Superior overall and progression-free survival with NALIRIFOX compared to nab-paclitaxel + gemcitabine in first-line metastatic pancreatic ductal adenocarcinoma
TALAPRO-2 is the first phase III study investigating the efficacy of a PARP inhibitor (talazoparib) with enzalutamide as first-line therapy for men with metastatic castration-resistant prostate cancer. Compared to enzalutamide alone, this combination led to a significant improvement in radiographic progression-free survival and a delay in the time to a clinically meaningful deterioration in quality of life. The toxicity of this combination regimen was generally manageable and in line with the expected safety profiles of both agents
Background
The prognosis for patients with metastatic pancreatic cancer remains to be very poor, underscoring the need for more effective treatment strategies for these patients. The combination of irinotecan with 5-fluorouracil/leucovorin (5-FU/LV) is already approved for the treatment of mPDAC patients with disease progression on gemcitabine-based therapy. Building on this, a phase 1/2 study showed promising anti-tumor activity with the NALIRIFOX regimen, consisting of a combination of liposomal irinotecan (50 mg/m2), 5-FU (2400 mg/m2), LV (400 mg/m2) and oxaliplatin (60 mg/m2), in previously untreated mPDAC patients. In turn, these data formed the basis for the randomized, open-label, phase III NAPOLI 3 study in which NALIRIFOX was compared to the standard combination of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) (Gem+NabP) as first-line therapy for patients with mPDAC. Earlier this year, data presented at ASCO GI showed the superiority of NALIRIFOX over Gem+NabP in terms of OS and PFS. During ASCO 2023, additional data were presented for this study, including the rates of PFS and OS at the 12- and 18-month landmark.
Study design
NAPOLI 3 enrolled a total of 770 patients with histopathologically, or cytologically confirmed previously untreated mPDAC and randomized them (1:1) to receive either NALIRIFOX on days 1 and 15 of a 28-day cycle or Gem+NabP on days 1, 8 and 15 of a 28-day cycle. The primary endpoint of the study was OS; with PFS, overall response rate (ORR) and safety as secondary objectives.
Results
At the time of the presented analysis, 85.1% of patients in the NALIRIFOX arm and 96.1% in the Gem+NabP arm had discontinued therapy. The main reasons for this treatment discontinuation were progression or clinical deterioration (48% vs. 45.7%) and adverse events (AEs, 14.1% vs. 23.8%). The median age of patients in the trial was 65 years, 57% of patients had an ECOG performance status of 1 and 80% had liver involvement. Furthermore, roughly a third of patients had 3 or more metastatic lesions and about 80% had a baseline CA19-9 level ≥37 U/mL.
The median OS for patients treated with NALIRIFOX was reported at 11.1 months, which is significantly longer than the 9.2 months median OS seen with Gem+NabP (HR[95%CI]: 0.83[0.70-0.99]; p= 0.04). At 12 months, this translated into an OS rate of 45.6% with NALIRIFOX and 39.5% with Gem+NabP. At the 18 months landmark, these rates were reported at 26.2% and 19.3%, respectively. Importantly, the OS benefit obtained with NALIRIFOX was maintained across all investigated subgroups, irrespective of sex, age, the presence of liver metastases, the number of metastatic sites, the baseline ECOG performance score and the main pancreatic tumor location (head or other). Also in terms of PFS, NALIRIFOX outperformed Gem+NabP with a median PFS of 7.4 and 5.6 months, respectively (HR[95%CI]: 0.69[0.58-0.83]; p< 0.0001). The corresponding PFS rates for NALIRIFOX and Gem+NabP at 12 and 18 months were reported at 27.4% vs. 13.9% and 11.4% vs. 3.6%, respectively. The ORR obtained with NALIRIFOX was 41.8%, which is significantly higher than the 36.2% ORR seen with Gem+NabP. Responses with NALIRIFOX were also more durable with a median response duration of 7.3 months as compared to 5.0 months with Gem+NabP.
Importantly, the incidence of grade ≥3 treatment-related AEs was fairly similar in both arms at 70.8% and 68.1% with NALIRIFOX and Gem+NabP, respectively. The same held true for the incidence of serious treatment-related AEs at 54.3% and 51.5%, respectively. Treatment-related AEs leading to death occurred in 1.6% of patients in the NALIRIFOX arm and in 2.1% in the Gem+NabP arm.
Conclusions
NALIRIFOX is associated with a significantly better OS, PFS and ORR compared to Gem+NabP in the first line treatment of patients with mPDAC. This benefit translated into markedly superior rates of OS and PFS with NALIRIFOX after 12- and 18-months. The safety profile observed with NALIRIFOX was manageable and consistent with the toxicity profiles of the different treatment components. As such, these data support NALIRIFOX as a new reference regimen in the first line treatment of patients with mPDAC.
Reference
O’Reilly E, 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. Presented at ASCO 2023; Abstract 4006.
