Navigating Complexities of Localized Pancreatic Cancer, NETs

Brandon Scalea

Philip A. Philip, MD, PhD, FRCP

Philip A. Philip, MD, PhD, FRCP

Recent years have been transformative in terms of headway made with adjuvant chemotherapy for patients with locally advanced pancreatic cancer, said Philip A. Philip, MD, PhD, FRCP, and the next steps for research are to determine whether these regimens can be moved into the neoadjuvant setting.

Based on the PRODIGE 24/CCTG PA.6 trial, FOLFIRINOX has emerged as the preferred adjuvant approach in this patient population, but it’s not an easy regimen to tolerate, said Philip, who is a professor of Medicine at Wayne State University School of Medicine and clinical professor of oncology at Barbara Ann Karmanos Cancer Institute. For certain patients, gemcitabine plus capecitabine may be a reasonable option.

Meanwhile, in the field of neuroendocrine tumors (NETs), the peptide receptor radionuclide therapy (PRRT) Lutathera (lutetium Lu 177 dotatate) has addressed a significant unmet need, leading to tumor shrinkage in a subset of patients. Results from the phase III NETTER-1 study led to the January 2018 FDA approval of this therapy, thus adding another tool to the treatment arsenal for patients with inoperable, advanced gastroenteropancreatic NETs who progress on somatostatin analogues.

In an interview during the 2019 OncLive® State of the Science Summit™ on Gastrointestinal Malignancies, Philip discussed recent studies that have impacted locally advanced pancreatic cancer treatment and shared key updates in the NETs paradigm.

OncLive: What are the biggest advances in the adjuvant and neoadjuvant settings of locally advanced pancreatic cancer?

Philip: Adjuvant chemotherapy has undergone significant improvement over the last decade. We've seen an evolution from single-agent gemcitabine, to combination therapy of gemcitabine and capecitabine, to the most recent advancement, FOLFIRINOX. We first heard about this combination in 2018 during a presentation. [Data from a French study] showed a significant improvement in survival with FOLFIRINOX compared with gemcitabine. [Since then, this regimen] has really increased our survival of patients who have localized disease—which is, by itself, a real improvement. You must keep in mind that the majority of patients do not have localized disease. Nevertheless, for that subset of patients, this has been a nice improvement from what we’re used to [seeing with] adjuvant therapy. Not only that, looking at the study itself, there is evidence suggesting that with some modification of the FOLFIRINOX dose, we can treat patients with less toxicity. However, if you look at the study itself, you still see that many patients may not be able to [tolerate] the treatment because of the adverse events (AEs).

This leads to the next point, which is what the next phase of development will be. In fact, we are now giving combination chemotherapy before surgery. Starting treatment before surgery means that we can give the combination before it becomes more difficult for the patients to tolerate it. At this point in time, you may argue that it's still experimental. This may be the case, but many people have moved toward the use of neoadjuvant therapy now. The neoadjuvant therapy in the United States is FOLFIRINOX, which is used mostly in patients with borderline resectable disease. Slowly, we will learn how to use combination chemotherapy, even in patients with resectable disease.

There's also evidence that another combination we use in the advanced setting, gemcitabine plus nab-paclitaxel (Abraxane), can help patients in the locally advanced setting. Based on that data, this could be another option for patients who cannot receive FOLFIRINOX. We have to also wait for some other data [that will answer the question]: when you have the 2 regimens available for the patient, which one is better? There is a SWOG study that has completed accrual; this trial is looking at the regimen of FOLFIRINOX compared with gemcitabine plus nab-paclitaxel. 

What is important to know about the PRODIGE 24/CCTG PA.6 study?

The key takeaway there was that the use of FOLFIRINOX resulted in a significantly better overall survival and disease-free survival. This is something we haven't seen in prior use of adjuvant chemotherapy. The other key thing is that there was no use of radiation. This was pure systemic therapy. However, some of the patients were not able to complete the 6 months of treatment that was planned in the protocol. This raises the point that patients, or at least some patients, who undergo surgery may not able to tolerate chemotherapy as well because of the impact of surgery. Nonetheless, this was a good study showing that combination treatment is improving the survival of the patients in the adjuvant setting.

The other interesting thing about this study was the fact that patients who received gemcitabine alone, the control arm, also did well. Again, it tells you a little bit about the selection that went into this study. At the same time, it means that subsequent treatments we have now might be a factor in improving outcomes. In other words, having more options in this setting is pushing our survival forward. Overall, this was a positive trial that changed the standard of care. We used FOLFIRINOX in the past without any evidence, but now we have evidence to support that. The other point to make about this study was that the dose of irinotecan had to be reduced from 180 mg to 150 mg. 

What were the key takeaways from the phase II LAPACT trial?

The LAPACT trial was a single-arm trial of over 100 patients. It was a global trial that included patients in the United States and in Europe. In the study, patients received gemcitabine plus nab-paclitaxel; these were patients with unresectable disease. For the patients who received the treatment, we followed up their response to therapy and saw a 30% response rate, which is somewhat comparable with what we've seen in patients with the same disease who received FOLFIRINOX. Again, this was not a head-to-head comparison; it was a single-arm study. The treatment was very well tolerated, and a proportion of patients were able to undergo resection as a result of the chemotherapy. There was an update on the survival [with this approach], and hopefully we will see a full publication shortly. 

What should be noted about the phase III PREOPANC-1 study? 

This was a study looking into the use of neoadjuvant chemoradiation. Patients also received systemic therapy in the form of gemcitabine alone. The trial showed that the use of concurrent neoadjuvant chemotherapy and radiation improved the outcomes of patients who had resectable and borderline resectable pancreatic cancer. I personally believe that these data are still too premature to make a final decision about this trial. The study was not mature enough to [support the notion] that chemoradiation in the neoadjuvant setting should be the standard of care at this time. However, it's certainly a thought-provoking trial because another study led by the Alliance for Clinical Trials in Oncology raised the question of whether chemoradiation [can be used] in the neoadjuvant setting.

In my opinion, systemic therapy is necessary; there's no question about it. In my opinion, administering it before surgery improves the ability to give that therapy and maybe improve the outcome. The use of neoadjuvant chemoradiotherapy is still questionable, especially in patients who have resectable disease. 

Based on these data, what can be accomplished in the next 3 to 5 years?

There are several questions that we are still waiting to hear answers for. There is a trial being conducted in the adjuvant setting that is testing whether radiation treatment is necessary or not on top of adjuvant chemotherapy. That will be something we have to settle because we still struggle with [whether we should use] radiation or not.

 Recently, we heard that the gemcitabine plus nab-paclitaxel APACT trial, which was completed in the adjuvant setting, did not meet its primary endpoint. It really was a disappointment because that was the alternative treatment to FOLFIRINOX. We still have to wait to see the details of this study, and we hope to learn something from it. At this point in time, however, the primary endpoint was not met.

There's also the appetite to test more targeted agents in the adjuvant setting. For example, there's the possibility of adding PARP inhibitors in situations where patients have certain DNA repair defects. This accounts for a small subset of patients, certainly less than 10%, but using a PARP inhibitor in the adjuvant setting could be another step in the right direction. This is based on the recent press release from the POLO trial. There are several other approaches [under investigation], but it's still very early. For the adjuvant setting, we need to get active agents that have been tested in the advanced setting. 

Moving into NETs, what is the role of PRRT and what are the data that support this approach?

PRRT is a new treatment for us in the United States. It's an approach that has been utilized for longer in Europe and other parts of the world. At this time, Lutathera was FDA approved in January 2018. Basically, it targets the somatostatin receptor, which is expressed in 80% to 90% of patients who have NETs that are well-differentiated. In some patients with poorly differentiated NETs, there still might be some expression of it. The better-differentiated tumors tend to have a higher expression; these are used as targets for diagnostics and treatment. We have been using octreotide (Sandostatin) and lanreotide (Somatuline) as drugs to target this.

Now, Lutathera is another option that uses a radioactive payload that is attached to the ligand that binds to the receptor. We try to kill the cancer that way. The radioactive isotype we use in Lutathera is lutetium-177; this is given systemically, and the way it is given is in 4 treatments, 2 months apart. The treatment itself is given intravenously, and it only takes about a half hour. NETTER-1 showed a remarkable improvement in progression-free survival (PFS) of patients with advanced NETs.

The important thing is that we didn't have systemic therapies that would lead to tumor shrinkage in the past. We are now seeing shrinkage in close to 20% of patients with this therapy. In many more patients, we still stable disease for a long time. Therefore, if you look at the PFS curves, they are dramatically separated in this study.

The downside of PRRT is with some of the AEs we see, such as bone marrow suppression. There is a risk of myelodysplasia or even leukemia, which probably around 1%. This can damage the kidneys, but then we counteract that by infusing amino acids. The downside of the amino acid infusion has been nausea and vomiting. Lutathera itself does not cause nausea, but the amino acid infusion we give to protect the kidneys can cause it. This is controllable, of course.

For the first time, we have an effective systemic therapy available for these patients. Is this the end of our research? No. It's just the beginning, because we are now trying to learn several things. One of them is patient selection and the other is sequencing. Are we going to start with PRRT at the outset of diagnosis? Another line of research is combining PRRT with other drugs like immunotherapy. We know that radiation can sometimes enhance immune response. It's a very exciting time for NETs. We also want to make sure that we keep the patients' quality of life in mind. Normally, my patients go back to work and continue their daily routines. 

How do you approach managing AEs associated with Lutathera?

To be honest, when we treat the patients, there isn't something too specific that we do for them. We warn the patients about the AEs, and that fatigue will be one of them. They might need to adjust their lifestyle accordingly. There is no real advice we give to them regarding diet or anything like that; it's the usually advice about health practices. We certainly warn them about the effects [of the treatment] on blood counts, but it's not like we're seeing patients come in with neutropenic fever or anything like that. Sometimes, the myelosuppression will delay getting the next treatment, but there isn't much in the way of managing these AEs. 

What are some emerging therapies for NETs?

One ongoing study is looking at the use of cabozantinib (Cabometyx). There was a prior trial that showed an improvement in patients with pancreatic NETs and small bowel primaries. We are watching this study carefully because it could be another systemic therapy option. There are also other targeted agents out there, such as mTOR inhibitors. Going back to PRRT, we are looking at other isotopes and possibly changing the ligand. All of these things are currently being tested. 
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