NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial

Author(s): Zev A Wainberg, MD¹; Davide Melisi, MD²; Teresa Macarulla, MD³; Roberto Pazo Cid, MD⁴; Sreenivasa R Chandana, MD⁵; Christelle De La Fouchardière, MD⁶; Andrew Dean, MD⁷; Igor Kiss, MD⁸; Woo Jin Lee, MD⁹; Thorsten O Goetze, MD¹⁰; Eric Van Cutsem, MD¹¹; A Scott Paulson, MD¹²; Tanios Bekaii-Saab, MD¹³; Shubham Pant, MD¹⁴; Richard A Hubner, MD¹⁵; Zhimin Xiao, MD¹⁶; Huanyu Chen, PhD¹⁶; Fawzi Benzaghou, MD¹⁶; Eileen M O’Reilly, MD¹⁷

Source: DOI:https://doi.org/10.1016/S0140-6736(23)01366-1

Dr. Maen Hussein's Thoughts

You may have enrolled a patient in this trial, but it seems we may have a new first line regimen. Surprisingly toxicity simar in both arms, but there was improvement in PFS and OS (17% reduction in death) although it wasn’t statistically significant in OS.
More diarrhea with nalirifox, but more neutropenia with gem abraxane.

BACKGROUND

Pancreatic ductal adenocarcinoma remains one of the most lethal malignancies, with few treatment options. NAPOLI 3 aimed to compare the efficacy and safety of NALIRIFOX versus nab-paclitaxel and gemcitabine as first-line therapy for metastatic pancreatic ductal adenocarcinoma (mPDAC).

METHODS

NAPOLI 3 was a randomised, open-label, phase 3 study conducted at 187 community and academic sites in 18 countries worldwide across Europe, North America, South America, Asia, and Australia. Patients with mPDAC and Eastern Cooperative Oncology Group performance status score 0 or 1 were randomly assigned (1:1) to receive NALIRIFOX (liposomal irinotecan 50 mg/m2, oxaliplatin 60 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2, administered sequentially as a continuous intravenous infusion over 46 h) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2, administered intravenously, on days 1, 8, and 15 of a 28-day cycle. Balanced block randomisation was stratified by geographical region, performance status, and liver metastases, managed through an interactive web response system. The primary endpoint was overall survival in the intention-to-treat population, evaluated when at least 543 events were observed across the two treatment groups. Safety was evaluated in all patients who received at least one dose of study treatment. This completed trial is registered with ClinicalTrials.gov, NCT04083235.

FINDINGS

Between Feb 19, 2020 and Aug 17, 2021, 770 patients were randomly assigned (NALIRIFOX, 383; nab-paclitaxel–gemcitabine, 387; median follow-up 16·1 months [IQR 13·4–19·1]). Median overall survival was 11·1 months (95% CI 10·0–12·1) with NALIRIFOX versus 9·2 months (8·3–10·6) with nab-paclitaxel–gemcitabine (hazard ratio 0·83; 95% CI 0·70–0·99; p=0·036). Grade 3 or higher treatment-emergent adverse events occurred in 322 (87%) of 370 patients receiving NALIRIFOX and 326 (86%) of 379 patients receiving nab-paclitaxel–gemcitabine; treatment-related deaths occurred in six (2%) patients in the NALIRIFOX group and eight (2%) patients in the nab-paclitaxel–gemcitabine group.

INTERPRETATION

Our findings support use of the NALIRIFOX regimen as a possible reference regimen for first-line treatment of mPDAC.

FUNDING

Ipsen.

Author Affiliations

¹David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; ²Università degli studi di Verona and Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy; ³Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; ⁴Hospital Universitario Miguel Servet, Zaragoza, Spain; ⁵Cancer and Hematology Centers of Western Michigan, Grand Rapids, MI, USA; ⁶Centre Léon Bérard, Lyon, France; ⁷St John of God Subiaco Hospital, Subiaco, WA, Australia; ⁸Masaryk Memorial Cancer Institute, Brno, Czech Republic; ⁹National Cancer Center, Goyang, South Korea; ¹⁰Krankenhaus Nordwest, Frankfurt am Main, Germany; ¹¹University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium; ¹²Texas Oncology-Baylor Charles A Sammons Cancer Center, Dallas, TX, USA; ¹³Mayo Clinic, Scottsdale, AZ, USA; ¹⁴MD Anderson Cancer Center, Houston, TX, USA; ¹⁵The Christie NHS Foundation Trust, and Division of Cancer Sciences, University of Manchester, Manchester, UK; ¹⁶Ipsen, Cambridge, MA, USA; ¹⁷Memorial Sloan Kettering Cancer Center, New York, NY, USA

Nimotuzumab Plus Gemcitabine for K-Ras Wild-Type Locally Advanced or Metastatic Pancreatic Cancer

Asian study of nimotuzumab (humanized EGFR-inhibitor) + gemcitabine (gem) vs. gem alone. The overall survival (OS) was 10.9 vs. 8.5 months in favor of the combination arm. While the OS difference is small, recall that the OS in the NALIRIFOX and FOLFIRINOX studies are similar. The safety profile of nimotuzumab + gemcitabine is superior to a triplet or double cytotoxic chemotherapy combination regimen. This drug is currently not available in the USA but is approved for nasopharyngeal carcinoma in China.

Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial

Somewhat disappointing as this was a negative study, however it is still an option for patients who are not candidates for mFOLFIRINOX.

Randomized Study of Temozolomide or Temozolomide and Capecitabine in Patients With Advanced Pancreatic Neuroendocrine Tumors (ECOG-ACRIN E2211)

Positive study for the combo of TMZ + cape vs. TMZ alone in met-pNET, confirming a regimen that is already widely used. Patients were first-line, and those with MGMT-def had a better response.

NAPOLI-3: A randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).

The NAPOLI-3 study assessed FOLFOX+ liposomal irinotecan vs. gemcitabine + nab-paclitaxel. NALIRIFOX was superior, with an OS of 11.1 vs. 9.2 months. Criticisms of modern gem trials are often that of rigid dosing requirements that differ from modern clinical practice. Additionally, it is unclear whether NALIRIFOX provides any meaningful benefit over FOLFIRINOX, and the cost is always a consideration.

Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer

Another maintenance trial, NO statistically significant OS benefit but prolonged time to second-line chemotherapy. HR was favored Olaparib.