4 weeks.

Changes from baseline to week 12 in functional scores varied across domains. In both treatment arms, physical and role functioning scores declined [physical: LS mean −6.4 (95% CI −9.7 to −3.1) versus −5.3 (95% CI −8.7 to −1.9); role: LS mean −7.2 (95% CI −11.9 to −2.5) versus −4.4 (95% CI −9.2 to 0.5)], whereas emotional functioning scores increased [6.4 (95% CI 3.2-9.7) versus 9.6 (95% CI 6.2-12.9)]. The direction of change varied across treatment arms for the social [−5.2 (95% CI −9.7 to −0.7) versus 0.8 (95% CI −3.8 to 5.5)] and cognitive [−1.5 (95% CI −4.6 to 1.7) versus 1.1 (95% CI −2.1 to 4.4)] functioning domains. There was no worsening of functional scores in the NALIRIFOX arm relative to the Gem + NabP arm from week 16 onwards (Figure 1).

Across both treatment arms, symptom scores increased (symptom burden worsened) or remained stable between baseline and week 12 for diarrhea [LS mean 24.6 (95% CI 19.7-29.5) versus 4.5 (95% CI −0.5 to 9.6)], fatigue [LS mean 6.9 (95% CI 2.8-10.9) versus 2.6 (95% CI −1.6 to 6.7)], dyspnea [LS mean 0.1 (95% CI −4.0 to 4.2) versus 4.3 (0.1-8.5)], and financial difficulties [LS mean 7.0 (95% CI 2.9-11.2) versus 3.3 (95% CI −1.0 to 7.6)]. Scores decreased (symptom burden improved) for pain [−13.3 (95% CI −17.2 to −9.4) versus −14.7 (95% CI −18.7 to −10.6)], insomnia [−9.2 (95% CI −13.8 to −4.7) versus −11.0 (95% CI −15.7 to −6.3)], and constipation [−11.7 (95% CI −16.1 to −7.2) versus −15.8 (95% CI −20.4 to −11.2)] in both treatment arms. Direction of change varied across treatment arms for nausea and vomiting [5.0 (95% CI 2.0-8.1) versus −2.5 (95% CI −5.7 to 0.7)] and appetite loss [1.5 (95% CI −4.0 to 7.0) versus −12.8 (−18.4 to −7.1)]. From week 16 onwards, there was no worsening of fatigue, pain, dyspnea, constipation, and insomnia symptom scores in the NALIRIFOX arm compared with the Gem + NabP arm (Figure 1).

Time to deterioration in EORTC QLQ-C30

The median TUDD of GHS score was 15.7 months with NALIRIFOX and 12.2 months with Gem + NabP (stratified Cox HR 0.74, 95% CI 0.53-1.04, nominal P = 0.08) (Figure 2). At 3, 6, and 12 months, 18.8% versus 18.9%, 26.4% versus 31.7%, and 39.8% versus 48.7% of patients in the NALIRIFOX and Gem + NabP arms, respectively, experienced deterioration in GHS. Median TUDD was longer for physical, role, and emotional functioning, and pain, dyspnea, and constipation, with nominal P ≤ 0.05, in patients who received NALIRIFOX versus Gem + NabP (Figure 3).

Figure 2.

Kaplan–Meier estimate of TUDD in EORTC QLQ-C30 global health status score (EORTC QLQ-C30 population). CI, confidence interval; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life core questionnaire; Gem, gemcitabine; HR, hazard ratio; NA, not available; NabP, nab-paclitaxel; NALIRIFOX, liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin; QoL, quality of life; TUDD, time until definitive deterioration.

Figure 3.

TUDD in selected EORTC QLQ-C30 scale scores (EORTC QLQ-C30 population). CI, confidence interval; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life core questionnaire; Gem, gemcitabine; HR, hazard ratio; NA, not available; NabP, nab-paclitaxel; NALIRIFOX, liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin; TUDD, time until definitive deterioration.

Time to deterioration in ECOG PS score

Analyses were conducted in the ITT population (NALIRIFOX, n = 383; Gem + NabP, n = 387). The median follow-up for ECOG PS was 5.6 months and 4.3 months in the NALIRIFOX and Gem + NabP arms, respectively. Treatment with NALIRIFOX was associated with a longer TTD of ECOG PS score to ≥2 than Gem + NabP (HR 0.72, 95% CI 0.55-0.92, nominal P = 0.009) (Figure 4). Additional analyses using different definitions of ECOG PS score deterioration (deterioration to PS score ≥3, deterioration by ≥1 PS level, and deterioration by ≥2 PS levels) yielded similar results (HR 0.67, P = 0.087; HR 0.85, P = 0.066; and HR 0.75, P = 0.097, respectively) (Supplementary Figure S2, available at https://doi.org/10.1016/j.esmoop.2025.105534).

Figure 4.

Kaplan–Meier estimate of TTD in ECOG PS score. CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; Gem, gemcitabine; HR, hazard ratio; NabP, nab-paclitaxel; NALIRIFOX, liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin; NE, not evaluable; NR, not reached; TTD, time to deterioration.

Efficacy in patients with maintained ECOG PS score

In the ITT population, 315 patients in the NALIRIFOX arm and 296 patients in the Gem + NabP arm had an ECOG PS score of 0 or 1 at baseline that was maintained at the end of treatment. Among these patients, median OS was numerically longer for those receiving NALIRIFOX than Gem + NabP (12.3 versus 11.4 months; HR 0.88, 95% CI 0.72-1.07) (Supplementary Figure S3A, available at https://doi.org/10.1016/j.esmoop.2025.105534). Median PFS was also numerically longer in the NALIRIFOX arm than in the Gem + NabP arm (7.7 versus 5.7 months; HR 0.69, 95% CI 0.56-0.86) (Supplementary Figure S3B, available at https://doi.org/10.1016/j.esmoop.2025.105534).

Discussion

Patients with mPDAC typically experience poor QoL owing to symptom burden and potential treatment-related toxicity. In this exploratory analysis, baseline GHS scores for patients receiving NALIRIFOX and Gem + NabP in NAPOLI 3 were lower than general population norms [NALIRIFOX: mean 62.1 (± SD 20.4); Gem + NabP: 61.2 (±21.5); general population: 66.1 (±21.7)]²⁰ but were consistent with those reported in other clinical trials of 1L treatments for mPDAC.^21,22 In the NAPOLI-1 trial in patients with mPDAC previously treated with a gemcitabine-based regimen, liposomal irinotecan, a component of the NALIRIFOX regimen, in combination with 5-fluorouracil/leucovorin (5-FU/LV), maintained QoL and significantly improved OS versus 5-FU/LV alone.²³ Similarly, in the PRODIGE trial, FOLFIRINOX (non-liposomal irinotecan plus 5-FU/LV plus oxaliplatin) maintained QoL and significantly improved clinical outcomes compared with gemcitabine, albeit with increased toxicity.²⁴ The present exploratory analysis of QoL and ECOG PS data from NAPOLI 3 suggests that the significant and clinically meaningful improvements in OS and PFS with 1L NALIRIFOX compared with Gem + NabP were achieved without compromising the QoL or PS of patients with mPDAC.

In NAPOLI 3, patients in both treatment arms experienced an initial decline in GHS, as well as several functional and symptom domains, from baseline to week 12. Changes in the nausea and vomiting, diarrhea, and appetite loss symptom scores reflected the observed adverse event (AE) profiles of NALIRIFOX and Gem + NabP in NAPOLI 3. As such, these data could be attributed to the impact of AEs on QoL because the burden of treatment-related symptoms, such as diarrhea, appeared to increase, whereas the burden of disease-related symptoms (e.g. pain and insomnia) appeared to decrease. The stabilization of functional and symptom domain scores at week 16, with no further deterioration, could reflect the impact of treatment on cancer control as well as other factors such as adequate toxicity management (e.g. dose reduction or other supportive measures). In addition to stabilization of EORTC QLQ-C30 scores at week 16 across both treatment arms, this analysis demonstrated a numerically longer median TUDD in GHS and significantly longer (nominal P ≤ 0.05) TUDD in physical, role, and emotional functioning, and some symptom domains, including pain, with NALIRIFOX than with Gem + NabP. This was similar to reports from the PRODIGE trial, in which significant increases in TUDD in QoL were also noted in the FOLFIRINOX arm versus gemcitabine arm for all functional and symptom scales at 6 months after treatment initiation.²⁴

Rapid identification and management of AEs is critical to optimize treatment benefit and maintain QoL. Although the proportions of patients with grade ≥3 TEAEs (87% versus 86%) and TEAEs leading to dose reduction (56% versus 50%) or discontinuation (32% versus 30%) were similar in the NALIRIFOX versus Gem + NabP arms in NAPOLI 3, the tolerability profiles of the two treatments differ.¹¹ In a systematic review and meta-analysis including data from 2581 patients with mPDAC receiving 1L NALIRIFOX, Gem + NabP, or FOLFIRINOX in seven phase III clinical trials, NALIRIFOX was associated with a lower incidence of grade ≥3 anemia and neutropenia than Gem + NabP and a lower incidence of thrombocytopenia (1.6%) than Gem + NabP (10.8%) and FOLFIRINOX (11.8%).²⁵ Compared with the other regimens, NALIRIFOX was associated with the highest incidence of diarrhea, Gem + NabP with the highest incidence of anemia and peripheral neuropathy, and FOLFIRINOX with the highest incidence of febrile neutropenia and vomiting.²⁵ Of note, pharmacological management of diarrhea per institutional or international guidelines was permitted but not mandated in NAPOLI 3. Current management recommendations include the administration of atropine for early-onset and loperamide for late-onset diarrhea of any severity, and the next chemotherapy treatment cycle is held until diarrhea resolves (severity of less than grade 1).^14,15 Exploratory analyses of AE management strategies in NAPOLI 3, including pharmacological management of diarrhea and use of granulocyte-colony stimulating factor for neutropenia, are ongoing.

Data from this post hoc exploratory analysis of TTD of ECOG PS with NALIRIFOX versus Gem + NabP suggest that NALIRIFOX maintains the health of patients for longer than Gem + NabP. Preservation of PS may enable patients to receive further treatment with improved outcomes. Among patients in whom an ECOG PS score of 0 or 1 was maintained at the end of treatment in this analysis, NALIRIFOX was also associated with a numerical improvement in OS and PFS compared with Gem + NabP and compared with the overall trial population.¹¹ However, these analyses should be interpreted with caution owing to the high proportion of data that were censored.

Limitations of this analysis include potential outcome bias owing to the open-label study design, as well as the number of missing HRQoL assessments, which declined gradually on a week-by-week basis. It is unclear whether the stabilization of EORTC QLQ-C30 scores at week 16 across both arms and the improvement in median TUDD with NALIRIFOX were related to the attrition in questionnaire compliance, which may have led to selection of patients with better HRQoL. In addition, although the EORTC QLQ-C30 is a validated, cancer-specific questionnaire, it may not fully capture the lived experience of patients with mPDAC or the burden of therapy-specific AEs.

Conclusions

Taken together with the results of the NAPOLI 3 trial, these data suggest that 1L NALIRIFOX provides efficacy benefits without compromising HRQoL or PS compared with Gem + NabP. These data support the approval of NALIRIFOX as a new 1L treatment for patients with mPDAC.^14,15