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SAN FRANCISCO -- A four-drug chemotherapy combination coaxed a statistically significant 2-month improvement in overall survival (OS) in untreated metastatic pancreatic cancer versus a gemcitabine-containing regimen, a large randomized trial showed.

Median OS was 11.1 months with liposomal irinotecan (Onivyde), 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (NALIRIFOX) as compared with 9.2 months with gemcitabine and nab-paclitaxel (Abraxane). Median progression-free survival (PFS) increased from 5.6 months with gemcitabine/nab-paclitaxel to 7.4 months with NALIRIFOX.

All-grade, grade ≥3, and serious treatment-emergent adverse events (TEAEs) occurred in a similar proportion of patients in the two groups, reported Zev Wainberg, MD, of UCLA Medical Center-Santa Monica in California, at the ASCO Gastrointestinal Cancers Symposium.

"The OS and PFS benefits are generally consistent, regardless of ECOG [performance] status, region, and liver metastatic disease, and the safety profile with NALIRIFOX was manageable and consistent with the profiles of the treatment components," said Wainberg. "These results support NALIRIFOX as a new reference regimen for the first-line treatment of patients with metastatic pancreatic cancer and, hopefully, something we can build off of in the future."

NALIRIFOX does indeed represent a new standard of care for untreated metastatic pancreatic ductal adenocarcinoma, agreed ASCO invited discussant Laura Goff, MD, of Vanderbilt-Ingram Cancer Center in Nashville. She agreed with Wainberg and colleagues that NALIRIFOX led to clinically meaningful and statistically significant improvement in OS and PFS, and that the benefits were generally consistent.

However, Goff quibbled with the investigators' conclusion that NALIRIFOX toxicity was manageable and consistent with known effects of the regimen's components. Both regimens were highly toxic but with different toxicity profiles, which could factor into treatment decisions for patients who are unfit and unable to tolerate aggressive regimens, she said.

"I do feel that for fit patients, these results support NALIRIFOX as the new reference regimen for first-line treatment of metastatic pancreas carcinoma," Goff concluded.

Gemcitabine-based therapy has remained the standard first-line therapy for metastatic pancreatic cancer for decades. Liposomal irinotecan plus 5-FU and leucovorin is approved for second-line treatment after progression with gemcitabine-containing treatment, Wainberg noted.

In a the NALIRIFOX regimen achieved "promising" activity as second-line therapy for metastatic pancreatic cancer. The results supported the current phase III trial to evaluate NALIRIFOX as first-line therapy for metastatic pancreatic cancer.

NAPOLI-3 involved 770 patients with untreated metastatic pancreatic cancer, randomized to NALIRIFOX or gemcitabine/nab-paclitaxel. The primary endpoint was OS. The trial had a median follow-up of 16.1 months.

The primary analysis showed that NALIRIFOX reduced the survival hazard by 17% (95% CI 0.7045-0.9881, P=0.0355). The 1.8-month difference in PFS represented a 31% reduction in the risk of disease progression or death versus the control arm (95% CI 0.5786-0.8334, P<0.0001). Objective response rate also favored the NALIRIFOX arm (41.8% vs 36.2%).

Almost 90% of patients in both treatment groups had grade ≥3 TEAEs, which were treatment-related in about 70% of cases. More than half of the patients in each arm had serious TEAEs, which were related to treatment in 26.5% of the NALIRIFOX arm and 19.0% in the control group. Fatal TEAEs occurred in about 6% of both groups and were treatment related in about 2% of each group.

Gastrointestinal TEAEs were more common with NALIRIFOX, whereas anemia and pyrexia occurred more often in the control arm.

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