Treatment Selection, Sequencing, and, Unmet Needs in GEP-NETs

Hagen F. Kennecke, MD

Hagen F. Kennecke, MD, Virginia Mason Medical Center, an expert in the treatment of patients with gastroenteropancreatic neuroendocrine tumors (NETs), discusses treatment selection, peptide receptor radionuclide therapy, and remaining challenges in the field.

OncLive: When you treat patients with gastroenteropancreatic neuroendocrine tumors (NETs), what are some of the principles that guide treatment selection and sequencing?

Kennecke: In terms of the advanced disease, we always consider surgery first and then stage [patients] with a gallium [ga] 68 [dotatate] Netspot. Subsequently, if there’s advanced disease, we offer surgery. And if that’s not possible, liver-directed therapy followed by targeted treatment for somatostatin analogues gallium[68 and] lutetium 177 and chemotherapy, and, of course, targeted therapies. Somatostatin analogues generally are reserved for first-line disease as well as for symptomatic patients, preventing progression, reduce symptoms, and improving quality of life.

I believe sequence matters less than how well the treatments are working and how urgently patients need them. If patients really need debulking therapy, then surgery or liver-directed therapy or chemotherapy will get you there fastest.

How can clinicians and academic institutions optimize treatment selection?

Detailed discussions with the patient, preferences, as well as proper staging with NETSPOT and conventional CT imaging [are important]. We always do multiple disciplinary tumor boards to make sure surgeons, endocrinology (if they have symptoms), medical oncology, nuclear medicine, and radiology have their opinion.

[At my institution,] we present their history and give the background, then sequentially review pathology. It’s really important to review pathology; if it’s done externally, [clinicians should] make sure the tumor grade is assessed, [do a] Ki-67 differentiation review, and then review the imaging or repeat any imaging if multiphase CT is not done, and review that to look for extended disease, and look closely at gallium 68 Netspot. We also assign a cranial score to all patients, to grade the tumors from 0 to 4 to make sure that they express metastatic analogue receptors; if they don’t, then that takes us down a completely different pathway. From those reviews, we decide on the best first strategy, and then we take that back to the patient and discuss that with them.

What is the role of peptide receptor radionuclide therapy (PRRT) in the evolving treatment spectrum for NETs?

It’s been a game-changer. There’s a strong preference for it in patients who are familiar with it because of the targeted nature of it. It has very limited [adverse] effects. We also have systemic therapy with chemo[therapy] as well as targeted agents but for small bowel NETs, and the majority of endocrine tumors are advanced NETs. We don’t really have other treatment options beyond the somatostatin analogues, so it’s really given us a brand-new treatment option for patients. We obviously have everolimus for the midgut NETs and now also the tyrosine kinase inhibitors, and we have new data with ponatinib [Iclusig]. We do have a broader range of treatment, but the PRRT is very dominant for those midgut NETs.

The dominant effect of PRRT is stabilization of disease, and we see 60% response rates including disease state stabilization, and a 15% good clinical radiographic response rate to therapy. We see an average progression-free survival of 2 years—and approaching 3 years in patients [who] have a partial response radiographically. There’s also evidence that it didn’t improve symptoms for patients [who] have pain in… secretory tumors, [and] they feel better once they are treated with PRRT compared [with] those who don’t get PRRT.

What are the most significant challenges in the NET space, and what are the greatest unmet needs in the treatment landscape?

Certainly, the tumors that are high grade or don’t have somatostatin receptor analogue [are most challenging] because if they don’t have some somatostatin receptor positivity on gallium 68 in a Netspot, then you’re really losing treatment options; some would even say that [patients] shouldn’t be treated with somatostatin analogues if they don’t have that, so those patients who don’t have receptor positivity are where we are struggling. There are trials for those patients but not everyone can go on a trial and there are quite strict criteria as well, so that’s a limitation. And then, of course, in patients with a high grade of disease that is progressing quickly, we generally start [with] chemotherapy—either platinum-based if the Ki-67 is very high, over 55%, or if they’re over 55—although we’re still not sure if they’re going to respond to treatment.

We have better treatments now, but there’s still a long way to go, so it keeps everyone motivated to work for [the] better.