Jordan D. Berlin, MD, discusses the unmet needs in pancreatic cancer treatment and ongoing research efforts with nanoliposomal irinotecan.
The treatment arsenal for pancreatic cancer has been historically limited, with chemotherapy serving as the strongest weapon of choice, according to Jordan D. Berlin, MD; however, now, targeted agents are emerging for certain subsets of patients and a key focus of research has been focused on determining the role of nanoliposomal irinotecan (Onivyde) in the paradigm.
“In terms of chemotherapy, we currently have gemcitabine, nab-paclitaxel [Abraxane], and FOLFIRINOX [leucovorin/5-fluorouracil (5-FU)/irinotecan/oxaliplatin]. However, these therapies are for patients with good performance status; they’re not for all patients,” Berlin explained. “Looking forward, I believe that…there is a potential role for nanoliposomal irinotecan, either in the first-line setting, if the NAPOLI-3 trial turns out positive, or certainly after gemcitabine-based chemotherapy, due to results from the NAPOLI-1 trial. I don’t believe we have all the answers we need yet. However, the future looks very promising.”
In October 2015, the FDA approved nanoliposomal irinotecan for use in combination with 5-FU and leucovorin in patients with metastatic pancreatic cancer following a previous gemcitabine-based regimen, based on data from the phase 3 NAPOLI-1 trial (NCT01494506). Specifically, results showed a 1.9-month improvement in overall survival (OS) with the addition of nanoliposomal irinotecan to 5-FU/leucovorin.1 The median OS was 6.1 months versus 4.2 months with the combination versus 5-FU/leucovorin alone (HR, 0.57; 95% CI, 0.41-0.80; P =.0009).
The ongoing, open-label, randomized phase 3 NAPOLI-3 trial (NCT04083235) trial is examining the nanoliposomal irinotecan regimen plus oxaliplatin in the frontline setting for treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma.2 The primary end point of the trial is OS, with key secondary end points being progression-free survival and overall response rate. “At the end of the day, this could shift how we do things. Ultimately, it’s going to be a very interesting study and we are anticipating the results,” said Berlin.
In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on Gastrointestinal Malignancies, Berlin, Ingram Professor of Cancer Research, professor of medicine, VICC associate director for clinical research strategy, director of the Phase I Program in Gastrointestinal Malignancies, Clinical Trials, in the Department of Medicine at Vanderbilt University Medical Center, discussed the unmet needs in pancreatic cancer treatment and ongoing research efforts with nanoliposomal irinotecan.
Berlin: There is a limited treatment armamentarium in pancreatic cancer. We currently [really only] have chemotherapy. You could argue that we do have some targeted therapies because you could treat NTRK fusions with TRK inhibitors, microsatellite instability (MSI)–high disease with immunotherapies, and germline BRCA-mutated disease with PARP inhibitors although, this [accounts for] less than 5% of the pancreatic cancer population.
Chemotherapy has done well for us, but not well enough. Many unmet needs remain in pancreatic cancer. The holy grail would be to figure out a way to make immunotherapies [effective] in this disease. Currently, there is no reason to use [that approach], except in those who have MSI-high disease.
Furthermore, [we need to look at] metabolism, other [agents] that inhibit DNA damage repair, and PARP inhibitors. Of course, we must define some of the more common mutations in pancreatic cancer such as CDKN2A, P53, and the grandfather of them all, RAS. A KRAS G12C inhibitor is being evaluated but, once again, that's not the mutation that [often] happens in pancreatic cancer; it will only affect a very small minority of patients. As such, we need agents that will target the disease that we face [in practice].
The NAPOLI-1 trial was very interesting. They initially designed the study to compare single-agent, nanoliposomal irinotecan with 5-fluorouracil (5-FU)/leucovorin. However, they added on the combination arm of nanoliposomal irinotecan plus 5-FU/leucovorin, and that was the arm that successfully beat 5-FU/leucovorin for patients with pancreatic cancer after they received previous gemcitabine-based therapy in a randomized trial.
This has not moved the bar a lot because we haven't clarified the differences between nanoliposomal irinotecan and standard irinotecan in terms of efficacy. Clearly, nanoliposomal irinotecan has a slightly different toxicity profile and it may also be less toxic [than the standard]. You get more SN-38 per mg of drug in the tumor; however, you also use a lower number of drugs; as such, it is unknown how much more SN-38 is really delivered to the tumor. [We do know that it] doesn’t overcome resistance to irinotecan; that would not be expected.
This did show that irinotecan plus 5-FU and leucovorin is clearly [another] regimen [to consider]. It’s possible that nanoliposomal irinotecan plus 5-FU/leucovorin is better than 5-FU, leucovorin, and irinotecan (FOLFIRI), but we don’t know for certain. FOLFIRI does not have any [data from] randomized trials; nanoliposomal irinotecan plus 5-FU and leucovorin is the combination that has level-one evidence. Due to the quandary with irinotecan, the uptake is not as great as we had hoped, but we would love to learn more about its role versus irinotecan.
NAPOLI-3 is ongoing; no data are available yet. This trial is going to answer a major question in the space, which is: Is a FOLFIRINOX-type regimen better or the same as gemcitabine and nab-paclitaxel, when tested on the same grounds?
The difference between FOLFIRINOX and this is that they are using nanoliposomal irinotecan instead of standard irinotecan. It will not be definitive for FOLFIRINOX versus gemcitabine and nab-paclitaxel because there is a chance that nanoliposomal irinotecan produces a better regimen when used in the combination with leucovorin/5-FU/oxaliplatin. If that’s the case, and if the nanoliposomal irinotecan regimen [is better], then we must determine if that is translatable to FOLFIRINOX or do we have to go with the regimen that has level-one evidence.
If they are equivalent, it will not move the bar much on what we currently do. I tend to use FOLFIRINOX as frontline therapy in eligible patients, although a larger number of patients are eligible for gemcitabine and nab-paclitaxel. This is because there were broader eligibility criteria in that first-line study than there was with the FOLFIRINOX regimen.
There's room for nanoliposomal irinotecan in many diseases. However, if irinotecan is already used, sooner rather than later we need to prove the benefit of nanoliposomal irinotecan over the standard. It's difficult to justify the increased costs without knowing that there's truly a benefit. When furthering this research, they could choose any disease they wish [to evaluate this], because many diseases are responsive. They can also go to diseases that don’t have much irinotecan-based data available, such as high-grade neuroendocrine tumors and small cell lung cancer.
For example, in one randomized trial, cisplatin/irinotecan did not beat cisplatin/etoposide in the United States, but it beat it in Japan. It’s possible that they could beat it with nanoliposomal irinotecan. There are many areas that they can explore in terms of research, although I don't believe there's anywhere else they need to go in pancreatic cancer.
I believe they're doing the right trial for the drug and there's nowhere else that they would need to study, unless they want to look at it in combination with other DNA damage repair–affecting agents like ATR inhibitors. ATR inhibitors could potentiate the irinotecan, making it a better agent for this disease.
Nanoliposomal irinotecan is supposed to have less of the toxicities that are typical of irinotecan, such as diarrhea. We currently are not sure if there is less cholinergic syndrome. We don’t have a head-to-head comparison of these agents yet, due to the different doses. As such, we can’t be certain that [nanoliposomal irinotecan is safer], but one would hope that this is the case.
Targeted therapies are still limited in the pancreatic cancer space. They're limited to the small subset of patients who may be able to respond to TRK inhibitors and the small subset who may be able to respond to PARP inhibitors. We recently studied patients with germline BRCA mutations, which is a good subset; however, it is a small portion of the total patients that have trouble with DNA damage repair. This includes patients with non-germline BRCA mutations, as well as patients with both germline and somatic mutations of PALB2, ATM, POL, and ARID1A, which are all areas ripe for investigation in terms of PARP inhibition and ATR inhibition.
We have the RAS mutation and there are several drugs under development in this area. There are drugs that are trying to take advantage of the RAS mutation to try and figure out a way to enhance the the immunogenicity of pancreatic cancer.
CDKN2A is a cyclin-dependent kinase that's mutated. Inhibitors such as CDK4/6 may work better or may enhance the effects of other agents. So, there's a lot of areas that are worth investigating. We also don't fully understand the transforming growth factor beta (TGF-β) pathways, but there are TGF-β inhibitors. SMAD4 is in that pathway and certainly is abnormal in a significant portion of patients with pancreatic cancer.
Finally, there may be ways to take advantage of P53. The WEE1 inhibitors were thought to be a way, and they still may be, we just have to learn how to use these agents. This is the focus of some ongoing studies.
To date, the biggest study is the Precision Promise study, which is being carried by the Pancreatic Cancer Action Network. This trial is trying to understand the biology of pancreatic cancer, while also learning from each patient and targeting specific abnormalities that are unique to the disease. This should hopefully yield a lot of scientific knowledge, as well as hopefully some positive clinical trials. Ultimately, there is a lot going on in the space and we foresee a bright future.