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Novel Therapies Emerging for the Treatment of NETs

Panelists: Simron Singh, MD, Odette Cancer Centre; Jonathan R. Strosberg, MD Moffitt Cancer Center
Published: Friday, Jan 11, 2019



Transcript:

Jonathan R. Strosberg, MD:
We’ve had some new studies, and some of them are being presented at this ESMO [European Society for Medical Oncology] meeting. What are your thoughts on some of these new abstracts? The data are just coming out now.

Simron Singh, MD: I think it’s an exciting time in neuroendocrine cancer. It’s only been in the last decade that we’re starting to see abstracts and randomized trials come out. In an evolving treatment landscape, there are many unanswered questions related to PRRT [peptide receptor radionuclide therapy]—when, and how, and whether we should re-treat, for example. We have a number of trials coming out on targeted agents in both pancreatic and gastrointestinal neuroendocrine tumors. We are looking at using cabozantinib and other targeted agents. Some are just recruiting. Some are ready to report. Immunotherapy is, of course, all of the rage in the oncology world. Our first immunotherapy results are starting to come out. We previously saw the KEYNOTE trial, which showed fairly modest rates in a very limited population. I think I was hesitant to make too many conclusions on that. It was 12% in the gastrointestinal population and 6% in the pancreas population.

We now have the largest immunotherapeutic trial in neuroendocrine tumors [NETs] looking at PDR001 in patients with neuroendocrine tumors of the pancreas or gastrointestinal tract. This is also being looked at in thoracic and poorly differentiated neuroendocrine carcinomas. It is going to be interesting to see what the responses are, as well as the duration of response. When it comes to immunotherapy, it’s going to be important for us to delineate who the right patients are. I think we still have work to do, to try to understand who could potentially respond to immunotherapy or how we can make the tumors, on the other hand, more responsive. How can we make them more inflammatory so that we can have responses to traditional immunotherapeutic agents?

We know that neuroendocrine tumors generally don’t have a high mutational load at baseline. And the results so far have not shown dramatic effects with immunotherapeutic agents such as PDR001. But I do think there is a potential role in lung neuroendocrine tumors, especially where there may be certain patients who would respond quite well to immunotherapeutic manipulation. There may be other things that we can do to improve that.

Jonathan R. Strosberg, MD: I agree. The data with immunotherapy has been underwhelming. With PDR001, the highest response rate was seen in atypical lung neuroendocrine tumors. It was approximately 20%, but in most cases was not durable. Then, in the remaining cohorts, it was pretty much single digits. I think there was some surprise regarding the fact that we haven’t seen much response in poorly differentiated or high-grade neuroendocrine carcinomas where we were expecting to see more responders.

Simron Singh, MD: The response rate in the thoracic cohort for the study was 20%. All of the people who responded were atypical. So if you take the atypical lung neuroendocrine tumors out, the response rate starts to go up. There are still patients who are undergoing treatment. These are still preliminary responses. So I do think my interpretation would be that it definitely shows some promise. But you’re right. I think we still have to truly learn how we can improve the efficacy of neuroendocrine tumors, especially with this unmet need in neuroendocrine carcinomas where we have a shortage of treatments.

Jonathan R. Strosberg, MD: What about lenvatinib?

Simron Singh, MD: The lenvatinib results haven’t been fully released yet, but from what we’ve seen in abstract form, they do appear to be exciting. We’re starting to understand how more of the targeted agents beyond some of the traditional ones we use can be exciting. I’m not sure we know exactly where it needs to go quite yet as a single agent or in combination, and where it would sequence in. What are your thoughts?

Jonathan R. Strosberg, MD: Well, I just looked at the abstract. I haven’t seen the presentation yet. The objective response rate was exceptionally high. I think it was roughly 40% in pancreatic NETs and 18% in other gastrointestinal NETs. It’s definitely higher than what we’ve seen with other targeted agents. I think for a phase II study, response rate is a really important endpoint. It’s hard to know what to make of progression-free survival in a phase II study because of the heterogeneity of the population. But a high response rate is sort of a strong endpoint for a single-arm study, so it’s very encouraging. I have no doubt that we’ll be seeing more randomized studies with lenvatinib.

Transcript edited for clarity.

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Transcript:

Jonathan R. Strosberg, MD:
We’ve had some new studies, and some of them are being presented at this ESMO [European Society for Medical Oncology] meeting. What are your thoughts on some of these new abstracts? The data are just coming out now.

Simron Singh, MD: I think it’s an exciting time in neuroendocrine cancer. It’s only been in the last decade that we’re starting to see abstracts and randomized trials come out. In an evolving treatment landscape, there are many unanswered questions related to PRRT [peptide receptor radionuclide therapy]—when, and how, and whether we should re-treat, for example. We have a number of trials coming out on targeted agents in both pancreatic and gastrointestinal neuroendocrine tumors. We are looking at using cabozantinib and other targeted agents. Some are just recruiting. Some are ready to report. Immunotherapy is, of course, all of the rage in the oncology world. Our first immunotherapy results are starting to come out. We previously saw the KEYNOTE trial, which showed fairly modest rates in a very limited population. I think I was hesitant to make too many conclusions on that. It was 12% in the gastrointestinal population and 6% in the pancreas population.

We now have the largest immunotherapeutic trial in neuroendocrine tumors [NETs] looking at PDR001 in patients with neuroendocrine tumors of the pancreas or gastrointestinal tract. This is also being looked at in thoracic and poorly differentiated neuroendocrine carcinomas. It is going to be interesting to see what the responses are, as well as the duration of response. When it comes to immunotherapy, it’s going to be important for us to delineate who the right patients are. I think we still have work to do, to try to understand who could potentially respond to immunotherapy or how we can make the tumors, on the other hand, more responsive. How can we make them more inflammatory so that we can have responses to traditional immunotherapeutic agents?

We know that neuroendocrine tumors generally don’t have a high mutational load at baseline. And the results so far have not shown dramatic effects with immunotherapeutic agents such as PDR001. But I do think there is a potential role in lung neuroendocrine tumors, especially where there may be certain patients who would respond quite well to immunotherapeutic manipulation. There may be other things that we can do to improve that.

Jonathan R. Strosberg, MD: I agree. The data with immunotherapy has been underwhelming. With PDR001, the highest response rate was seen in atypical lung neuroendocrine tumors. It was approximately 20%, but in most cases was not durable. Then, in the remaining cohorts, it was pretty much single digits. I think there was some surprise regarding the fact that we haven’t seen much response in poorly differentiated or high-grade neuroendocrine carcinomas where we were expecting to see more responders.

Simron Singh, MD: The response rate in the thoracic cohort for the study was 20%. All of the people who responded were atypical. So if you take the atypical lung neuroendocrine tumors out, the response rate starts to go up. There are still patients who are undergoing treatment. These are still preliminary responses. So I do think my interpretation would be that it definitely shows some promise. But you’re right. I think we still have to truly learn how we can improve the efficacy of neuroendocrine tumors, especially with this unmet need in neuroendocrine carcinomas where we have a shortage of treatments.

Jonathan R. Strosberg, MD: What about lenvatinib?

Simron Singh, MD: The lenvatinib results haven’t been fully released yet, but from what we’ve seen in abstract form, they do appear to be exciting. We’re starting to understand how more of the targeted agents beyond some of the traditional ones we use can be exciting. I’m not sure we know exactly where it needs to go quite yet as a single agent or in combination, and where it would sequence in. What are your thoughts?

Jonathan R. Strosberg, MD: Well, I just looked at the abstract. I haven’t seen the presentation yet. The objective response rate was exceptionally high. I think it was roughly 40% in pancreatic NETs and 18% in other gastrointestinal NETs. It’s definitely higher than what we’ve seen with other targeted agents. I think for a phase II study, response rate is a really important endpoint. It’s hard to know what to make of progression-free survival in a phase II study because of the heterogeneity of the population. But a high response rate is sort of a strong endpoint for a single-arm study, so it’s very encouraging. I have no doubt that we’ll be seeing more randomized studies with lenvatinib.

Transcript edited for clarity.
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