Exploring the role of targeted radiopharmaceutical treatment in NETs

Speaker 1 The majority of the patients that we will use PRT tends to be second line and and beyond. And when we put in context all the treatments that we have, I think especially for the midca tumors, PRT is definitely the winner when it comes to second line treatments is exciting time to be a doctor taking care of neuroductant tumors. Speaker 2 This podcast is for healthcare professionals only and is supported by an independent educational grant from ITM. Speaker 3 Hello everyone, welcome back to the Oncology Brothers Podcast. I'm Rohit Ghosain along with my brother and Co host Rahul Ghosain with our goal to keep our community oncologist up to date in the world of cancer. Today we are going to be talking about Nets neuroendocrine tumors. Briefly, we will touch on the treatment landscape, but the focus of the discussion will be on Radioligand therapies available and how to best use them. Speaker 4 To touch on this, we're excited to welcome doctors Aloysa Suarez, a medical oncologist focusing on neuroendocrine teamers, and doctor Ken Herman, a nuclear medicine physician from Europe. Ken Eliza, welcome. Speaker 1 Thank you, thank you, thank you for having us. Speaker 3 Thanks so much for joining us. Before we go any further, let's set the stage for neuroendocrine tumors where we stand from the treatment landscape. We divide them basically into functional versus non functional where often the non functional ones were rather asymptomatic. But the active treatment options that are available for functional Nets are somatostatin analogs. We recently saw approval of cabozantinib and we also have radioligand therapy such as PRRT and also for high grade tumors, we take this treatment from small cell lung cancer that is the chemo option. Before we dive into more in the treatment world, let's touch on the imaging modality where octrotide scans used to be our thing, but now we have been relying heavily on gallium dosatate scan. And Louisa, I'll start off with you here. Could you start us out where, where do you get this gallium dosatate scan? Is it that initial diagnosis or rather progression? And if so, what's exactly the utility of it and importantly outside clinical other radio tracers that are available that you rely on your practice? Speaker 1 I think we use the imaging studies in combination with the cross section with studies. So typically I will have my patient have a assuming that yeah, I get that, I'll have my patient having the MRI of abdominal pelvis with contrast or ACT of abdominal pelvis with the arterial face of this portion of the liver to really be able to identify the tumors. In addition to that, a diagnosis that will definitely try to get a somatostine receptor functional imaging to help and complement the work up and plan for my patients. And yes, we have the Gallium 68 Dota Tate scan PET CTS. We can also use Copper 64 that's also available in the US. So we have these two radioisotopes that we can use. I'll typically use at the time of diagnosis, typically if the patient is going for surgery or certainly try to have also a Dota Tate pet CT. Even that the sensitivity of of the Dota Tate is much higher tends to be up to 90%. So it's excellent to try to identify what we called quote UN, quote UN, quote disease. Speaker 4 Thanks for getting us started. You brought up Dota Tate be a gallium or copper in the community settings. If I don't have one or the other available, am I missing out on some critical information? Is one more sensitive than the other? Speaker 1 No, absolutely not. I think there's a slightly difference in sensitivity and and background noise depending of which radioisotope you use. But in general the concept if you can use one or the other and you are not missing in in quality or information choosing one over the other. Speaker 4 And can if the disease is progressing on somatostatin analogs. Rohit brought up a few treatment options, Everolimus, cabozantinib and PRT. For PRRT, we often get nuclear medicine or radiation oncologist on board in a patient that has dilitate positive disease and you're seeing this patient to consider PRT. What do we have to support this practice and in real life, what does that conversation look like for that patient in front of you? Speaker 5 So first of all, I'm going to say that what Eliza alluded to us and indeed there's a lot of very, very good data to to underline that some other sudden 2 SEPTA imaging with PET, it's better than anything else. Nevertheless, I think it's very important that we actually perform this imaging technology always in addition of the contrast enhanced CTI think it's very important. Why do I actually don't answer your question is because this is actually leading me to my answer. We need to know that the lesions which are disease dominating are so much certain tools that are positive. And for this, we need the additional information from the CT plus the PET information. And in these patients actually we really discussed depending on the previous treatment, if the patients are candidates for PRT. Now we know that there are different grades obviously for for very differentiated tumors lessen K67 of 20%. We have I think quite solid data. You can also discuss a little bit later about patients who have a more aggressive pattern. But overall, right now in daily routine, we really focus on the patients who have AK 67 less than 20%. We have progressed to cold somatostatin receptor analogues and where we are discussing the the next lab treatment. And we actually usually perform this in MDT where we bring all together the different level of information. And also something which we also have to discuss how, how quickly is the disease evolving. Because POT is not a, not a therapy which you, you treat one time and you will see a response within one or two days. It's a treatment which needs time to be efficient. Speaker 3 Thanks so much for touching all that, Ken. And we will be diving into the world of MDT multidisciplinary approach because again, oncology in general is a team sport, but there are some cancers where this team sport applies more than others and neuroendocrine tumor is certainly part of that. Yeah, Louise, with regards to the available treatment options now, where do you use PRRT? Is it upfront or relapsed refractory in your settings? And also if you could touch on any rule of this in high grade as well. Speaker 1 We do have data from the net or two that shows that in patients with more aggressive disease, we think the well differentiated gap net worth, there is a role for first line treatment with PRRT. Having said that, the majority of the patients that we will use PRT tends to be second line and and beyond. And when we put in context all the treatments that we have, I think especially for the mid got tumors period is definitely the winner when we comes to second line treatments. You know, we had another one study that show the use of 177 versus 60 milligrams of octriotype and then and then show that PRT was better was superior in terms of progression for survival. And just this year in March, we had a presentation doing the European Society meeting that showed via the a complete study that Nutrition 177 Dota talk was superior to a verilimus and they use the active compared to Nova verilimus. So and that really to me consolidated the role of period D, particularly in second line. I think the decision of first line is a little bit more complex, even though the data was positive. Do you miss too much and is still using a somatosty analog? We have that data in progression free survival benefit, but we don't have overall survival. So I think definitely for the higher grade tumors is a little bit more of a discussion. And in terms of well differentiated G3 tumors because we don't have this population of patients, we potentially see the the benefit as well. It's just a question as how fast the tumor is progressing and do we have to start with something else sooner because sometimes depending where you are, it might take time to set up PRT and there's lots of nuances that, you know, Ken and I can discuss as well about the decision for the higher grade tumors. Speaker 4 One thing important here is the logistics. It's not just saying, all right, this patient's going to get PRT, off you go. That coordination takes a while. Ken, coming back to you setting that right expectation with the patients as well saying you're not going to see a response within a day or two. It's not one and done. So these are the things that we have to keep in mind. Ken, is your practice any different in Europe in terms of sequencing? Are you relying on this upfront? Are you saving PRT for refractory relapse disease? Speaker 5 I had the pageant work actually on both sides of the continent. So and I have to say that overall it's not that different the the difference I rather subtle to be honest. So regarding the clinical center, the data is the same in Europe as in US, right? Pretty much what it always said. It's we have very, very compelling data for second line in Midgard. I think also now with compete also with peanuts and very differentiated ones. Neta 2 is very interesting data, right. I'm very curious to see what composers doing to give us, but we also have to be very honest that bring it really to first line probably needs a little bit more than just what we have seen so far in in the higher grade tumors. Now regarding the practice, one of the big differences I think is that in in the US it's an outpatient treatment. So you really get the treatment and the patient is sent home the same day, whereas for example in Germany we like to keep the patients two days with us. Speaker 4 Can keeping that patient in mind that's getting PRT under your care, What are some of the side effects that we see with this modality? Any clinical pearls to manage this and is it safe for renal dysfunction? What are some of the contraindications? Speaker 5 Then the most important toxicity depends on the on the angle, you know, if you talk to the patient. Actually for them, for us, the most important is that they really do not like nausea which is actually not associated directly and to the treatment itself, but rather to the kidney protection is amino acids which are infused. So these are usually the the thing that patients complain the most about when you talk to the regulators, they actually worry the most about the kidney dose and the potential kidney toxicity even. So we know now that we have pretty very long term, actually very long term data showing that this is actually very, very tolerated even regarding the kidney toxicity. And the third one is in the clinical angle and the clinical angle is something long term we are the most concerned about is actually the bone marrow function. So bone marrow function and potential secondary maintenances, not very frequent, but still something to to worry about South. In summary, three different toxicities complete different angles, nausea for the patient, kidney toxicity for the regulator, and for me in the clinic it's a bone marrow. Speaker 3 And with regards to trying in with the bone marrow aspect, Louis, I'll go to you for this one where bone marrow suppression is certainly a concern. Any risk of when you're talking about secondary malignancies, can Louis, have you seen any MD's or AML being transformed, any role of bone marrow biopsies and how do you go about that? Speaker 1 Absolutely. And that's the, the big conversation that I have with my patients in clinic is about this risk of MD's and acute leukemia, the mind develop, which typically on the phase three studies has been between 2 to 3%. And then I think there is more emerging evidence showing that if you were at some point also having your treatment journey, the patient having the treatment journey, alkaline agent chemotherapy, that risk of acute leukemia, RMDS, my increase, the percentage of the my increase. We don't have prospective data, but there's some retrospective studies and one of the highest that I seen has been from the Moffett group of John Strauss. But then when he look at the patients that he had in clinic that received temozolomide at some point and PRT at some point, it was up to like 10%, right. So that's a big conversation with the patients, particularly those they're going to be using chemotherapy. They they the clear example here is the patients with pancreatic neuroendocrine tumors will keep site to be and temozolomide is very used. So that's the big conversation. The timing of when they look hemardemius will happen is is a little bit all over the place right now. So it can be right away or or right away after finishing treatment or might take some some years. So to answer your question about bone marrow biopsies, I typically would expect that the the bone marrow will recover because we see some decrease sometimes in, in the, in the accounts for a while. But typically if they don't fully recover by a year, that's when I start discussing bone marrow biopsy. Obviously if before that there is some concerns, we see blasts in the, in the, in the CBC, in the peripheral smear, that's a different story. But if it's just that the counts are not recovery, I'll wait up to a year before I refer to my colleagues in hematology for additional work up and potentially a bone marrow biopsy. Speaker 5 I really want to emphasize what the reason I just said, right? I mean literature gives you MD's rates between one to 10% and and I think there's one very nice data set. I want to mention the long term follow up of the type one, really five term, five year follow up. And there to be honest is as the loser correctly mentioned the MDS rate more on the lower end of the spectrum, so more like the 2% rate. So that's why I think it's very important to mention. Of course, also the additional use of chemotherapy would of course increase that. Speaker 4 So again, coming back to that patient education, setting that right expectation on our end as practicing physicians, we have to get comfortable in what to look out for. Loiza, coming back to that patient who is getting PRT and setting that expectations with your patients keeping the data in mind. What are you expecting with your repeat scans? How frequently are you getting that repeat scan, which modality is ACT scans, is a PET CT? What is that conversation and is there any role of chromogram in monitoring here? Speaker 1 I'll start with the easy one. There's no role for chromograming. We should not be checking that period on the patients for monitoring. That's the that's not appropriate. It's a very non sensitive insensitive test. So let's forget about chromograning. And then in terms of which scans to do, all these studies have been with cross-sectional imaging. So we should monitor patients with cities or Mr. is and then they studies typically did that every three months, IE my practice for most of my patients, if they truly have very indolent disease, I will do CT or MRI just before starting treatment to have my baseline. And the 1st CT or MRI that I'm going to do is about 3 months after completing 4 cycles. If I have a patient that's a little bit more aggressive in terms of the disease that they have or the burden of diseases, a little bit more than I will do between psycho 2 and cycle three, I will do the scan and I think many of my colleagues will do scans in in between can. I'll have to see how you do it. But for the for the very indolent tumors, I tend to wait until the end of the four cycles and I don't do the Dota T pet cities during or just after treatment. I don't think that's yet I established role for for that. Speaker 5 We, we actually perform that Dota scans right after end of treatment because we can and we don't have the same cost as in the US to be honest. Interim, we do the same as you if there's no clinical reason to, to suspect progression or we have a patient maybe from the beginning think that this is a borderline great candidate for PRT and we, we don't do interim imaging anymore. We have done this for many, many years. We've performed PRT actually for more than 10 years already and we have stopped this with the high numbers of patients are being treated. We just cannot do this logistically. Speaker 3 But before we close this conversation, it is important to stress the importance of what you started off with initially can that is the multidisciplinary approach. It is an extremely important part of the patient care management here, especially when you're tying in surgery, liver directed therapy, systemic therapy and also radio ligand therapy. And this is all to make sure patients have the best outcome. Can any final thoughts or rather clinical takeaways from today's discussion? Speaker 5 MDT is key. There are certain standards we follow, but the truth is that many of the patients at least in this very specialized centre like ours and he'll probably also allows us, they are not the ones who follow set of care. And for this we need to have these MDT discussions. Where do we add, for example, chemo on top? Where do we add a targeted therapy? Where do we actually go directly to radio bolitization? So MDT is key. Speaker 3 And agree more and again, this is part of the disease where the treatment does not fit everyone. So you have to again, maneuver through this complicated course. We have to tailor things accordingly for our patients. Eloise, any final thoughts or clinical takeaways from your end? Speaker 1 Yeah, thank you. I would definitely agree that, you know, MDT is absolutely essential even from beginning with the pathology, right. Having an over reading the pathology, make sure that the the the pathology is correct. And then really explaining to to patients and to everybody that's caring for the, the patient that this is really for most of the patients a journey. And then it's just about deciding how to sequencing the treatments in the, in a, in a way that makes sense clinically or medically, but also take into account the patient's priorities and goals as well, right? Because thankfully, because this patients leave for, for so long, we really need to see what makes sense at what time of the patient's life and and so forth. So really having a good team partnership with the patients and the rest of the groups. And I think it's exciting time to be a doctor taking care of neuron docking tumors. We have so many new treatments coming and I think PRT is here to stay. And then I think very soon we will be talking even about retreatment with PRT because we now have trials that are even assessing the goal of very challenging patients with PRT if they had the initial response to that. So very, very exciting times for the treatment of neuroendocrine tumors. Speaker 4 Eliza, I would just echo what you're saying. Patient shared and informed decision is critical. And the other thing to reiterate as neuroendocrine is not as rare as it was one thought to be. This is something that we're seeing day in, day out in our clinics. Ken, Eliza, thank you so much for walking us through the current role of targeted radio ligant treatment options in neuroendocrine tumors. It is important for us to appreciate available options, how to sequence these options and importantly how to manage the side effects that come along with these options for our listeners. Let's go over a quick recap from today's discussion. In today's discussion with Doctor Iloisa Suarez, a medical oncologist, and Doctor Ken Herman, a Nuclear Medicine specialist, we had a chance to focus on PRRT radio lichens as treatment options in neural endocrine tumor. There are multiple different molecules that will soon be available to us and this field is moving fast now. We also have positive data from complete study for first and second line PRRT in well differentiated grade one or grade 2 tumors. But selecting that right patient and pairing them with the right treatment option is the key. Speaker 3 Yes, Rahul, Multi D is critical and referring and partnering up with tertiary or coordinary centers early for us in the community is extremely important. As we heard data for Lutitium Dota talk when compared to Everolimus has now consolidated the role of PRRT as a second line therapy for neuroendocrine tumor, but it is also showing promising results in first line as well. And then we also touched on the importance of managing the side effects that come along with our available options here. Thanks for joining us. We are the oncology brothers. Speaker 2 If you enjoyed this podcast and want to find out more than please look for the Oncology Medical Conversation Podcast under the account of Core to add medical education. Also, don't forget to rate this podcast, subscribe to our channel and share it with your colleagues. Thank you for listening and see you next time. This podcast is an initiative of Core to Add and developed by Netconnect, a group of international experts working in the field of neuroendocrine tumors. The views expressed are the personal opinions of the experts and they do not necessarily represent the views of the experts, organizations or the rest of the Netconnect Group. For expert disclosures on any conflict of interest, please visit the Cortuet website.