Developments in the NETs Treatment Landscape

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Jonathan R. Strosberg, MD: There are several promising new therapies on the horizon. They haven’t completed testing yet, so we don’t know how active they’ll be. Some of them exploit the somatostatin receptor, so there are new somatostatin analogs conjugated to cytotoxic drugs that deliver cytotoxic therapy to neuroendocrine tumors. That’s quite interesting. There’s bispecific antibodies that target both the somatostatin receptor as well as T cells. They basically bring T cells to the proximity of the tumors. That may be an exciting immune approach that’s different from the checkpoint inhibitors. There’s also new forms of peptide receptor radiotherapy. There’s always been a lot of interest in alpha-emitting radioisotopes. They’re quite hard to work with, and that’s been a challenge. But we’re starting to see clinical trials with alpha emitters that really pack a large radiotherapeutic punch at an extremely short range, potentially improving the therapeutic index.

We’re just starting to learn about immunotherapy in neuroendocrine tumors. The first data recently came from subset results of a basket trial that included neuroendocrine tumors. The response rates were modest—roughly 5% to 10%. I think there’s an emerging consensus that the response rate is likely not going to be very high. But there’s certainly some patients who respond. We need to start trying to predict who these patients might be.

Initially, I think it’s going to be clinical factors. Maybe aggressive pancreatic neuroendocrine tumors or atypical lung carcinoids—tumors with a higher mutational burden compared with midgut neuroendocrine tumors that tend to be mutationally quite inactive? Maybe those are more likely to respond? Eventually, maybe we’ll have better predictive factors in this disease and for cancer, in general. So, I think immunotherapy will play a role. But it’s certainly not going to be as active as it is in some cancers, like melanoma or lung cancer.

Heloisa P. Soares, MD: The role of immunotherapy in neuroendocrine tumors has yet to be established. I think it’s much more unknown in well-differentiated and intermediate-grade tumors. If anything, we will hopefully be looking for some success with immunotherapy in high-grade, poorly differentiated tumors. The jury is still out. We don’t have many trials that have already published results, but we are looking forward to these results. We have trials, from pharmaceutical companies, that look into well-differentiated and moderately differentiated tumors. We are waiting on the results. There is a Cooperative Group trial that had a subgroup of patients receiving immunotherapy. We are also waiting on these results. Hopefully, we will have that in the next few years, and that will be very important. In Merkel cell carcinoma, which is a neuroendocrine tumor disease from the skin, we already have some data on immunotherapy. In fact, an anti—PD-L1 was approved for the treatment of Merkel cell disease. So, I’m hopeful that immunotherapy will play a big role, particularly in patients with more aggressive or poorly differentiated high-grade disease.

Timothy J. Hobday, MD: We have a number of very promising research avenues emerging for future therapies. They are targeted therapies that are ready to be tested in large randomized trials throughout the United States and the world that will build on the mTOR inhibitors and the VEGF pathway inhibitors that are already a standard part of our care. In addition, many small trials have looked at the role of immunotherapy in well-differentiated neuroendocrine tumors. We will await, with great interest, the results of these trials. There has been a lot of preclinical data looking at various subpopulations of patients with neuroendocrine tumors, trying to understand which may be more amenable to immunotherapy and to help us refine patient selection for future clinical trials.

In addition, there are some ideas that suggest that combining peptide receptor radiotherapy with immunotherapy may be an interesting avenue of research. Given the potential for radiation to further increase the results of responses to immunotherapy, generally, throughout oncology, we would hope that would be the same for our patients. So, the future of immunotherapy and how it will be deployed or tested within these patients is really just in its infancy, getting off the ground. It’s quite exciting.

Transcript Edited for Clarity