 There have been many studies in neuroendocrine cancers that have looked at the role for immunotherapy, in particular checkpoint inhibitors. Most of those studies haven’t panned out to be helpful in terms of improving progression-free survival or response rate. There are reports in studies of small response rates, but it hasn’t shown the promise that we wanted. There’s been a lot of emphasis in looking at poorly differentiated neuroendocrine carcinomas in high-grade neuroendocrine cancers to see if that patient population would be the most ideal. The reason for that is, those patients tend to have a higher mutational burden and may be more responsive to immunotherapies compared with our lower or intermediate-grade neuroendocrine cancers, where the mutational burden is generally very low.

Those trials are still ongoing. There’s 1 trial of combination of ipilimumab-nivolumab that did look like there was a positive response, but unfortunately, that study and subsequent studies haven’t been replicated. That the jury is still out on the role of immunotherapy with our disease. Importantly, as a result, since the checkpoint inhibitors by themselves haven’t been proven to be helpful, adding that on to therapies that we know already have promise and activity and could potentially result in a better outcome or better progression-free survival. That’s where the money will be. But by itself, unfortunately, we haven’t seen the results that wanted to date.

What’s exciting about neuroendocrine cancers is we were the first to have a targeted approach. Somatostatin analogues 30 years ago were a targeted approach. PRRT [peptide receptor radionuclide therapy], 177Lu-DOTA-TATE is a targeted approach to target the somatostatin receptor, and it works incredibly well. We’re all very excited about that, and we want to build on that. There are other opportunities and things in the pipeline to think about how we can improve the outcomes for our patients of as well as our tomorrow.

For example, 177Lu-DOTA-TATE is a very exciting drug. Could we potentially use other therapies or other alpha emitters, for example, other types of radiolabeled therapies to improve patient outcomes? Those studies are ongoing. Alpha therapies, for example, have shown promise in prostate cancer. That’s being tested in neuroendocrine cancers. The role for other types of somatostatin receptors with other radiolabeled therapies is something to look out for that we’re all excited about.

We’re constantly looking for other targeted approaches as well. Tons of work, for example, on CAR [chimeric antigen receptor] T cells, which haven’t panned out in terms of finding the right antigen for neuroendocrine cancers, but that’s something to be mindful of. There are other types of VEGF approaches. Surufatinib is very exciting, and maybe combinations with those VEGF inhibitors could be something to look out for. It’s very important to try to use big databases to help us understand what we could learn from big patient populations of sequencing of treatments and when the right time is for these different therapies. That’s where the money is for neuroendocrine cancers: to try to understand what’s the right approach for all these therapies that we have, to better build on that, and to give a better outline of when we should give these therapies and to whom.

The unmet needs for NETs [neuroendocrine] are many. The good news is our patients can live for a very long time. The not-so-good news is that they have to endure a lot of adverse effects sometimes from all these therapies. Patient-reported outcomes and quality-of-life questionnaires are really important.

I always want to give a plug for the caregiver. There’s an unmet need to make sure we understand that these diseases are family diseases. It’s not just the patient population and the biological and clinical needs that patients have but also the emotional and psychological needs that come along with such a diagnosis and a chronic disease and focusing on the whole family. Many of our patients are quite young. With young patients and the financial toxicities that some of our patients endure, we have to study more. Taking care of the patient as a whole is something that I’m passionate about.

Lastly, we’re constantly trying to get to the cure. We want to be proud of the work that’s been done in this disease. No other GI [gastrointestinal] cancer has had so much promise like neuroendocrine cancers. We’ve talked about many of them today with surufatinib, other VEGF inhibitors, and PRRT. They’ve completely changed the natural history of this disease, which is incredibly exciting. But we still have more work to do. Finding more novel therapies and potential approaches with fewer toxicities is something that we’re all mindful of and passionate about.

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Looking toward the future management of neuroendocrine tumors, Diane Reidy-Lagunes, MD, shares insight on possible therapy evolutions and ongoing unmet needs.

Future Directions in the Management of Neuroendocrine Tumors

 There were 2 very important and exciting studies in China in the role of surufatinib in our patients with neuroendocrine cancers. Both of those studies showed improved progression-free survival as well as response rate when compared with placebo. The first study was SANET-p, which was in patients with pancreatic neuroendocrine tumors. There were 172 patients randomized in a 2:1 setting to receive either 300 mg daily of surufatinib or placebo. That study was positive with a progression-free survival of 19.3 months in the surufatinib arm vs 11 months in the placebo arm, again leading to the FDA approval in China of surufatinib.

The second study was SANET-ep, which was patients with extrapancreatic neuroendocrine cancers. It was a 2:1 randomization where our patients on the experimental arm received 300 mg of surufatinib daily vs placebo. The progression-free survival was 9.2 months vs 3.8 months, indicating an FDA approval in China for this drug in extrapancreatic neuroendocrine cancers. It’s of note that it’s the first antiangiogenic inhibitor in extrapancreatic neuroendocrine cancers since 2011, when sunitinib was approved in the United States for pancreatic neuroendocrine cancers. Both studies showed that the adverse-event profile was consistent where it was mostly hypertension, proteinuria, and some fatigue.

The ideal patient for surufatinib would be someone who had a progressive disease after somatostatin analogue therapy, where particularly they may have disease outside the liver and need good disease control. We still need to do research into understanding who the ideal patient would be. Is there a biomarker, for example, that you’d consider for the VEGF inhibitors compared with, for example, PRRT [peptide receptor radionuclide therapy]? We don’t have that data. We’re hoping those data will come, but it’s very exciting that we have another drug to potentially consider for our patients with these diseases.

In the future we’re going to see a lot of studies that are thinking about combinations of therapies, such as surufatinib with other drugs. One could envision potentially a role with immunotherapy as we’ve seen in other disease, like where cabozantinib showed to be promising. That would be something to consider in the context of a clinical trial. We know unfortunately immunotherapies in our diseases in general have not been very helpful, unlike other solid-tumor malignancies. There could be potential for very exciting opportunities for these combinations of therapies where you have an active drug. Potentially by giving that active drug, you could add on a therapy such as immunotherapy and see if we could offer more of a promising combination. It would be exciting to see such a trial be considered.

The promise of surufatinib is 1) we’re very excited about adding to our armamentarium for our different drugs and opportunities for our patients to control these diseases. In addition to the potential to add on to other therapies in the future, it will be very important to start doing our best to understand which drugs can control the disease for the longest, while providing an appropriate adverse-event profile. To date, the drug seems to be well tolerated. If there’s something different about that in the US patient population, we don’t know. There’s a phase 1 study ongoing to test the safety of the drug in the United States, and we’re all excited about that. The role of questionnaires in terms of quality of life is very important as we do these trials and better understand the different adverse-event profiles with the efficacy of these therapies and try to weigh which ones are best for our patients.

Considerations for use of surufatinib in patients with neuroendocrine tumors in light of the SANET-p and SANET-ep clinical trials.

Advanced Neuroendocrine Tumors: Clinical Trials With Surufatinib

 The role of VEGF is critical in neuroendocrine cancer, and it’s one of the drivers that allows our cancers to grow and divide. In 2011, we had the first VEGF inhibitor that was approved for pancreatic NETs [neuroendocrine tumors], and that’s been an FDA indication since then. More recently, there have been other VEGF inhibitors that have been tested or are being tested, to try to improve progression-free survival and improve outcomes for our patients with these diseases. The various VEGF inhibitors include, for example, axitinib, which was a study in the phase 2 setting that showed a lot of promise. More recently, they did report on the role of axitinib with a somatostatin analogue that did not meet its progression-free survival end point, although it did show some activity, but did not reach the primary end point of the study. We have other drugs, such as surufatinib, which was recently FDA approved based on 2 studies in China. They did surufatinib in pancreatic NETs as well as extrapancreatic NETs…both of them improved progression-free survival, which was very exciting. It’s notable that surufatinib would be, at least in China, the first FDA-approved drug that is a VEGF inhibitor for extrapancreatic NETs. Remember, the sunitinib is approved for pancreatic NETs. And then Jennifer Chan, MD, MPH, is leading a study of cabozantinib, which is another VEGF inhibitor, through the NCI [National Cancer Institute] cooperative groups, and we are testing the role of that in extrapancreatic as well as pancreatic NETs.

There’s no question that VEGF is a very important driver in neuroendocrine cancers and has shown activity and promise in our diseases. What are the adverse event profiles?Most of them are hypertension, some fatigue, some proteinuria, manageable adverse effects that most of us as oncologists understand when we’re using these tyrosine kinase inhibitors. Again, it’s very mindful and important to remember in our patient population that we’re asking these questions and how they’re feeling.

What’s unique about surufatinib is that in addition to targeting the tyrosine kinase inhibitor of VEGF, it also inhibits the FGF receptor, as well as the CSF1R [colony stimulating factor-1 receptor] inhibitor. It may be that the combination of those 3 tyrosine kinase inhibitors could be more effective and more promising in our patients with neuroendocrine cancers. That new drug application was submitted to the FDA. It was approved to be submitted, and we’re hoping to hear by April of next year what the outcome is for surufatinib in the United States, based on those 2 studies, which is surufatinib in extrapancreatic, as well as surufatinib in pancreatic neuroendocrine cancers. Those were a Chinese patient population, both phase 3 data that improved the progression-free survival.

Expert reflections on VEGF-targeted therapy’s role in the treatment of patients with neuroendocrine tumors.

Advanced Neuroendocrine Tumors: VEGF-Targeted Therapies

: I tell my patients our goals of therapy for advanced neuroendocrine cancer that’s incurable is quality and quantity. We want to make sure that we keep our patients with us for as long as possible and thank heavens our patients with neuroendocrine cancers can live for many years and often many decades. Because of that, the quality, and the therapies that we choose are critically important. We have to be very mindful of those toxicities. Grade 1 to 2 fatigue, for example, in a patient where they’re going to be on that therapy potentially for many months, into many years is a quite significant adverse effect. Having grade 2 fatigue is a very hard thing for our patients to endure over a long period of time. We’re constantly weighing the benefits and the risks of these different therapies and being mindful about dose reducing and really being careful that we’re asking our patients how are they feeling, how are they doing? Many of our patients will do whatever we tell them to ensure that the disease stays stable. But again, we want to make sure we’re being mindful of the adverse effects that they have and that we’re treating at appropriate times. When the disease grows, we need to be on these therapies, but sometimes there are opportunities for treatment holidays that we really want to take advantage of. We can’t let our patients come back in 6 months when they’re on a treatment holiday, but we want to be mindful of the ability to potentially give our patients breaks when they need them.

Most oncologists would agree that first-line therapies are somatostatin analogues. Second-line therapy can be a bit more challenging to choose for our patients because we don’t have those clinical trials to really drive the decision of what should be done with an evidence-based approach. We use our best tools to understand the patient in front of us to better decide what those second-line therapies should be. In a patient with a higher burden of disease where response rate is something that’s important, we’ll use cytotoxic therapies. The role, for example, of peptide receptor radionuclide therapy [PRRT] is one that is critically important. It came and was finally FDA approved in the United States back in 2018. At that time, we were using it in much more advanced patient populations. Now we know that although there are very serious and concerning adverse effects, they’re pretty rare. The 2% to 3% risk of MDS [myelodysplastic syndromes] is something that we worry about. But in patients, for example, in small bowel where we’re really limited on other additional therapies after somatostatin analogue therapy, PRRT can be incredibly helpful, and I tend to use it a little bit earlier now. I will often use it actually after somatostatin analogue progression in patients who have extrahepatic disease and disease in different places where I want a really good systemic approach. Second-line therapy, for example, in a small bowel NET [neuroendocrine tumor] could be mTOR inhibitors, it could be PRRT. It comes down to adverse event profile, knowing your patient population, knowing that patient and what risks you’d be willing to take, based on their burden of disease and how well they’re doing. In the so-called foregut tumors, where you have other options, again it depends on how much response you need, how well the patient is doing, and if they’re symptomatic or not.

Diane Reidy-Lagunes, MD, outlines goals of therapy and selection of systemic therapy for patients with neuroendocrine tumors.

Systemic Therapy for Advanced Neuroendocrine Tumors

 In our patients who have stage IV unresectable neuroendocrine disease, treatment options and selection can be challenging for the oncologist. There are a couple of predictors that we use, or a couple of clues we use, to better define the best treatment for the patient we’re caring for. Generally, first-line treatments are somatostatin analogues because they are so well tolerated. Second-line therapies are based on a couple of features. In a patient who has a higher burden of disease, where you want some good tumor shrinkage, we often try to go to a therapy where we know that response rates are higher. For example, in the so-called foregut neuroendocrine cancers, cancers of the pancreas, lung, stomach, and duodenum, those tumors can be quite responsive to oral chemotherapy such as 5-FU [fluorouracil]-based therapies or capecitabine plus Temodar [temozolomide], sometimes even other cytotoxic therapies such as oxaliplatin-based therapies. If you want tumor shrinkages in a high burden of disease, cytotoxic therapies could be considered. 177Lu-DOTATATE is another option in those patients where response rate is something that we want to consider. We know that response rates can be higher in those patient populations than the so-called targeted therapies, which are very good at stabilizing the disease and cause some tumor shrinkage but not as much as the cytotoxics or the PRRT [peptide receptor radionuclide therapy].

Targeted therapy such as everolimus, sunitinib for pancreatic NETs [neuroendocrine tumors], and other therapies again could be considered in the second- and the third-line setting where we have disease growing, particularly when it’s disease outside the liver. In patients with liver predominant disease, we’d like to try to do a liver-directed approach, but we want to be careful because if it’s a lot of burden of disease, that could actually cause some harm to the patient. It’s a combination of knowing the adverse event profile of those drugs, and knowing the patient and what their situation is. In a patient with poorly controlled diabetes, you may not want to start with an mTOR inhibitor. Understanding the patient as well as the drugs can be very important in allowing us to select what therapies are best for that patient.

One of the most important biomarkers we have, and the most important biomarker that we have, in neuroendocrine cancers is the presence of the somatostatin receptor. The way that we look for that is by doing a Gallium-68 DOTATATE scan. I tell my patients we want the tumors to light up like a Christmas tree because if those tumors are very bright that suggests there are a lot of receptors on the outside of the cell. That’s important for 2 reasons. First, we know that the presence of the somatostatin receptor is a good prognostic feature. The brighter it is, the more indolent or the better the outcome of those patients as opposed to those that tend to be somatostatin receptor-negative. Those tend to be FDG [fluorodeoxyglucose] PET [positron emission tomography]-positive, and those portend a sort of potentially more progressive or aggressive type of biology. The first reason is it’s important for prognostic benefit.

The second is that it can actually tell us exactly where the disease is. And most importantly, it helps us ensure that we can use therapeutic options such as 177Lu-DOTATATE, which will bind to that receptor. I tell my patients when that therapy binds to that receptor, the radiation gets internalized and then it zaps the cancer, and it can actually result in tumor regression as well. It is an incredibly important biomarker, not only from a prognostic perspective, but also to allow us therapeutically to use therapies such as 177Lu-DOTATATE.

A detailed explanation on how disease and patient factors inform selection from the treatment armamentarium for neuroendocrine tumors.

Neuroendocrine Tumors: Factors That Inform Therapy Selection

: Thankfully in the last decade, the treatment landscape for neuroendocrine cancers has actually changed a lot. We offer many more opportunities for our patients who are fighting these diseases. The most important thing I always share with my patients and my fellows is that it’s always about quality and quantity. In many of our patients, for example, with low-grade, low-volume, asymptomatic tumors, we could actually watch them. I have patients for years who I just see once or twice a year, and their cancer is totally stable. They’re totally asymptomatic, and this is a cancer that allows us to watch those types of patients. You want to be very careful though that those are patients without symptoms, typically low-grade and very low-volume disease that can’t be easily resected by surgery.

We have 3 reasons for which we want to decide to start treatment. One is that the cancer is growing under observation. The second is the tumors themselves have high burden of disease, so there’s a lot of disease on imaging. The third is that they’re symptomatic. Whether the tumors themselves, because they’re high burden are causing symptoms, or whether they’re making hormones or are functional tumors, those are the 3 reasons why we decide we want to start treatment. Disease growth under observation, functional or symptomatic tumors, and high burden of disease. The first line of therapy, which I call my “first string” players, are generally somatostatin analogues. That’s either lanreotide or octreotide, and I call them my “first string” players because they’re really good at putting the brakes on the tumor and stopping it from growing and spreading with very mild adverse effects. It’s a shot in the bottom once a month. It’s a hormone as opposed to chemotherapy. The adverse event profile is very well tolerated compared to other cancers.

Once the tumor progresses on somatostatin analogue therapies though, it gets much trickier because unfortunately, we don’t have large, randomized trials to tell us what sequencing therapies are best, what to give in the second line, what to give in the third line. Given the heterogeneity of the disease and given the more uncommon nature of this cancer, we just don’t have those studies that help us guide therapies. This is where it becomes very important to know your patient, know their burden of disease, know the location of the disease, and where that cancer might be growing. Second-line therapies can often, for example if it’s growing in the liver, be liver-directed therapies. If it’s growing outside of the liver, it could be other systemic types of treatments and even if it’s in the liver. There are lots of different variables we use in the second-line setting to better understand what’s the right treatment option for that patient in front of us.

The role of surgery and other modalities such as radiation therapy are important. In any patient with localized disease, if it can surgically be removed in a safe way, we really encourage our patients to have that surgery. Primary tumors, for example, of the small bowel, which is very common, can and often will obstruct if we get into trouble leaving them there. In a localized setting, we always want to surgically remove it if deemed safe to do so. Traditional radiation, which is that beam where patients come in and they get their fraction of radiation every day for a certain period of time, is often used, for example, for palliation of symptoms. For anyone with bone metastasis, the role of radiation can be very important in preventing that tumor from spreading and causing trouble in the bone and preventing pain. We have other types of radiation, such as systemic radiation, which is 177Lu-DOTATATE, as another potential very important treatment option for our patients with neuroendocrine cancer.

Standard treatment pathways for patients with neuroendocrine tumors involving systemic therapy, surgery, and radiation.

An Overview of Treatment Approaches for Neuroendocrine Tumors

 The role of molecular testing in neuroendocrine cancers continues to evolve.Unlike other solid tumor malignancies, where the molecular genetics become critically important in terms of treatment, neuroendocrine cancers have not panned out in helping potentially, for example, to find a mutation that can help us drive treatment. The molecular alterations can help us in prognosis. We know that there are certain genes that can portend a poorer or more aggressive course, but we haven’t yet translated that piece into the clinic to say that all patients with neuroendocrine cancers should be molecularly tested. We do know that there are definitely some germline mutations that are familial genetic predispositions, such as VHL [Von Hippel-Lindau syndrome], or MEN1 [multiple endocrine neoplasia type 1], or tuberous sclerosis. All of those genetic predispositions should definitely be screened, particularly for our younger patient populations. There we’re looking for a strong family history, other characteristics based on physical examinations. We want to make sure we’re always ruling out the familial predispositions that our patient may potentially have. But the so-called somatic mutations have not yet panned out to help us drive treatment for neuroendocrine cancers in 2021.

There are guidelines certainly for germline mutations, based on family history, based on physical exam. Genetic counselors should most certainly be involved in a patient where there is a concern for familial predisposition, and genetic counseling and testing should certainly be considered in that patient population. For somatic mutations, we are looking in patients who have higher grade tumors, if there’s any question that maybe they could have high mutational burden or MSI [microsatellite instability] as per NCCN [National Comprehensive Cancer Network] guidelines and as per FDA-approved indications. If there is MSI, patients should be considered for immunotherapy. The reality is that most of our patients do not have MSI-high tumors, and most neuroendocrine cancers actually have what we call low mutational burden. That may be why our cancers tend to be a little bit more indolent or slower growing compared to other cancers because they don’t have high mutational burden and don’t have a lot of these alterations. In general, patients with germline mutations or suspicion for germline mutations should be sent to genetic counseling, but the role of somatic mutations outside of a potential MSI patient is very limited, unfortunately.

The tumor microenvironment of neuroendocrine cancers, we’ve actually known for a very long time it really is driven in part by VEGF and blood vessels. These neuroendocrine cancers really require that blood vessel nourishment for them to grow and propagate. We’ve actually for a couple of decades used the role of liver-directed embolization to block off those blood vessels and prevent it or allow a change in the microenvironment to not allow the cancers to grow. More recently in the last decade or so there’s been a big push to go even more to a micro level to use VEGF inhibitors to again impair that angiogenesis and prevent the cancers from growing and spreading. There are lots of opportunities with different types of VEGF inhibitors to inhibit the cancer through antiproliferative effects, focusing on that microenvironment with angiogenesis playing an important role.

Expert insight on the pathogenesis of neuroendocrine tumors and the best use of molecular testing to inform treatment decisions.

Neuroendocrine Tumor Pathogenesis and Molecular Testing

 Neuroendocrine cancers are a little bit tricky because they’re uncommon cancers, though not as rare as people think. There are probably about 8000 to 10,000 patients a year, but what’s challenging about them is they’re quite heterogeneous. What I mean by that is there are certain classifications that we need to understand when we’re seeing a patient faced with neuroendocrine cancers, so that we could better understand the type of cancer and then ultimately the types of treatments that we’re going to offer. The first thing is where the cancer starts. These are diseases that can start anywhere in the body. The most common location is somewhere in the GI [gastrointestinal] tract or in the lung, but again it can also develop in the GYN [gynecologic] as well as GU [genitourinary] systems. Where the cancer starts is very important. The second thing we look at is what the cancer looks like under the microscope. The grade of the cancer can also help us further classify the disease, understand how aggressive could it potentially behave, and how aggressive we want to be in the types of treatments that we’re offering. The primary site of origin, the grade of the tumor, and then the third thing is the burden of disease. How much cancer that patient may have can also help us better understand and classify how we’re going to treat it.

For the diagnosis of neuroendocrine cancers, it really demands a multidisciplinary approach. The most important member of that team is the pathologist because what they look and confirm for neuroendocrine cancer is obviously critically important. The pathologist will give us 2 pieces of information. The first thing they do is they look at the cells and tell us what the architecture of those cells look like. Are they well differentiated or poorly differentiated? Treatments vary depending on if it’s well differentiated or poorly differentiated. The second thing that they tell us is the grade of the tumor, and that’s based on the WHO [World Health Organization] classification where we have grades 1, 2, and 3, grade 1 being low grade, grade 2 being intermediate grade, and grade 3 being high grade. That’s very important for us in terms of our pathology diagnosis. We also have other team members that can help us. Our gastroenterologist will also help us often find the primary, which is very often in the small bowel but also in other locations, and then we have the medical oncologist as well as surgeons to help us define the treatment options.

When we find the classifications and the pathology of NETs [neuroendocrine tumors], they can be very helpful for us to understand prognosis and treatment recommendations that we’re going to have. We know that the grading is the most important prognostic feature that we have in neuroendocrine cancer, so we can’t trump the biology. Biology is the most important piece of information that we have, and the best way that we have today, in 2021, is to define that by grade. Tumors that are low grade, which is a Ki-67 [index] less than 3%, tend to portend the best prognosis. Intermediate-grade cancers, which are Ki-67 between 3% and 20%, tend to behave like low grade potentially, and sometimes unfortunately more like high grade. Then those high-grade tumors, which are Ki-67 greater than 20%, are the tumors that we worry about the most because they can portend a more aggressive course.

Diane Reidy-Lagunes, MD, provides an overview of neuroendocrine tumors, along with specific considerations for optimal diagnosis and prognostication.

Diane Reidy-Lagunes, MD, Memorial Sloan-Kettering Cancer Center

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