Second-line Pancreatic Cancer: Nanoliposomal Irinotecan

George Kim, MD:After patients have been treated with gemcitabine-based therapy; typically gemcitabine and nab-paclitaxel; we have to think about second-line therapies. There is a very important regimen that is available. It’s called the Nal-IRI regimen. It’s nanoparticle liposomal irinotecan which is combined with infusional 5-FU and leucovorin. Now, this Nal-IRI drug is very intriguing in, that it has more favorable pharmacology than irinotecan by itself. What am I speaking of, 80,000 molecules are in a liposome, that it circulates throughout the body for up to 1 week; 95% of the irinotecan stays in the liposome, allowing the half-life of irinotecan and its active metabolite, SN-38, to increase by 4-fold.

Data shows that with nanoparticle liposomal irinotecan, there’s about a 50-fold higher exposure, compared to regular irinotecan. This translates to about a 5-fold difference in the actual tumor with the liposomal formulation versus regular irinotecan, that then translates into radioactivity in preclinical mouse models, which then translates into a survival benefit in a clinical trial called the NAPOLI-1 study. This was a randomized prospective global phase III study that showed survival of 6.1 months versus 4.2 months, and had a 2-month delta in the second line, which is the standard in GI cancers. That has become a regimen that we’ve accepted in the second-line post-gemcitabine use.

What you have then is, and this is according to the National Comprehensive Cancer Network or NCCN, is the category 1 recommendation that patients are given gemcitabine-based therapy in the frontline progress, or proceed to 5-FU—based therapy in the second-line. You would give a patient gemcitabine/nab-paclitaxel when the tumor progresses or they develop toxicities such as neuropathy or thrombocytopenia. Then you would go on to 5-FU–based therapy; that being 5-FU combined with Nal-IRI showing survival benefit, FDA approved, category 1 recommendation. It does not have similar toxicities to the first-line regimen. Again, the neuropathy and thrombocytopenia are not observed with the second-line therapy.

Alternatively, if you were to choose a 5-FU—based therapy, FOLFIRINOX in the frontline, what do you do in the second line? Because the patients typically come off with residual neuropathy. Are you going to use gemcitabine/nab-paclitaxel? It’s difficult to do due to the neuropathy, and also thrombocytopenia that is observed with this first-line regimen. That is why that first sequence is so attractive and becoming more and more used; gemcitabine/nab-paclitaxel followed by 5-FU/Nal-IRI in the second-line setting.

Transcript edited for clarity.

A 57-Year-Old Man With Abdominal Pain and Unexplained Weight Loss

• A 57-year-old man was referred from his primary care clinician with complaints of persistent pain in his upper abdomen that radiate to his back
• History
  • Former smoker (35 years, quit 5 years ago)
  • Was obese (BMI 29.0), but began losing weight despite not changing his eating habits
  • Reports feeling “tired” despite regular sleep habits
  • Treated for DVT 8 months ago
  • Hypertension controlled on medication, impaired glucose tolerance
  • Family history: mother alive with type 2 diabetes, father died (MI)
• Clinical evaluation
  • CT reveals mass in head of pancreas with metastases in liver and blood vessels
  • CA19-9 level: 55 times upper limit of normal
  • ECOG PS: 1
• Diagnosis: unresectable metastatic pancreatic cancer
• Patient began treatment with IV nab-paclitaxel (125 mg/m²) plus IV gemcitabine (1000 mg/m²) on days 1, 8 and 15 of a 28-day cycle
  • Experienced grade 3 neutropenia; did not require growth factors
  • Had mild peripheral neuropathy that did not progress or require dose adjustment
• At 6 months, patient progressed and received second-line treatment with liposomal irinotecan in combination with 5-FU/LV