Episode 1: The NAPOLI-3 study, the benefit of triplet therapy in first-line treatment of metastatic pancreatic ductal adenocarcinoma
Presented by Prof Eric Van Cutsem (University Hospitals Leuven) and Prof Marc Van den Eynde (Cliniques Universitaires Saint-Luc)
The NAPOLI-3 study emerges as a pivotal contribution to the field of metastatic pancreatic cancer. This phase 3 study undertakes a comparative assessment of two contemporary regimens for first-line treatment of pancreatic cancer. One arm of the study administered NALIRIFOX, a triplet regimen comprising liposomal irinotecan with 5-fluorouracil/leucovorin + oxaliplatin. The other arm employed a chemotherapy regimen of nab-paclitaxel + gemcitabine (Gem+NabP). The primary endpoint, overall survival (OS), is a clinically pertinent marker in first-line treatment for metastatic pancreatic ductal adenocarcinoma (mPDAC) patients.
The study unequivocally demonstrated the superiority of the triplet regimen in terms of OS, yielding a median OS benefit of approximately 2 months, accompanied by a favourable impact on progression-free survival (PFS). Safety considerations revealed regimen-specific toxicities, with heightened digestive toxicity in the triplet regimen group and increased general toxicity in the Gem+NabP cohort.
Historically, the debate surrounding the efficacy of triplet versus doublet regimens lacked comparative data. This study is groundbreaking in definitively asserting the superior OS benefits associated with initiating a triplet therapy in mPDAC patients, thereby offering crucial insights for clinical practice. Questions persist regarding whether the positive outcomes of NALIRIFOX triplet therapy can be ascribed to superior tolerance and dose adaptations or if the concept of triplet therapy inherently surpasses doublet regimens in efficacy. Additionally, deliberations revolve around the applicability of this regimen to all patients.
In the context of treating diseases with poor prognoses, experts advocate for the early use of a triplet regimen. Although cross-study comparisons are challenging, earlier FOLFIRINOX findings demonstrated increased OS. Given the significant digestive and haematological safety concerns associated with the initial FOLFIRINOX, experts recommend the modified regimen. Therefore, under the correct dose and patient selection, the triplet regimen is deemed superior for these patients.
The relevance of these findings lies in the establishment of a new feasible standard regimen, challenging the prevailing Gem+NabP standard for select patients. Anticipation surrounds the incorporation of this therapy into guidelines by regulatory authorities. Experts deliberate on whether NALIRIFOX treatment forms the basis for future studies, potentially in combination with novel agents. While a direct comparison with modified FOLFIRINOX may not be forthcoming, the identified superiority of triplet therapy for OS underscores its significance.
Gem+NabP retains its value for patients ineligible for triplet therapy, yet, in cases of favorable general patient status, the initiation of triplet treatment in the first line is advocated.
References:
Wainberg ZA. et al. (2023) 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). Journal of Clinical Oncology 41:4_suppl, LBA661.