Nanoliposomal irinotecan: patient selection

Nanoliposomal irinotecan with 5-FU/LV (nal-IRI +5-FU/LV) has become accepted as a second-line treatment for PDAC after gemcitabine-based therapy. In NAPOLI-1, key inclusion criteria were good performance status and adequate hematological (absolute neutrophil counts >1.5×109 cells/L), hepatic (normal total bilirubin, and albumin levels ≥30 g/L), and renal function. Patient groups were further stratified by ethnicity, time since receiving most recent anticancer therapy, tumor stage at diagnosis, status of liver metastases, and baseline CA19-9. Adjusting for all these prognostic factors, nal-IRI +5-FU/LV showed an OS benefit in most of these patient populations. The only sub-groups favoring 5-FU/LV over nal-IRI +5-FU/LV were those treated on irinotecan previously, but definite conclusions cannot be made due to the small sample sizes of the subgroups. Since this study included few patients who were previously treated with irinotecan, the study concluded that the efficacy of nal-IRI after FOLFIRINOX is not clear. Also, it might be prudent not to offer systemic therapy in patients with poor performance status, as they were excluded from the study.19

Glassman et al demonstrated that the performance statuses of patients receiving nal-IRI are not significantly correlated with median OS and PFS. They enrolled 56 patients, and of those more than 20% had an ECOG (Eastern Cooperative Oncology Group) status of two or worse, compared with only 8.5% of patients who had a Karnofsky performance status of 70 or worse in NAPOLI-1 study. Median OS and PFS were not significantly different among different ECOG groups. However, it was reported that patients who previously progressed on previous irinotecan-based chemotherapy had significant short PFS and OS. They also compared the differences in median OS and PFS in treatment sequences. The OS seen across all sequences of treatments with FOLFIRINOX and/or nab-paclitaxel/gemcitabine prior to nal-IRI +5-FU/LV significantly increased with small differences in median OS. Median OS for patients with stage III or IV PDAC receiving nal-IR regardless of their first-line treatment since their first diagnosis was 24.2 months, ranging from 23 to 28 months. Also, it was shown that there is a trend that patients receiving nal-IRI +5-FU/LV in earlier lines of therapy had significant longer PFS and OS, although the sample size was very small.40 This is a potential source of future research, looking into other settings for nal-IRI usage in real-time practice experience.

Nanoliposomal irinotecan: toxicities

Studies have also examined nanoliposomal irinotecan’s toxicities, and the NAPOLI-1 study showed that diarrhea, vomiting, and anorexia were some of the most common toxicities. The percentage of adverse effects among three groups, nal-IRI +5-FU/LV, nal-IRI monotherapy, and 5-FU/LV alone, were detailed in Table 2. Patients receiving nal-IRI with and without 5-FU/LV experienced higher rates of adverse effects compared with 5-FU/LV alone. The overall percentages of patients experiencing various adverse effects were similar between those two groups, but those receiving nal-IRI and 5-FU/LV had a significantly higher rate of neutropenia. Furthermore, a significant percentage of patients experiencing neutropenia had grade 3 or 4 toxicity (27%) compared to 15% of irinotecan monotherapy and 2 (1%) of 5-FU/LV group. Patients receiving nal-IRI had higher rates of gastrointestinal (GI) complications. Specifically, 14% of nal-IRI patients had vomiting, whereas 11% of patients receiving dual therapy and 4% of those receiving 5-FU/ LV had this side effect.19 A long acting 5HT3 antagonist, such as palonosetron, can help with the delayed nausea and vomiting of patients on chemotherapy, including those receiving nal-IRI.43 Since one of the adverse events of 5-HT3 antagonist is constipation, it might also help with the diarrhea associated with use of cytotoxic chemotherapeutic agents. Approximately one third of patients receiving nal-IRI, whether as mono or dual therapy, required dose reduction. It was shown that 70% of monotherapy with nal-IRI patients had diarrhea, whereas 59% of patients receiving dual nal-IRI/5-FU/LV and 26% of those who receiving 5-FU/LV had this side effect.19

These findings are similar to phase I and phase II trials of nal-IRI. In a study by Ko et al, which was a phase II trial, 75% of all patients had diarrhea. Fatigue was seen in 62% of patients and 20% had grade 3 or 4 toxicity in this regard.39 Forty percent of patients had neutropenia, and this was grade 3 or 4 in 30%. Chang et al (2015) detailed phase I findings, with high rates of patients with diarrhea and vomiting.44 Similar to later studies, neutropenia was common, with 33% experiencing this. Overall, the dose-limiting toxicities of nal-IRI seem to be myelosuppression and diarrhea. Kipps et al (2017) also reviewed the data on nal-IRI and offered interesting perspectives. They posit that a few different therapies can offer extended OS in the second-line setting, giving nal-IRI some value. However, they argue the strong rates of neutropenia and GI side effects are not insignificant in the palliative setting.45

Furthermore, the CONKO 003 study showed the benefit of aggressive second-line therapy in terms of OS in patients with metastatic PDAC. Specifically, they used oxaliplatin, 5-FU, and folinic acid. Although there is no clear comparison between that regimen and the 5-FU/ nal-IRI/ folinic acid used in the NAPOLI-1 trial, nal-IRI has the benefit of not being associated with paresthesia and neurotoxicity. Therefore, this helps to manage and maintain quality of life in patients with advanced malignancy and to offer a non-neurotoxic regimen since the majority of first-line chemotherapy causes neurotoxicity.25

The Memorial Sloan Kettering study experiences and outcomes with liposomal irinotecan toxicity were similar to prior studies – with nausea, vomiting, diarrhea, and neutropenia as common adverse events. The recommended dosage of nal-IRI is 70 mg/m2, but the median starting dose used in this study was 55 mg/m2, based on their physician’s preference.40 The effects of lower dose on percentage of adverse effects in the study cannot be completely excluded. They also described how dose reductions were most frequently due to fatigue and diarrhea. However, it is worth noting that dose reductions were not associated with worse outcomes. Overall, side effects were similar compared to the NAPOLI-1 trial, but lower rates of grade 3–4 toxicities may be due to the group’s lower starting doses. Common adverse events associated with liposomal irinotecan and 5-FU were anemia (89%), neutropenia (29%), diarrhea (63%), anorexia (57%), and vomiting (32%). Serious adverse events were less than 5% except for anemia 15%.40

The NAPOLI-1 trial did not compare nal-IRI with traditional irinotecan, either in outcomes or in toxicities. However, it is worthwhile to compare the two formulations of the drug, especially in terms of safety, and in a similar context. Neuzillet et al evaluated the regimen of folate, 5-FU, and irinotecan (FOLFIRI) in patients with PDAC who failed gemcitabine or platinum chemotherapy. They described approximately 57% of patients required a dose reduction. The investigators showed that hematologic and GI disturbances were common problems with patients receiving this regimen. They reported grade 3–4 hematologic toxicity in 17.5% of patients, and similar grade GI toxicity in 6.3% of patients.33

A recently presented poster from the ESMO conference also corroborated these findings. Ahn et al queried data from the Flatiron Health medical record database, which included over 2 million US cancer patients and 265 clinics. For similar dosages and lower mean performance status, in this real-world data, the authors found their cohort had fewer dose modifications than the NAPOLI-1 group. Overall, 27.2% of patients underwent a dose reduction. Progression was the most common cause for discontinuation, and overall, this study reported similar discontinuation rates compared to the NAPOLI-1 study.46

Overall, nal-IRI’s side effects and toxicities are similar to other cytotoxic chemotherapies. However, fewer toxicities were seen compared to traditional irinotecan. Furthermore, managing and preparing patients for these toxicities is where clinical experience is particularly useful. Although many patients experienced diarrhea, the drug’s stimulation of gut function can be a useful side effect in patients with metastatic PDAC who are on large doses of opiates, which can cause constipation and slowing of bowel function. However, in advanced pancreatic cancer patients who are not on opiate therapy, use of antimotility agents like loperamide and diphenoxylate-atropine (IMODIUM®) should be highly recommended. Irinotecan-based chemotherapy and chronic diarrhea also causes lactose intolerance, so it is advised for patient to avoid dairy products. Nausea and vomiting were also seen in high rates in patients receiving nal-IRI and is often seen in many patients on traditional irinotecan. Therefore, it is prudent to use long-acting anti-5-HT3 antagonists, such as palonosetron, to manage nausea and vomiting. It is important to treat these side effects preemptively rather than reactively. This is particularly important as a good way to encourage nutrition and maintain good quality of life while on treatment.

Clinical trials

The utilities of nal-IRI are being investigated in a number of clinical trials. In a few clinical trials including FUNGEMAX and FOOTPATH, the efficacy of nal-IRI/5-FU/LV is directly compared to gemcitabine and nab-paclitaxel as first-line therapy. Both of these trials are phase II. In another trial, nal-IRI is replacing traditional irinotecan as part of neoadjuvant FOLFIRINOX for patients who may undergo resection of pancreatic cancer. This is a single institution phase I trial seeking to recruit 30 patients. Another phase II trial is comparing nal-IRI with cabiralizumab and nivolumab immunotherapy and combinations of immunotherapy plus traditional chemotherapy. Another active, non-recruiting phase II trial is assessing the safety and efficacy of nal-IRI plus other therapies in previously untreated PDAC. This is a multi-site, combined phase I/II trial, with 56 actual participants, and is scheduled to be completed in 2020. Also, in the FOOTPATH trial, efforts are being made to find an optimized treatment sequence to ensure for maximal survival with more tolerable adverse effects. Examples of the ongoing clinical trials involving nal-IRI combination therapy are summarized in Table 3.47–52