The NAPOLI 3 trial was designed to answer a very important question in the treatment of pancreas cancer – to evaluate whether NALIRIFOX, which is comprised of nanoliposomal irinotecan, oxaliplatin, infusional 5-FU and leucovorin, compared to gemcitabine and nab-paclitaxel could lead to an improvement in survival for patients who had not had prior treatment for their cancer. So this is a question that has been on the table for essentially a decade now and this is the first trial to definitively show that a quadruplet combination compared to a two-drug combination impacted outcome in all the survival parameters that one evaluates in an advanced disease trial.
The NAPOLI 3 trial was a randomised phase III trial. It was conducted in a global context, part in North America, about two-thirds in the world beyond North America and a percentage of patients were enrolled in East Asia. It was a 1:1 randomisation for NALIRIFOX compared to gemcitabine and nab-paclitaxel. The key eligibility criteria were untreated metastatic pancreas cancer, age 18 or higher, performance status of ECOG 0-1. One could not have had prior treatment except if one had had adjuvant therapy and that was completed more than a year ago. The primary endpoint was overall survival and, secondarily, progression free survival, response rates, quality of life and biomarker analysis, the latter we’re still awaiting data on.
The important outcomes of this study were that the primary endpoint was met. I’ll just make note of that because that’s not a common occurrence in pancreas cancer. In this study the median overall survival was 11.2 months compared to 9.1 months for patients with untreated metastatic pancreas cancer, a hazard ratio of 0.83. So, again, statistically significant and, more importantly, clinically meaningful. Secondary endpoints were progression free survival and that was also met with a hazard ratio of 0.65 in terms of progression free survival. So that was substantive. There was a numerical increase in response rate for NALIRIFOX compared to gemcitabine and nab-paclitaxel.
For the side effect profiles of each regimen, it was as you might expect based on the composition of the regimen. So for gemcitabine and nab-paclitaxel the main side effects were haematologic toxicity, so myelosuppression, anaemia, thrombocytopenia and neutropenia. For NALIRIFOX it was more gastrointestinal toxicity, so more nausea, vomiting, diarrhoea and hypokalaemia. Relative to other studies somewhat lower rates of neuropathy and that might relate, at least in the NALIRIFOX arm, to the use of a lower dose of oxaliplatin – it was 60mg/m2. Grade 3 neuropathy rates were, relatively speaking, acceptable compared to other studies.
How might these results impact clinical practice?
How do we utilise this information and what does it mean for the patient in front of us? To me, I think it’s clear that for a patient who has a good functional status, who has untreated metastatic disease, a combination regimen of oxaliplatin, irinotecan and 5-FU is superior to gemcitabine and nab-pacltiaxel and that’s the go-to regimen. We’re awaiting regulatory review of NALIRIFOX, so it’s not yet available in terms of immediate day-to-day practice. The implications of this trial are practice changing or practice endorsing in pancreas cancer.
I’ll just also make the note that this is the first positive phase III trial that we’ve seen in this space in a decade, outside of a maintenance setting, which applied to a relatively small group of biomarker selected individuals.
Why is pancreatic cancer so difficult to treat?
This is a common and important question is why is this disease so challenging? I think we don’t have a straightforward answer for that but a number of considerations are, firstly, there is no early detection, there’s late presentation. Patients tend to have metastatic disease at presentation. In some senses it’s a genomically complex disease with a lot of heterogeneity, but in other senses it’s relatively homogeneous in that we see almost ubiquitous KRAS, to a lesser extent P53, SMAD4 and CDKN2A mutations which, to now, have been considered undruggable but that’s changing. We are in the era of RAS therapeutics so there’s a lot of hope that that’s going to impact outcomes.
Some of the other factors are that histologically it’s a very hypovascular tumour, it has this dense stromal matrix and it has an immune suppressive microenvironment. All of these, to a greater or lesser degree, may impact why it’s so challenging. But, at the same time, I just want to make sure our viewers are aware that things are changing and the results of the NALIRIFOX trial speak to that, that we have some new options. We’re looking to identify more targeted subsets of patients where we can select a particular treatment and that has not been the context for a long time but we’re getting there in pancreas cancer.
