Personalizing Therapy With PRRT and Improving Imaging With SSTR-PET Brings Novel Options to NETs Landscape

Thomas Hope, MD

The anticipated FDA approval of Lutathera (lutetium [177Lu] oxodotreotide) for the treatment of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) could potentially lead to significant improvements in disease progression for these patients, as well as others with NETs, explains Thomas Hope, MD.

The FDA accepted the supplemental new drug application for Lutathera in August 2017, which was based on findings of the phase III NETTER-1 trial.¹The study compared Lutathera, which is a peptide receptor radionuclide therapy (PRRT), with high-dose long-acting octreotide for patients with grade 1/2 metastatic midgut NETs; results showed that there was a 79% reduction in the risk of progression or death with Lutathera compared with octreotide (Sandostatin).

Though the agency issued a complete response letter in December 2016 informing the manufacturer that the NDA would need to be resubmitted to include new subgroup information, updated safety findings, and revisions to previously submitted data, the agency is now expected to make a decision on the approval by January 26, 2018.

In addition to this personalized treatment poised to hit the market, Hope also said the FDA-approved imaging agent somatostatin receptor PET (SSTR-PET) has more diagnostic sensitivity and specificity and is able to image patients within 1 hour—a quicker and more quantitative approach compared with standard octreoscan.

In an interview withTargeted Oncology^TMduring the 10th Annual NANETS Symposium, Hope, assistant professor, Abdominal Imaging and Nuclear Medicine, University of California, San Francisco, spoke on personalizing therapy for patients with NETs with Lutathera as well as the significance of SSTR-PET to the treatment landscape.

Targeted Oncology^TM: How are you seeing therapy for NETs become more personalized with regards to imaging?

Hope: It is an exciting year in our field in medicine and targeted therapy because of the publication of the NETTER-1 trial, which was the first randomized, controlled trial of patients with NETs treated with PRRT. That was really the first time that the community got to see randomized trial data demonstrating the efficacy of these treatments in patients with midgut NETs.

The exciting part of our field is now—we’re just beginning to get started. This is the beginning, and there are a number of questions we have to address as we move forward. The trials [were conducted] for [patients with] midgut NETs, but it looks like it should be applicable in some pancreatic NETs, bronchial carcinoids, and paragangliomas.

Do we need to think about which patient populations [to use this in, for example] high-grade NETs? Should we be using different radionuclides—yttrium-90 versus alpha emitters? What type of co-administered therapies can we use? [Can we use] immunotherapies or PARP inhibitors? There are trials out there [looking at] capecitabine or temozolomide chemotherapy combined with PRRT.

As we await the approval of Lutathera (lutetium [177Lu] oxodotreotide) in January, it will be an exciting time for us to now step forward and think about the questions that are going to occur when we have this therapy available in the United States.

What is the mechanism of action of Lutathera?

Lutathera is termed a PRRT; the “P” is peptide, the somatostatin analog binds to the somatostatin receptor, which is the first “R” in PRRT. You have the peptide-binding receptor and it carries with it a radionuclide, the second “R”—the radionuclide in this case is Lutathera—which is a radium metal that decays by giving off an electron, and that electron will travel about 2 to 3 millimeters in maximum distance from wherever it ends up and kills cells around it. It takes about 1000 electrons to kill a cell, so you need a lot of cross talk between these decaying atoms. However, data from the NETTER-1 trial show that this is efficacious in treating tumors. Obviously, the final letter, “T,” is for therapy.

Can you reflect on the most significant findings from the NETTER-1 trial?

The first thing to keep in mind with the NETTER-1 trial is the population [of patients with] midgut NETs were progressive on long-acting octreotide therapy. Therefore, it is important to keep in mind that it also required patients to have avid disease as determined by an octreoscan. Obviously, we won’t be performing octreoscans anymore, so it’s a little hard to determine how to do patient selection based on Gallium-68 SSTR-PET scans.

The key take-home points from NETTER-1 are 2-fold. One is the progression-free survival [PFS]; that was a primary endpoint of the study. In patients treated with Lutathera, the PFS rate was approximately 67% in patients who had not yet progressed. In patients treated with double-dose long-acting octreotide, only 11% of patients had not yet progressed; it was a big difference in PFS at 20 months, which was their primary endpoint.

The other take-home point is the percentage of patients who had RECIST criteria response. Typically, in oncology trials, we think of a therapy as being efficacious when tumors shrink. However, if you look at the NETTER-1 trial, less than 20% of patients had tumors that shrunk, which is remarkable given that there was such a low or partial response in terms of size change, but there was such a prolongation of PFS. Therefore, it’s really, to me, unexpected that there is such a disconnect between PFS and response. Overall, it clearly demonstrates that it is very effective in preventing progression in patients with midgut NETs.

Is this being explored in other types of NETs, as well?

There are actually tons of clinical data—phase II, retrospective, single-arm, non-randomized data—on using PRRT in a number of types of cancers out there. When I say cancers, I mean all subtypes of NETs. Bronchial is probably the second most commonly studied outside of midgut and pancreatic NETs, and [PRRT] has demonstrated good efficacy [there]. People have used it in paragangliomas and other types of tumors.

The other side of it is not just the site of origin but also the grade; there is a little bit of evidence suggesting that, with multi-differentiated grade 3 tumors, there might be some efficacy. However, there are more data needed, [especially] in higher-grade NETs as to whether it can be effective.

You also lectured on the Gallium-68 PET/CT scan. How is this changing the landscape?

We recently completed the appropriate use criteria of somatostatin receptor PET (SSTR-PET). This was done as a collaboration between the Society of Nuclear Medicine and Molecular Imaging, North American Neuroendocrine Tumor Society, and members from ASCO, AACR, and a number of other organizations. It was just published in theJournal of Nuclear Medicine.²

This document was designed to describe in which clinical circumstances SSTR-PET should be utilized. There are 3 general areas that we graded indications as to whether or not it should be used, [such as] initial staging. When you have a patient initially diagnosed with a NET, when should you be using SSTR-PET? Generally, the group believed that in patients who had a histological diagnosis of NET should be indicated.

What are the most important things people should know about this imaging agent?

In June 2016, it was FDA approved and is covered by Medicare. It is significantly better in terms of diagnostic sensitivity and specificity compared with the octreoscan. We now have a much more improved study that occurs in 1 day; patients can get the injection, they image 1 hour later, and then you’re done 1 hour after that. It is a lower radiation dose, is easier to interpret, and is quantitative.

The other side of it, which is important, is how to use it in terms of following patients over time. SSTR-PET shouldn’t be used for routine surveillance in patients to see whether their tumors progress. That should be done with conventional imaging. For patients who have liver-dominant NETs, for example, they should be getting an MRI routinely, rather than repeating SSTR-PET every 3 to 6 months.

Considering the future, do you see any next steps with SSTR-PET?

Now that we have SSTR-PET available, [we need to] just get it used in the clinic. The main thing is to make it the clinical standard, which it is [becoming] very quickly.

In terms of improving imaging for NETs, I’m not sure there is a lot of need beyond SSTR-PET to have a better imaging modality that would be of a nuclear medicine-based modality. This is quite a good modality. However, there are other things in terms of imaging associated with PRRT—for example, dose-symmetry imaging. [We are] trying to understand how much dosage goes to the tumor and its relationship with side effects and things like that to optimize patients’ specific therapies. That has very little to do with SSTR-PET, but more to do with posttreatment imaging and things like that.

References

1. Strosberg JR, Wolin EM, Chasen B, et al. NETTER-1 phase III: Efficacy and safety results in patients with midgut neuroendocrine tumors treated with 177Lu-DOTATATE.J Clin Oncol. 2016;34(suppl; abstr 4005).
2. Hope TA, Bergsland E, Bozkurt MF, et al. Appropriate use criteria for somatostatin receptor PET imaging in neuroendocrine tumors [posted online October 12, 2017].J Nucl Med. 2017. doi: 10.2967/jnumed.117.202275.