Analysis Confirms Survival Benefit With Nanoliposomal Irinotecan Regimen in Pancreatic Cancer

Li-Tzong Chen, MD, PhD

Patients with metastatic pancreatic ductal adenocarcinoma lived longer and had slowing of disease progression when nanoliposomal irinotecan was added to 5-fluorouracil (5-FU) and leucovorin, irrespective of treatment history, a posthoc analysis of a randomized trial showed.

Treatment with irinotecan plus 5-FU/leucovorin led to a median overall survival (OS) of 7.1 months versus 4.3 months with 5-FU/ leucovorin alone among patients with disease progression after gemcitabine monotherapy. Patients who initially received a gemcitabine combination had a median OS of 6.1 versus 4.2 months in favor of 5-FU/ leucovorin plus irinotecan.

Median progression-free survival (PFS) improved by about 1.5 to 2.0 months with the addition of irinotecan to 5-FU/ leucovorin, according to a report at the Gastrointestinal Cancers Symposium in San Francisco.

“Numerical differences favoring irinotecan plus 5-FU/ leucovorin were observed for all efficacy outcomes,” Li-Tzong Chen, MD, PhD, an investigator at the National Institute of Cancer Research in Taiwan, and colleagues concluded in a poster presentation. “Therefore, this sensitivity analysis supports the benefit of irinotecan plus 5-FU/ leucovorin in patients who previously received gemcitabine monotherapy or gemcitabine combination therapy.

“The safety profiles observed in the individual subgroups were similar to those in the parent patient populations and did not appear to be influenced by prior treatment,” they added. “These results show consistent benefit of nal-irinotecan plus 5-FU/ leucovorin across subgroups of patients who had previously received gemcitabine-based therapy.”

The results came from a post-hoc analysis of the phase III NAPOLI-1 trial, which compared the combination of irinotecan and 5-FU/ leucovorin versus 5-FU/ leucovorin alone in patients with metastatic pancreatic ductal adenocarcinoma that had progressed after gemcitabine-based therapy. The primary results showed significant improvement in OS, PFS, and objective response rate (ORR) with the combination versus 5-FU/ leucovorin alone.

FOLFIRINOX chemotherapy and the nab-paclitaxel/gemcitabine doublet are the principal first-line therapies for metastatic pancreatic cancer, and no second-line standard has yet to emerge, Dr. Chen and colleagues noted. The NAPOLI-1 trial was conducted before nab-paclitaxel/gemcitabine received approval as first-line treatment for metastatic pancreatic cancer.

The post-hoc analysis was designed to evaluate the efficacy and tolerability of irinotecan plus 5-FU/ leucovorin in patients according to prior gemcitabine-based therapy: monotherapy or a combination, including nab-paclitaxel/gemcitabine. The analysis included 236 of the original 417 participants in NAPOLI-1, 117 randomized to irinotecan and 119 assigned to 5-FU/ leucovorin monotherapy.

Patients previously treated with a gemcitabine combination had a more extensive treatment history, as about half of the patients in that subgroup had received 2 or more prior regimens. Otherwise, the gemcitabine monotherapy and combination groups were similar.

Median duration of treatment among patients who received gemcitabine monotherapy was 15 weeks for irinotecan and 5-FU/ leucovorin and 10 weeks for 5-FU/ leucovorin. In the subgroup that received a gemcitabine combination, median treatment duration was 19 weeks with irinotecan and 8 weeks without.

The efficacy analysis showed that patients previously treated with gemcitabine monotherapy had a 19% reduction in the survival hazard when treated with irinotecan plus 5-FU/ leucovorin (95% CI, 0.54-1.22). Among patients who received a gemcitabine combination, the hazard ratio was 30% lower with nal-irinotecan (95% CI, 0.48-1.02). By comparison, the overall NAPOLI-1 results yielded a 33% reduction in the hazard ratio in favor of nal-irinotecan (95% CI, 0.49-0.92, P = 0.012).

The analysis of PFS showed a median of 4.1 months with irinotecan and 2.2 months without in the subgroup that received gemcitabine monotherapy (HR 0.63, 95% CI, 0.41-0.95). In the gemcitabine combination subgroup, the median PFS was 3.1 vs 1.4 months in favor of irinotecan (HR 0.54, 95% CI, 0.36-0.81).

Similar to the overall NAPOLI-1 results, overall response rates favored irinotecan treatment, regardless of whether patients had previously received gemcitabine alone or as a component of combination therapy.

In the subgroup of patients who received gemcitabine monotherapy, treatment-related adverse events (AEs) led to dose modification (including delay, reduction, and discontinuation) in 69% of patients assigned to nal-irinotecan versus 38% of those who received only 5-FU/ leucovorin. Corresponding rates in the gemcitabine combination subgroup were 76% and 35%.

Neutropenia was the AE that most often led to dose modification in patients who previously received gemcitabine monotherapy (33%) or combination therapy (35%). Other AEs leading to dose modification in the gemcitabine monotherapy group were diarrhea (17%) and vomiting (11%). In the patients previously treated with a gemcitabine combination, other notable AEs leading to dose modification were decreased white blood cell count (16%), anemia (10%), and diarrhea (10%).