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Breaking Developments in Neuroendocrine Tumor Research With Samuel Kareff, MD, MPH, and Aman Chauhan, MD

In this Fellows Forum interview, Samuel Kareff, MD, MPH, interviews Aman Chauhan, MD, Leader of the Neuroendocrine Tumor Program at the University of Miami, Sylvester Comprehensive Cancer Center, about how he became involved in neuroendocrine cancer research, the latest developments in novel therapies, and the future of using radiopharmaceuticals and theranostics to revolutionize the treatment of neuroendocrine tumors.  

Samuel Kareff, MD, MPH: Welcome, everyone, to another edition of the Fellows Forum. Today, I'm joined by Dr. Aman Chauhan, who is an Associate Professor of Medical Oncology at the University of Miami, Sylvester Comprehensive Cancer Center. He's the leader of our Neuroendocrine Tumor Program, as well as the Co-Director of our Theranostics Program. Dr. Chauhan, welcome.

Aman Chauhan, MD: Thank you so much, Sam. How are you doing?

Dr. Kareff: Doing well, thank you very much. I appreciate your time and energy today. I wanted to ask you a few questions about your tumor type of focus, which is neuroendocrine tumors (NETs). With that being said, let's go ahead and get started. Dr. Chauhan, could you tell us a little bit about your interest in this tumor type and how that came about, either in your personal or professional life?

Dr. Chauhan: Yes, I think it was by chance. When I first started, I was doing a combined Internal Medicine/Pediatric Residency, with the intention to specialize in adolescent/young adults (AYA). That's why I was kind of seeing the full spectrum during my residency. But in New Orleans, we had a very strong neuroendocrine cancer program, and I got plugged in with some of the mentors there. It was just fantastic to see their passion in neuroendocrine cancer. My earlier publications and research work were centered around neuroendocrine cancer, and that's how I slowly gravitated more and more towards neuroendocrine cancers.

Some of my early mentors during residency were all well-known surgical oncologists with specialization in neuroendocrine cancers. When the time came to do a fellowship, they asked me to go to the University of Kentucky, where two world-renowned neuroendocrine cancer specialists, Dr. Lowell Anthony and Dr. Ed Wolin, were there at that time. They took me under their wing and trained me.

During my hematology/oncology (heme/onc) fellowship, I had a dedicated sub-fellowship in neuroendocrine cancer, so I saw NETs in the continuity clinic right from the first day of my fellowship. I stayed at the University of Kentucky for my early career years, and I focused my practice on the whole spectrum of neuroendocrine cancer, from low-grade NETs to high-grade small-cell and large-cell neuroendocrine carcinomas. That's how my journey took me from New Orleans to Kentucky and now in Miami.

Dr. Kareff: Awesome. Hearing about a continuity clinic focused on NETs is pretty atypical, so it's great that you were able to have such a good experience from the get-go. I think a lot of the themes you focused on really highlight the importance of mentorship. We've covered this in previous episodes of the Fellows Forum, but it's really all about getting those experts in the field to help train you and help guide you in specialized career paths. To watch your career taking off is really awesome to see, so thank you for all you do for mentoring us fellows as well.

Dr. Chauhan: Thank you. Yes, one of the things that's very crucial is to try to find your focus early. The longer you're able to stick in your area of interest, the better off you are. You get more opportunities to work, publish, network, and find your footing, be it through networking at different committees or at national levels. It's really important if you can find that interest area, the sooner the better.

Dr. Kareff: Awesome advice, not only for heme/onc fellows, but really any kind of subspecialty of medicine, so thank you for that. All right, the next question I wanted to ask you, Dr. Chauhan, what is one recent clinical advancement you'd like to highlight in the neuroendocrine cancer space?

Dr. Chauhan: Neuroendocrine cancer is a rare cancer. Unfortunately, unlike our lung cancer colleagues and breast cancer colleagues and so many other common cancers, we had not been able to do a whole lot of cutting-edge research for a really long period of time. Fortunately, that changed in last three to five years, where we now have a slew of new drugs and FDA approvals. In just the last 12 months, we've had some really exciting studies that have been positive. I can't pick just one of the three positive studies, so I'm going to say a little bit about all three of those because they're all very important.

The most recent was the NETTER-2 study presented last week at the American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium in San Francisco. Dr. Simron Singh showed that the peptide receptor radionuclide therapy (PRRT) called lutetium Lu-177 dotatate (177Lu-dotatate), which is a radiopharmaceutical directed against somatostatin receptor–positive disease. It works really well in higher-grade neuroendocrine tumors. These are neuroendocrine tumors with Ki-67 on a higher range—higher grade 2 and definitely grade 3 well-differentiated neuroendocrine tumors. Compared to somatostatin analog, there was a significant improvement in progression-free survival, so that was really good to know. This was probably the first prospective study showing the role of 177Lu-dotatate or a PRRT agent in the frontline setting in these higher-grade, well-differentiated neuroendocrine tumors.

A couple of months before that, Dr. Jennifer Chan from Dana-Farber presented data on the CABINET study. That was a randomized phase 3 study on cabozantinib in metastatic progressive well-differentiated neuroendocrine tumors, and that was a resounding success story as well. In fact, they had to stop the study sooner because it was unethical to randomize to the placebo control arm. It was a very, very positive study with significant improvement in responses as well as progression-free survival.

The third study, which I'm associated with, doesn't have data officially divulged, but it will be presented at upcoming European Neuroendocrine Tumor Society (ENETS) Conference in Vienna. However, the sponsors have released a press release. It's a phase 2 study of paltusotine, and they've revealed that it's a positive study. It is a significant advance in our field because for the longest time, we had octreotide and lanreotide. Those are two great drugs that are somatostatin analogs, but you have to inject them once a month. Now we finally have an oral alternative to a somatostatin analog. Paltusotine is an oral somatostatin analog, and based on the data, which is in the public domain, it is a positive phase 2 study. We look forward to revealing the finer data at the upcoming ENETS. So, a lot is happening, Sam. Sorry, I cannot pick one.

Dr. Kareff: That's certainly okay. It's so much better for patients when there's not only one thing to pick. I've heard so much from what you've just shared. We've got advancements with radionucleotides, tyrosine kinase inhibitors, and new novel somatostatin analogs, and this really adds to what we've known previously as somewhat limited options—the injectable somatostatin analogs, some chemotherapy drugs like everolimus, and that sort of thing. These are wonderful advancements, and we can't wait to see the final data, especially for the third trial that you mentioned today.

While we're on research note, Dr. Chauhan, what is one research interest or advancement you'd like to share in relation to the neuroendocrine space?

Dr. Chauhan: Within the spectrum of neuroendocrine cancer, on the slow-growing end of spectrum lie your typical carcinoid, atypical carcinoid, or what we like to call well-differentiated grade 1, 2, or 3 neuroendocrine tumors. On the other more aggressive end of spectrum for these neuroendocrine cancers lie the poorly-differentiated neuroendocrine carcinomas—we like to call them NECs. There are two different flavors of them, small-cell and large-cell. You've all heard about small-cell lung cancer. That's the most common type of high-grade neuroendocrine carcinoma.

High-grade, poorly-differentiated neuroendocrine carcinoma is a critical unmet need. We've really struggled to improve five-year outcomes, which are still unfortunately in the range of 10% to 12%, even in the era of immunotherapy. They're slightly better as compared to 5% without atezolizumab or durvalumab, but we have a long way to go. This is an area where I think we are seeing some significant advances, and I'm very, very optimistic.

There's a new DLL3-targeted bispecific T-cell engager (BiTE) category of drugs. DLL3 is a delta-like ligand. It's a notch pathway ligand which is heavily expressed in high-grade neuroendocrine cancers, be it small-cell lung cancer or extrathoracic high-grade neuroendocrine cancers. The phase 1 study done by various companies was revealed at the American Association for Cancer Research (AACR), ASCO, and the World Lung Conference last year. It looks extremely promising with objective responses from 20% to 35% or 40% responses reported in some studies. This is fantastic considering this was a population of very refractory third-, fourth-, and fifth-line patients, for whom traditional therapies have response rates in the range of 10%.

Not only were the response rates impressive, but also the durability of responses. I was able to enroll some of the patients in early phase studies, and I've seen these complete responses and really durable responses firsthand. So, this class of drugs, bispecific T-cell engagers targeting the DLL3-positive cancer cells, I think is looking very promising for addressing a critical unmet need. I'm very, very optimistic about this drug development story yet to be unfolded in various phase 3 studies.

Dr. Kareff: That's super exciting news. Just as a reminder for fellows and other trainees on the call, those BiTEs really act just like they sound. They grab a T cell and then the target of interest and bring them together to kind of eradicate things. It's a very novel mechanism, and more importantly, if it leads to improved outcomes—progression-free survival (PFS), durability of response, etc—these are things that would be crucially needed in the clinic like Dr. Chauhan was alluding to. Thanks for sharing that information with us today.

Dr. Chauhan: Absolutely.

Dr. Kareff: Awesome, Dr. Chauhan. That reaches the end of my prepared comments and questions. Is there anything else you'd like to share in this space for fellows and other trainees who are listening today?

Dr. Chauhan: Yes, I'll share a small sneak peek into the future of oncology, just a little clickbait for you there. We've all seen the wave of immunotherapy. I was a fellow when the whole immune checkpoint inhibitor story was being revealed, and we had some fantastic investigators who won Nobel Prizes. Then immune checkpoint inhibitors took over the whole world of oncology, from one drug to now several drugs, from one indication to now several indications.

Moving forward, I foresee that the next decade will be the era of radiopharmaceuticals or what we call theranostics (therapy and diagnostics). This is a field of medicine where we try to find the target of interest in a particular cancer. In prostate cancer, this might be prostate-specific membrane antigen (PSMA), or in neuroendocrine cancers, somatostatin receptors. There could be so many others—fibroblast-activating protein in pancreatic cancer, integrin in breast cancer, so on and so forth.

Once you have a target, you can link a radiopharmaceutical to a drug which attaches to that target, and then you can scan the patient and look at the tumors and the distribution of that target, unlike the current precision medicine where we are dependent on a biopsy of that one particular spot. Here, you get a real-time view of how the tumor target is expressed, what the quantity is, and what the burden of disease is. Then all you have to do is flip the radiopharmaceutical from an imaging isotope to a heavy-duty isotope, be it a beta emitter like lutetium or an alpha emitter based on actinium or lead, and then it's the same concept. A diagnostic agent become a therapeutic agent, so theranostics.

I foresee that this class of drug is going to have a meteoric rise. A lot of small and big pharmaceutical industries have heavily invested in it. It's a multibillion-dollar industry now. What is exciting to see is that drugs like 177Lu-dotatate and 177Lu-vipivotide tetraxetan popularized it, but it's moving forward into various solid cancers. I think it's going to take the oncology community by surprise, a very pleasant surprise.

Dr. Kareff: Oh, it's very exciting indeed. While we are here in the era of precision oncology, to see things evolving faster than they can be written in the textbooks, again, is always good for patients and of course the providers who are able to serve them. Thank you for foreshadowing that, and I'm also looking forward to seeing what comes down the pipeline.

All right, thanks so much for tuning into this episode of the Fellows Forum. Thanks again to Dr. Chauhan for sharing some of your expertise and experiences, and we look forward to touching base soon. Bye now.

Dr. Chauhan: Thank you, Sam. Thank you, everybody.

About Dr. Kareff and Dr. Chauhan

Samuel Kareff, MD, MPH, is a Medical Oncologist and a Hematology-Oncology Fellow at the University of Miami, Sylvester Comprehensive Cancer Center and Jackson Memorial Hospital in Florida. He has special research interests in health advocacy, public policy, global cancer care, and the development of cancer therapies.

Aman Chauhan, MD, is an Associate Professor of Medical Oncology at the University of Miami, Sylvester Comprehensive Cancer Center, where he is also Leader of the Neuroendocrine Tumor Program and Co-Director of the Theranostics Program. He specializes in the treatment of neuroendocrine cancers, and his research focuses on the use of theranostics to develop novel treatment and management strategies for these diseases.

For More Information

Singh S, Halperin DM, Myrehaug S, et al (2023). [177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: primary analysis of the phase 3 randomized NETTER-2 study. J Clin Oncol (ASCO GI Cancers Symposium Abstracts), 42(suppl_3). Abstract LBA588. DOI:10.1200/JCO.2024.42.3_suppl.LBA588

Chan J (2023). Alliance A021602: phase III, double-blinded study of cabozantinib versus placebo for advanced neuroendocrine tumors (NET) after progression on prior therapy (CABINET). Presented at: 2023 European Society of Medical Oncology Conference. Abstract LBA53. Available at: https://cslide.ctimeetingtech.com/esmo2023/attendee/confcal/session/calendar?q=cabinet

Crinetics Pharmaceuticals (2023). Crinetics announces positive initial findings from ongoing open-label phase 2 study of paltusotine for the treatment of carcinoid syndrome. Available at: https://ir.crinetics.com/news-releases/news-release-details/crinetics-announces-positive-initial-findings-ongoing-open-label/

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor. 


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