Findings from the phase 3 NAPOLI 3 trial support NALIRIFOX as a novel reference regimen for first-line metastatic pancreatic ductal adenocarcinoma.
Treatment with liposomal irinotecan (Onivyde) plus 5-fluorouracil/leucovorin (5-FU) and oxaliplatin (NALIRIFOX) resulted in a statistically significant and clinically meaningful improvement in overall survival (OS) and progression-free survival (PFS) vs gemcitabine plus nab-paclitaxel in patients with treatment-naïve metastatic pancreatic ductal adenocarcinoma (PDAC), according to findings from the phase 3 NAPOLI 3 study (NCT04083235).
“These results support NALIRIFOX as a treatment reference regimen in frontline untreated pancreas cancer,” lead author Eileen M. O'Reilly, MD, Winthrop Rockefeller Endowed Chair of Medical Oncology; co-director of Medical Initiatives at the David M. Rubenstein Center for Pancreatic Cancer Research; and section head of Hepatopancreatobiliary and Neuroendocrine Cancers at Memorial Sloan Kettering Cancer Center, said during a presentation on the findings. “[It is worth] noting that the last positive phase 3 study in that space...was a decade ago.”
The study findings, which were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, indicated that the median OS in patients treated with NALIRIFOX was 11.1 months (95% CI, 10.0-12.1) vs 9.2 months (95% CI, 8.3-10.6) among those treated with gemcitabine and nab-paclitaxel (Hazard ratio [HR], 0.83; 95% CI, 0.70-0.99; P = .04). Additionally, the 12- and 18-month PFS rates in each respective arm were 45.6% (95% CI, 40.5%-50.5%) vs 39.5% (95% CI, 34.6%-44.4%) and 26.2% (95% CI, 20.9%-31.7%) vs 19.3% (95% CI, 14.8%-24.2%).
“The major subgroups all favored NALIRIFOX, including age, [ECOG] performance status, region, and even the older population that was included in the trial,” O'Reilly said.
Additionally, the median PFS by investigator assessment was 7.4 months (95% CI, 6.0-7.7) vs 5.6 months (95% CI, 5.3-5.8) in the NALIRIFOX and nab-paclitaxel arms, respectively (HR, 0.69; 95% CI, 0.58-0.83; P <.0001). Investigators also reported that the 12- and 18-month PFS rates were 27.4% (95% CI, 22.3%-32.7%) vs 13.9% (95% CI, 9.7%-18.9%) and 11.4% (95% CI, 7.1%-16.9%) vs 3.6% (95% CI, 0.5%-12.3%).
The NAPOLI 3 trial included a total of 770 patients who were 18 years or older with confirmed PDAC that was not previously treated in the metastatic setting. Moreover, patients’ metastatic disease needed to have been diagnosed within 6 weeks or less prior to screening. Additional inclusion criteria included having 1 or more measurable lesions per RECIST v1.1 criteria and an ECOG performance status of 0 or 1.
Patients were randomly assigned 1:1 and stratified based on performance status, region, and presence of liver metastases.
Patients in the NALIRIFOX arm (n = 383) received 50 mg/m2 of liposomal irinotecan, 2400 mg/m2 of 5-FU, 400 mg/m2 of leucovorin, and 60 mg/m2 of oxaliplatin on days 1 and 15 of every 28-day cycle. Those in the control arm (n = 387) received 1000 mg/m2 of gemcitabine and 125 mg/m2 of nab-paclitaxel on days 1, 8, and 15 of every 28-day cycle.
The study's primary end point was OS, with key secondary end points including PFS, overall response rate, and safety. The trial also included 2 exploratory end points: health-related quality of life and biomarker assessment. The study had an overall median follow-up of 16.1 months (95% CI, 15.3-16.8).
Most patients in both the NALIRIFOX and nab-paclitaxel arms, respectively, discontinued treatment (85.1% vs 96.1%), with the most common reasons for discontinuation being disease progression (48.0% vs 45.7%), adverse effects (AEs; 14.1% vs 23.8%), death (8.4% vs 6.7%), and other reasons (14.7% vs 19.9%).
The median age for those in the NALIRIFOX arm was 64.0 years (range, 20.0-85.0) compared with 65.0 years (range, 36.0-82.0) in the nab-paclitaxel arm. Additionally, the majority of patients in each respective arm were male (53.3% vs 59.4%) and White (82.2% vs 83.7%). Moreover, most patients had 3 or more sites of metastatic disease (38.9% vs 36.4%) and liver metastases (80.2% vs 80.4%).
A total of 41.8% (95% CI, 36.8%-46.9%) of those in the NALIRIFOX arm and 36.2% (95% CI, 31.4%-41.2%) in the nab-paclitaxel arm achieved an objective response. Among those treated with NALIRIFOX, 0.3% had a complete response (CR), 41.5% had partial responses (PRs), 25.8% had stable disease, 9.9% had progressive disease, and 22.5% were not evaluable. In the doublet chemotherapy cohort, the CR rate was 0.3%, the PR rate was 35.9%, the stable disease rate was 26.1%, the progressive disease rate was 14.5%, and 23.3% were not evaluable.
The disease control rate was 67.6% in the NALIRIFOX arm vs 62.3% in the nab-paclitaxel arm. Moreover, the median duration of response was 7.3 months (95% CI, 5.8-7.6) vs 5.0 months (95% CI, 3.8-5.6), respectively.
Approximately half of the patients in the experimental and control cohorts, respectively, received subsequent anti-cancer therapy (50.5% vs 54.4%), including systemic anti-neoplastic therapy (50.5% vs 54.1%), surgery (0.3% vs 0.5%), and radiotherapy (0.5% vs 1.1%). Moreover, 41.4% of those in the NALIRIFOX cohort and 35.4% in the nab-paclitaxel cohort underwent 5-FU–based therapy.
In terms of safety, grade 3 or higher treatment-emergent AEs (TEAEs) occurred in 87.0% of those in the NALIRIFOX cohort and 86.0% of those in the nab-paclitaxel cohort. Additionally, grade 3 or higher treatment-related AEs (TRAEs) occurred in 70.8% vs 68.1%, serious TEAEs occurred in 54.3% vs 51.5%, serious TRAEs occurred in 26.5% vs 19.0%, TEAEs leading to death occurred in 5.9% vs 6.1%, and treatment-related TEAEs leading to death occurred in 1.6% vs 2.1%, respectively.
Common high-grade hematologic TEAEs in the NALIRIFOX and nab-paclitaxel arms, respectively, included neutropenia/febrile neutropenia (23.8%/2.4% vs 38.0%/2.4%), anemia (10.5% vs 17.4%), and thrombocytopenia (1.6% vs 6.1%). Non-hematologic, high-grade TEAEs included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), and vomiting (7.0% vs 2.1%).
O’Reilly EM, Melisi D, Macarulla T, et al. Liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): 12- and 18-month survival rates from the phase 3 NAPOLI 3 trial. J Clin Oncol. 2023;41(suppl 16):4006. doi:10.1200/JCO.2023.41.16_suppl.4006