Systemic Therapy for Tumor Control in Metastatic Well-Differentiated GEP-NETs Guideline

Dr. Jaydira Del Rivero and Dr. Kimberly Perez discuss the latest ASCO guideline featuring evidence-based recommendations on systemic therapy for well-differentiated grade 1 to grade 3 metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). They discuss the recommendations, insights from the guideline expert panel, impact for clinicians and patients, and outstanding questions in the field. Read the full guideline update, "Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline” at www.asco.org/gastrointestinal-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/gastrointestinal-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology,  https://ascopubs.org/doi/10.1200/JCO.23.01529   Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey and today I am interviewing Dr. Jaydira Del Rivero and Dr. Kimberly Perez, co-chairs on “Systemic Therapy for Tumor Control in Metastatic Well-differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline.”   Thank you for being here, Dr. Del Rivero and Dr. Perez.  Dr. Jaydira Del Rivero: Thank you.   Dr. Kimberly Perez: Thank you, Brittany.  Brittany Harvey: Then before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Del Rivero and Dr. Perez, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology which is linked in the show notes.   Now, to start us off on the content of this guideline, Dr. Del Rivero, can you provide an overview of both the scope and the purpose of this guideline?  Dr. Jaydira Del Rivero: Thank you so much, Brittany for the introduction. I would also like to thank ASCO as well for giving us the opportunity, me and Dr. Perez, to discuss briefly the guidelines for gastroenteropancreatic neuroendocrine tumors.   In terms of your question of providing an overview of the scope and purpose of this guideline, we wanted to make recommendations about the various systemic therapies and the management of advanced, unresectable, metastatic gastroenteropancreatic neuroendocrine tumors from grade 1 to grade 3. I’m fortunate to be the co-chair with Dr. Perez, but among the different experts and panelists on this guideline, it is important to establish a guide on how to manage patients with gastroenteropancreatic neuroendocrine tumors. And one of the reasons is because there really is not sequencing enough therapy, and there have been a lot of discussions even among the neuroendocrine tumor experts for at the same time provide information and guide to oncologists in the community to understand more about the management of these neuroendocrine tumors as well as provide in a more standardized manner about how a neuroendocrine tumor expert sees or manages a patient with neuroendocrine tumor.  Brittany Harvey: Great. Thank you for providing that overview.   So, you just mentioned that this guideline covers grade 1 to grade 3 gastroenteropancreatic neuroendocrine tumors. So, Dr. Perez, what are the general recommendations that the panel made for grade 1 to grade 3 gastroenteropancreatic neuroendocrine tumors?  Dr. Kimberly Perez: Thank you, Brittany. I think the biggest take home for treatment for this group of tumors is based on the heterogeneity of the disease. We can classify this very broad group of tumors into grade 1 to 3 based on histologic features, and we use that to guide treatment. But we also take use the functionality of the tumors to direct treatment, and that can be assessed clinically as well as by functional imaging or nuclear medicine-based imaging. And that’s really how our intention is in trying to provide recommendations for the treatment of these various tumor types. So, we, as a group in our discussions, it really came down to approaching the patient's situation, determining whether or not the patient had functional symptoms as a result of hormone excess, and then determining what their radiographic features were, specifically whether or not somatostatin receptor presence was noted and then the grade of the tumor and lastly, the bulk of disease and the rate of growth. And it’s really those features that drive the different treatment options.  Brittany Harvey: Excellent. Thank you for reviewing those general recommendations to identify those features that lead to specific treatment options.   So, Dr. Del Rivero, what systemic therapy options are recommended for first, second, and later line therapies for grade 1 to grade 3 gastroenteropancreatic neuroendocrine tumors?  Dr. Jaydira Del Rivero: As Dr. Perez mentioned earlier, neuroendocrine tumors are quite heterogeneous, and it's not a one-size-fits-all in terms of how we manage patients with neuroendocrine tumors. As Dr. Perez also mentioned, too, in terms of how we manage these neuroendocrine tumors, we need to consider the extension of the disease, whether it's low burden tumors versus high burden tumors. What is the pace of growth? Whether it's stable or rapidly progressive, and whether it's widely metastatic as well or if it's only localized in one area, liver-dominant disease. We also need to understand the primary site, and that's why these guidelines, we also divided it in terms of how we see it in terms of first and second line therapies between pancreas and small bowel neuroendocrine tumors. And as Dr. Perez said, the grade differentiation is also important. That's the reason why, when discussing and developing these guidelines, it was important to differentiate between grade 1, grade 2, as well as the grade 3. And also, as Dr. Perez mentioned, whether they are functional tumors, meaning they produce hormones or not and the symptoms related to that.   And I just would also like to mention that we are currently working on the symptom management of neuroendocrine tumors, taking into consideration the hormone status of the tumors. That  is something that we’ll follow up in these guidelines as well. And as Dr. Perez mentioned whether they express somatostatin receptors or not. So based on that, the expert panelists as well in developing these guidelines, we divided them into grade 1 and grade 2 GI (or gastrointestinal) neuroendocrine tumors or pancreas neuroendocrine tumors. And that is based on the proliferation index as well. If the proliferation index of the Ki-67 is greater than 20%, we know that this is a grade 3 gastroenteropancreatic neuroendocrine tumor, which that, in itself is a different category in terms of management.   Now, for gastrointestinal grade 1 and grade 2 neuroendocrine tumors, the first line of therapy, one of the things that we need to establish is whether the tumor expresses a somatostatin receptor or not, and that we confirm this via 68Ga-DOTA-peptides or 64Cu-DOTATATE scan. If they expressed the receptors, then I would initiate first line therapy or what is recommended in these guidelines is to start with a somatostatin agonist, either octreotide or lanreotide. One thing to mention here is that either octreotide or lanreotide is considered equivalent in terms of efficacy, we don’t have any head-to-head comparison to determine which one may be better. We think it's equivalent, the two of them. And because of that, whichever is available is what we recommend.   Now if there is evidence of disease progression after the use of a somatostatin agonist, we need to determine whether they still express somatostatin receptors. And as a second line therapy, we can consider patients as candidates for 177Lu-Dotatate or PRRT with 177Lu-Dotatate. Usually, our recommendations are, if the patient has a functional tumor, if it’s producing hormones and symptoms related to hormone excess, we still continue the somatostatin agonist. But if the tumor is a non-functional tumor after disease progression on a somatostatin agonist, we don’t necessarily need to continue with either lanreotide or long-acting octreotide.   Now, sometimes, some of the discussions that were done as well when developing these guidelines is a concern about hematologic toxicity. And if there is any concern of hematologic toxicity, the patient may not be a candidate for 177Lu-Dotatate. In these situations, everolimus can be considered as a second or later line therapy in patients with G1 or G2 gastrointestinal neuroendocrine tumors. If the patient is somatostatin receptor negative, we can consider everolimus as well. As you can see, with GI neuroendocrine tumors, we really need to take into consideration what we discussed earlier today, and also discussed with Dr. Perez.  Now, in terms of the grade 1 or grade 2 pancreatic neuroendocrine tumors, similar to what we discussed on the small bowel or gastrointestinal neuroendocrine tumors, we first need to determine whether the tumor is somatostatin receptor positive through scans such as 68Ga-DOTA-peptides or 64Cu-DOTATATE scan. Based on that, the first line is also considered, a somatostatin agonist, either octreotide or lanreotide. If there is disease progression on that, then we can consider other lines of therapy, such as Peptide Receptor Radionuclide Therapy or PRRT with 177Lu-Dotatate or chemotherapy with capecitabine and temozolomide, or everolimus, or sunitinib. Now, one thing to keep in mind whenever we make these recommendations is for those pancreas neuroendocrine tumors that, in addition to being somatostatin receptor positive, are the ones that have a lower volume of disease or without significant symptoms related to tumor burden.   Now we have pancreas neuroendocrine tumors with a higher volume of disease and symptoms related to tumor burden, regardless of somatostatin receptor expression, then usually what the panelists have considered as a first line therapy is chemotherapy with capecitabine and temozolomide. And if there is any disease progression after that, then we also need to establish as well whether they still retain somatostatin receptors avidity if it’s positive. Other options to consider will be 177Lu-Dotatate, everolimus, or sunitinib. Those are the FDA-approved agents for the management of neuroendocrine tumors. And if they are somatostatin receptor negative, it will be everolimus or sunitinib.  Now, in terms of grade 3 gastroenteropancreatic neuroendocrine tumors, when the Ki-67 is greater than 20%, there are various options as well. And a lot of the treatments that have been recommended for grade 1 to grade 2 neuroendocrine tumors can also be recommended for grade 3 neuroendocrine tumors. But that said, as we discussed earlier, we also need to understand the growth of disease or the aggressiveness of the disease, as well as the symptoms related to that as well as the tumor burden. But based on that, there may be other treatments available for grade 3 neuroendocrine tumors, such as various types of chemotherapy as discussed in the guidelines. There are also ongoing clinical trials that will help us better understand and have more evidence-based therapy for the treatment decisions of patients with gastroenteropancreatic neuroendocrine tumors.  Brittany Harvey: Dr. Del Rivero, I appreciate you reviewing those recommendations and the nuance from the panel's discussion.   Dr. Perez, is there anything you'd like to add about those recommendations?  Dr. Kimberly Perez: Dr. Del Rivero covered everything that we intended to impart to the community about treatment of gastroenteropancreatic neuroendocrine tumors. I think the only highlight I would make and was intentional on our part was separating gastrointestinal and pancreatic neuroendocrine tumors; because there have been clinical trials demonstrating the different efficacy of treatments based on the primary site of disease.  Brittany Harvey: Absolutely, that makes a lot of sense. So then, Dr. Perez, in your view, what is the importance of this guideline and how does it impact both clinicians and patients with gastroenteropancreatic neuroendocrine tumors?  Dr. Kimberly Perez: I think the importance of the guidelines, I found, was the common theme in our discussions with the other panelists on the group was because of the rarity of the disease and the clinical trials that we are drawing our experience from, there’s a lot of different ways to interpret the data that’s available. And we all spent a lot of time discussing how we've interpreted the data and how we implement it in our practice and how it’s influenced the development of current clinical trials and the ideas supporting future clinical trials. So I think that our intention was to provide community oncologists or general oncologists, who don't see patients with this disease very often, with an algorithm or review of what is available and how you can try to put your patients into the algorithm in a way that would result in best results or best outcomes.   Brittany Harvey: Absolutely. We hope this is a resource for community oncologists to help improve outcomes for their patients.   You also just mentioned future clinical trials, so I'll turn back to Dr. Del Rivero. What are the outstanding questions regarding systemic therapy for metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors?  Dr. Jaydira Del Rivero: Great, thank you for that question. I would like to mention that in the development of these guidelines, there were a few discussions about when to implement observation. Because we know that patients with neuroendocrine tumors, in terms of the biology, they may be very slow-growing tumors. One of the discussions was: when is observation recommended? Usually, what the discussion was based on the consensus from all the panelists is that observation could be considered in patients with low volume or very slow-growing disease in the absence of any symptoms, meaning from either tumor burden or functional tumors. I think this could still be considered in a subset of patients. It's not necessarily for everyone. I think we agree that a lot of the patients with neuroendocrine tumors, when they present to us, they already had metastatic disease and that's when they are sick. The recommendations of medical oncologists is to determine the next line of therapy.   One of the other discussions I would like to mention was about the deficiency of MGMT, and that was based on the data report by Dr. Pamela Kunz. This was also presented at the ASCO meeting and recently published in the Journal of Clinical Oncology, the validity of MGMT deficiency in patients with pancreas neuroendocrine tumors and how that correlates with response. That said, I think the consensus was that even though we can consider that as a predictive biomarker, it's still not something that is a primetime to use, but it was something that was recommended, was discussed during the discussion of the development of these consensus statements. Dr. Perez, we would also like to note that, also Dr. Perez, and what other important aspects were discussed during the development of the guidelines. With that said, a lot of the questions will be answered in ongoing critical trials as well from metastatic  neuroendocrine tumors.   I think we’re in a very exciting time where we have not seen a lot of more clinical trials for neuroendocrine tumors and a lot of treatment options than where it was more than 10 years ago. I think one of the questions about sequencing, too, and that's something where there's insufficient evidence in terms of what to recommend, a particular sequence of therapy. With that said, there have been ongoing studies presented at the ESMO Meeting as well, and that in terms of some of the trial results in patients with gastroenteropancreatic well-differentiated neuroendocrine tumors. But I say still, that’s an ongoing question too. And ongoing trials are also currently active, not only for pancreatic neuroendocrine tumors, but as well for gastroenteropancreatic neuroendocrine tumors. And that’s an exciting time to also learn more about these studies and looking forward to also learn about  the results of these studies.   And Dr. Perez, what are your thoughts?  Dr. Kimberly Perez: I agree with all of your sentiments. I think some additional topics of discussion that came up were in regards to: how to define the burden of disease? So we use that as one of the characteristics for determining what treatment option we want to consider. We found that the data really only addressed this when trialists were looking at liver burden of disease. I think that is something as a scientific and clinical community, we need to define a bit better in our future clinical trial efforts.   I think the second is this question of Ki-67 and rate of growth. In Jennifer Ead's study, looking at CAPTEM versus platinum and etoposide and the grade 3 group, the delineation made was a Ki-67 of around 55%. As her trials and other trials looking at the therapeutic options in this grade 3 category mature, we will be able to better characterize that, and I think it will be important to provide guidance to patients and providers on how to really define the Ki-67 that requires a certain type of treatment.   And then I think the last question I recall was in regards to using somatostatin receptor-based therapy when you don’t yet have somatostatin-based imaging or when you have somewhat of a mixed uptake in somatostatin imaging. I think that too, as the new radiopharmaceuticals are developed and technology improves, this question will be answered.  Brittany Harvey: Definitely, those are important questions to determine therapeutic options for patients. We'll look forward to those future developments ahead.     Thank you both so much for your work to develop this guideline and these recommendations, and I want to thank you so much for joining me here on the podcast today, Dr. Perez and Dr. Del Rivero.    Dr. Jaydira Del Rivero: Thank you, Brittany.  Dr. Kimberly Perez: Thank you so much for having us.   Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.  The purpose of this podcast is to educate and inform. 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