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.

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

: 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&mdash;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.

Articles

Hagen F. Kennecke, MD, discusses treatment selection, peptide receptor radionuclide therapy, and remaining challenges in the field of gastroenteropancreatic neuroendocrine tumors.

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

Over the past decade, there have been several key treatment advances in the treatment paradigm for patients with gastroenteropancreatic neuroendocrine tumors. In a wide-ranging interview, Aman Chauhan, MD, University of Kentucky, discussed recent developments and emerging therapies in the field.

: What is the current treatment strategy for patients with gastroenteropancreatic neuroendocrine tumors (NETs)?

: Fortunately, we have seen some advances in treatment strategies, especially [in the] last 5 to 7 years. The frontline treatment for metastatic disease is somatostatin analogues, and we currently have 2 agents that are FDA approved: [octreotide acetate] Sandostatin and lanreotide [Somatuline Depot]. [If] patients progress on frontline treatment, there is, at present, a lack of evidence regarding the next-best agent to choose from. Traditionally, an mTOR inhibitor—everolimus or even sunitinib [Sutent]&mdash;was our go-to second-line agent, but with the recent approval of PRRT [peptide receptor radionuclide therapy], we don’t know whether the next line of treatment is PRRT or an mTOR inhibitor; this is an area of ongoing research [in which] I hope we will have some answers soon.

In the refractory setting, we often encourage patients to participate in clinical trials. In third- and fourth-line [settings], there [are] some data regarding capecitabine/temozolomide, as well, especially in pancreatic NETs, [in which] the combination chemotherapy is definitely very active. For an early-stage disease, surgery [is] the mainstay of treatment if it is a resectable disease; if it’s a low-bulk liver-dominant metastatic disease, then we also often employ local therapies like embolization, hepatic artery, and selective surgical debulking.

How do you determine the optimal sequencing for treatment?

Hopefully, [in] the next 5 to 10 years, we will actually have some really solid prospective data to help guide these decision-making [processes]. At present, it is actually dictated by the presentation or the degree of tumor progression. For example, if I have a patient with metastatic disease who has a lot of pain, I would probably treat that patient with a PRRT agent up front or early on in the management strategies rather than waiting or trying out other agents. On the contrary, for a slow-growing tumor [when] the patient is completely asymptomatic and has a very low-bulk metastatic disease, I like to utilize somatostatin analogues and maybe [an] mTOR inhibitor [thereafter] before I expose them to a radionuclide-based therapy, and that’s just my practice pattern. Of course, we are looking for some conclusive prospective data to help guide us with this question.

What role do somatostatin analogues play in the treatment of these patients and what new data do we have on this class of agents?

Somatostatin analogues are the backbone of our treatment; [they] completely changed the way we manage [disease in] these patients. They work very well not just for functioning of NETs, but also nonfunctioning NETs. Results of the CLARINET study [NCT00353496] showed significant PFS [progression-free survival] benefit in favor of lanreotide in [patients with] metastatic NET.

 A somatostatin analogue [is] definitely my go-to medication for a patient with metastatic progressive disease; I use it front line and it’s quite well tolerated, [with a] reasonably good [adverse] effect profile as compared to our traditional chemotherapy, targeted therapy, and radiation-based therapy for NETs.

Regarding newer somatostatin analogues, lanreotide has a newer, improved injectable design and is a bit sturdier. This is an agent [that] is given subcutaneously. I know that in Europe lanreotide can also be self-administered by the patient or healthcare giver at home, which is unfortunately not allowed in the United States. There are some studies ongoing looking at the combination of various analogues with various systemic treatment[s]. [New investigations are] looking into somatostatin analogues in grade 3 well-differentiated NETs. [Early results] show that there were some patients who have stable disease and that there could potentially be a role for analogues, even in high-grade well-differentiated neuroendocrine tumors.

Could you discuss the role of PRRT and how that has affected clinical practice?

PRRT is a recent addition to our treatment paradigm in NETs based on the pivotal NETTER-1 phase 3 trial [NCT01578239], which randomized patients between 

Lu-Dotatate, a peptide receptor radionuclide therapy targeting somatostatin receptors, which are seen in these midgut NETs, and the control arm somatostatin analogue, [a] higher-than-usual dose of sandostatin. The median PFS was not even attained in the treatment arm, and [there] was a drastic improvement in median PFS compared with the control arm. Now we know [from] long-term follow-up data that the median PFS is in range of 35 to 40 months, significantly higher as compared with [the] control arm, which was 15 to 18 months.

 It has been a significant advancement in terms of how we treat NETs. I’m pretty much certain that this PFS benefit would eventually also [become] an overall survival benefit, but we are [currently] awaiting.

PRRT is not only a significant advancement in terms of controlling the progressive disease, but there [are] data [showing] that it improves quality of life and reduces symptomatic carcinoid syndrome—related symptoms, especially diarrhea and flushing. [Also,] for the first time, we are seeing an approved agent with significant radiological responses. Prior to 

Lu-Dotatate, somatostatin analogues and everolimus showed radiological responses in 5% or 7% of patients. 

Lu-Dotatate had about 17% to 18% objective responses, so this was a significant step in terms of cytoreductive capability; however, there is certainly a lot more room to improve in terms of radiological response, but it was a welcoming step.

What other therapies are emerging in the landscape?

I think our community has recognized that NET incidence is rising. A very impactful paper in

 summarized the SEER database trends and showed a 6- to 7-fold increase in NET incidence, which is in contrast with other major cancers over the past 40 years, which have basically plateaued over the same period.

 This has resulted in efforts, improved efforts, in terms of therapy development, development of neurodiagnostic modalities.

There are newer peptide receptor radionucleotide treatments, agents currently in development in various phases, such as

Lu-edotreotide. The [ongoing] phase III COMPETE trial [NCT03049189] is an international, multicenter [study] looking into antitumor activity of 177Lu-Edotreotide in randomizing patients against everolimus in patients with well-differentiated neuroendocrine tumors who have progressed on somatostatin analogues. I personally am excited about a combination PRRT phase I trial testing a drug called triapine, which is a ribonucleotide reductase inhibitor, and we are using triapine as a radiation sensitizer.

 Based on our preclinical data, we [are] very optimistic that this combination might help us improve efficacy of 

Lu-Dotatate even further. This phase I trial, I hope, will start enrolling [soon] and would be open throughout the Experimental Therapeutic Clinical Trials Network for other [patients] to [enroll in], and it’s primarily looking at finding the safe phase II dose of triapine in combination with 

There are certain tyrosine kinase inhibitors [that] are currently being evaluated in various subsets of NETs. Lenvatinib [Lenvima] data [were] presented last year at the annual American Society for Clinical Oncology and American Association of Cancer Research meetings and showed impressive results in pancreatic neuroendocrine tumors. I hope that drug is taken further into phase III. The currently ongoing cabozantinib phase III CABINET trial [NCT03375320] is very promising. The phase II data were very impressive in pancreatic NETs with response rates, I think, close to 18% to 20%.

 I look forward to seeing the phase III CABINET trial [results], and hopefully advance our field.

One area of critical unmet needs in NETs or [in the] neuroendocrine neoplasm realm, is the high-grade [therapy, because] we don’t really have a good treatment beyond frontline platinum-based chemotherapy, and I think we need to make some efforts to develop new treatments. Last year, some impressive data [were presented] on combination immunotherapy with ipilumab [Yervoy] plus nivolumab [Opdivo] in these high-grade, poorly differentiated neuroendocrine neoplasms and had showed about 40% responses. This was a small phase II study, and these data need to be validated in larger randomized trials. But combination immunotherapy might be something to look forward to in these high-grade, poorly differentiated neuroendocrine neoplasms.

Study of lanreotide autogel in non-functioning entero-pancreatic endocrine tumours (CLARINET). clinicaltrials.gov/ct2/show/NCT00353496. Updated March 6, 2015. Accessed March 26, 2020.

Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. 

. 2017;376(2):125-135. doi: 10.1056/ NEJMoa1607427.

A study comparing treatment with 177Lu-DOTA0-Tyr3-octreotate to octreotide lar in patients with inoperable, progressive, somatostatin receptor positive midgut carcinoid tumours (NETTER-1). clinicaltrials.gov/ct2/show/NCT00353496. Updated January 21, 2020. Accessed March 26, 2020.

Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. 

. 2017;3(10):1335-1342. doi: 10.1001/jamaoncol.2017.0589.

Efficacy and Safety of 177Lu-edotreotide PRRT in GEP-NET patients (COMPETE). clinicaltrials.gov/ct2/show/NCT03049189. Updated February 13, 2020. Accessed March 26, 2020.

Cabozantinib S-malate in Treating Patients With Neuroendocrine Tumors Previously Treated with Everolimus That are Locally Advanced, Metastatic, or Cannot be Removed by Surgery. clinicaltrials.gov/ct2/show/NCT03375320. Updated March 24, 2020. Accessed March 26, 2020.

Aman Chauhan, MD, discusses recent developments and emerging therapies in gastroenteropancreatic neuroendocrine tumors.

Expert Explains Latest Treatment Strategies in GEP-NETs

Approximately 175,000 Americans are affected by neuroendocrine tumors (NETs), 65% of which are gastroenteropancreatic (GEP) NETs. GEP-NETs represent a diverse family of tumors that arise in the gastrointestinal (GI) tract or pancreas.

 The overall incidence of NETs across all stages, sites, and grades has increased nearly 7-fold over the past 40 years, a greater increase than that of all other malignant neoplasms; this may be partly credited to enhanced technologies for detecting early-stage disease and stage migration.

The increasing incidence of GEP-NETs heightens the urgency to improve diagnostic and treatment approaches for these complex tumors. Regarding diagnostics, next-generation genetic sequencing techniques have gained traction, helping to identify patients at risk for future disease or in very early stages of disease. However, to guide individualized treatment decisions, additional research is needed to understand how specific genetic mutations influence GEP-NET behaviors.

 Evolving approaches are already helping investigators identify new biomarkers that may serve as better indicators for accurate GEP-NET diagnosis, prognosis, and therapy response than traditional biomarkers, which can sometimes lead to false positives (eg, chromogranin A, which increases in many non—GEP-NET conditions) or involve cumbersome testing (eg, insulin or gastrin).

 A large opportunity exists in research to identify biomarkers for poorly differentiated and high-grade tumors.

In terms of treatment options, most patients with GEP-NETs are not candidates for curative surgery, so they are offered long-term systemic treatment for antitumor effects and symptom relief.

 The current treatment landscape for GEP-NETs and the need for improved novel therapies was discussed on January 23, 2020, in San Francisco, California, during an 

 scientific interchange titled “Current and Emerging Treatments for Neuroendocrine Tumors.” The interchange was led by Carina Mari Aparici, MD, of Stanford University. Panelists were Walid Shaib, MD, of Emory University School of Medicine; Aman Chauhan, MD, of the University of Kentucky; Andrew E. Hendifar, MD, of Cedars-Sinai Medical Center in Los Angeles; Thomas Hope, MD, of the University of California, San Francisco; and Hagen F. Kennecke, MD, MHA, FRCPC, of Virginia Mason Medical Center. This article summarizes key data and discussion points from this scientific interchange, including current GEP-NET therapies—such as somatostatin analogues (SSAs), peptide receptor radionuclide therapy (PRRT), and emerging novel drugs&mdash;and their clinical trial data, as well as institutions’ varying therapy-sequencing strategies and the need for further research and guidelines for treating this complex disease.

The World Health Organization (WHO) 2010 and 2017 classification system categorizes GEP-NETs into 3 grades on the basis of histological differentiation and cell proliferation index, which assists in guiding treatment decisions. Tumor grade is determined by the highest number of either Ki-67 protein or mitotic count, and it offers an important prognostic value for GEP-NETs. Median survival rates have been determined for all NETs across all locations by tumor grade. For individuals with grade 1 tumors, median survival is more than 16 years; for grade 2, about 8 years; and for grade 3, about 10 months.

 In 2017, WHO updated the staging classifications for pancreatic NETs (pNETs) to recognize well-differentiated grade 3 tumors. This will allow for more precisely targeted treatment options for grade 3 tumors. Poorly differentiated grade 3 pNETs may continue to be treated with standard systemic chemotherapy, whereas well- and moderately differentiated grade 3 pNETs have been shown to benefit from targeted therapies (everolimus or sunitinib). Well-differentiated pNETs may even benefit from surgery.

Surgery, the only curative treatment for GEP-NETs, is generally considered a first-line treatment for localized NETs.

 However, despite advances in diagnostics, GEP-NETs are often not identified for up to 5 to 7 years after clinical symptoms appear, as the symptoms are not specific. Approximately 21% of well-differentiated NETs, 30% of moderately differentiated NETs, and 50% of poorly differentiated or undifferentiated NETs are diagnosed in the metastatic stage.

 Thus, a substantial number of patients with GEP-NETs are not candidates for surgery and require systemic therapy after diagnosis (

SSAs are generally considered first-line treatments for longterm systemic treatment of GEP-NETs.

 They are structured similarly to somatostatins, which are naturally occurring peptides that decrease the secretion of GI hormones, inhibit blood flow, and hinder cell proliferation. SSAs differ from somatostatins by providing a longer half-life,

 and they offer symptom control and antitumor effects for GEP-NETs. SSAs— specifically, octreotide and lanreotide&mdash;received a category 2A recommendation in 2019 from the National Comprehensive Cancer Network (NCCN) for managing GEP-NETs.

In 1988, octreotide became the first SSA approved by the FDA. Octreotide long-acting release (LAR) is indicated for severe diarrhea and flushing episodes associated with metastatic carcinoid tumors. It is also indicated for long-term treatment of the profuse watery diarrhea associated with vasoactive intestinal peptide-secreting tumors in patients in whom initial treatment with immediate-release octreotide has been effective and tolerated.

 In PROMID, a phase IIIb, randomized, double-blind, placebo-controlled trial, octreotide LAR also demonstrated an antiproliferative effect in patients with metastasized NETs of the midgut (N = 85). The median time to tumor progression was 14.3 versus 6.0 months for the octreotide LAR and placebo groups, respectively (HR, 0.34; 95% CI, 0.20-0.59; 

 = .000072). After 6 months of treatment, 66.7% of patients receiving octreotide LAR and 37.2% receiving placebo experienced stable disease.

Lanreotide, approved for adults by the FDA in 2007, is an SSA to slow the growth of GEP-NETs that have spread or cannot be removed by surgery. It is also indicated to treat carcinoid syndrome to reduce the need for the use of short-acting SSAs.

 The antitumor effects of lanreotide on GEP-NETs were demonstrated in CLARINET, a phase III, randomized, double-blind, placebo-controlled trial in 204 adult patients with metastatic grade 1 or 2 enteropancreatic NETs. Patients on lanreotide experienced significantly longer progression-free survival (PFS) than those on placebo (median not reached vs median of 18.0 months; HR, 0.47; 95% CI, 0.30-0.73; 

 <.001 by the stratified log-rank test), with a 53% reduction in risk of disease progression or death.

In the real world, the decision to start patients on an SSA is often based on whether patients exhibit symptoms. Patients who are symptomatic, particularly if they have carcinoid syndrome, are typically started on an SSA to manage symptoms. For those who are asymptomatic, some clinicians prefer to monitor until progression to protect their patients from toxicities and to reduce the financial burden associated with SSAs, particularly because many patients may not progress for several years. Delaying therapy can also give clinicians the opportunity to more accurately identify the pace of disease progression. However, this approach can vary, and certain patients, such as those with a high-bulk disease, may warrant a more aggressive treatment with SSAs up front. If there is a concern regarding SSA tolerance, patients may be started on a week of a short-acting SSA to confirm absence of an allergic response before initiating a long-acting SSA.

PRRT uses radiopharmaceuticals, such as 90Y-DOTA-Tyr3-octreotide and 177Lu-DOTA-Tyr3-octreotate (

Lu-Dotatate), that are developed by combining a synthetic SSA with a β-emitting radioisotope. These radiocompounds differ by their energetic features (because of the radionuclide) and peptide receptor affinity (because of the analogue) and bind to somatostatin receptors that are typically overexpressed in NETs.

Lu-Dotatate is indicated for the treatment of somatostatin receptor—positive GEP-NETs (including foregut, midgut, and hindgut); it is an NCCN category 1 recommendation for midgut tumors with somatostatin receptor–positive imaging and progression on octreotide or lanreotide.

 The NCCN recommends that patients with hormonally functioning tumors should continue octreotide or lanreotide treatment along with 

Lu-Dotatate can compete for somatostatin receptor binding, patients should not receive long-acting SSAs for 4 to 6 weeks before each 

Lu-Dotatate treatment, nor should they receive short-acting SSAs within 24 hours before each 

Lu-Dotatate treatment. These patients may receive short- or long-acting SSAs 4 to 24 hours after each 

Lu-Dotatate in combination with an SSA has demonstrated efficacy for the treatment of GEP-NETs. NETTER-1, a phase III, randomized, placebo-controlled trial, evaluated the efficacy and safety of 

Lu-Dotatate plus octreotide supportive therapy in patients with advanced, progressive, somatostatin receptor—positive midgut NETs. At month 20, the estimated rate of PFS was 65.2% for the 

Lu-Dotatate group (95% CI, 50.0%-76.8%) and 10.8% for the control group receiving only octreotide LAR (95% CI, 3.5%-23.0%). 

Lu-Dotatate also demonstrated a significantly higher response rate than that of only octreotide LAR (18% vs 3%; 

 In PRELUDE, an international, retrospective, noncomparative analysis using patient medical records, the combination of 

Lu-Dotatate and lanreotide showed promise for treating patients with progressive NETs in the lung (n = 1) or digestive system (n = 39). Although enrollment ended prematurely because of insufficient recruitment, data for effectiveness were encouraging.

Table. Clinical Trial Data for Gastroenteropancreatic Neuroendocrine Tumor Therapies

The mTOR is a serine-threonine kinase that stimulates cell proliferation, growth, and angiogenesis. It is involved in the pathogenesis of NETs. Inhibiting mTOR has resulted in a substantial antiproliferative effect on pNETs.

 The mTOR inhibitor everolimus, an NCCN category 2A recommendation for NETs, is indicated for adults with progressive pNETs and adults with progressive, well-differentiated, nonfunctional NETs of GI or lung origin that are unresectable, locally advanced, or metastatic. Its safety and efficacy in treating patients with carcinoid syndrome have not yet been determined.

 In RADIANT-3 and RADIANT-4, which were phase III, randomized, double-blind, placebo-controlled trials, PFS was more than double for those in the everolimus groups compared with those in the placebo groups. In patients with pNETs (RADIANT-3; n = 410), everolimus reduced risk of progression or death by 65%, with a median PFS of 11.0 versus 4.6 months with placebo (HR, 0.35; 95% CI, 0.27-0.45; 

 For patients with GI and lung NETs (RADIANT 4; n = 302), everolimus reduced the estimated risk of progression or death by 52% (HR, 0.48; 95% CI, 0.35-0.67; 

 <.00001). The median PFS was 11.0 months with everolimus and 3.9 months with placebo.

Everolimus is generally considered to be a third-line treatment for GEP-NETs after SSAs and PRRT, but the sequence can vary by disease characteristics. For patients with a pNET, the chemotherapy combination capecitabine—temozolomide (CAPTEM) may have a therapeutic opportunity equal to that of everolimus. Clinicians agree that everolimus should not be used either as a first-line option for high-burden disease (such as GEP-NETs with more than 80% liver involvement) or for a functional carcinoid accompanied by flushing and diarrhea. Everolimus may be appropriate as first-line treatment for patients with a low-volume small bowel NET or for those with insulinoma.

Eventually, resistance develops to the systemic therapies available for GEP-NETs, compromising PFS.

 At a cellular level, resistance can occur because of the congregation of many receptors on the same intracellular mechanisms, which allows an activated receptor system to bypass an inhibited system. Multitarget tyrosine kinase inhibitors (MTKIs), which compete with adenosine triphosphate to bind with cell surface receptors and ultimately block angiogenesis and tumor activity, have shown promise with mitigating this resistance by simultaneously targeting multiple receptors. Several MTKIs are currently being developed as novel therapies for solid tumors.

In the TALENT trial, the MTKI lenvatinib demonstrated promising PFS and OS for pretreated patients with pNETs and GI NETs (N = 111). Patients were treated with lenvatinib until disease progression or intolerable toxicity. With a 19-month median follow-up, patients with pNETs experienced a 15.5-month PFS (95% CI, 11.3—not reached) and a 29.2-month OS (95% CI, 23.2–not reached). Those with GI NETs experienced a 15.4-month PFS (95% CI, 11.5-19.4) and OS was not reached. The overall response rate (ORR) was 42.0% for pNETs and 16.3% for GI NETs. According to the investigators, these results demonstrate the highest ORR by central radiology assessment to a targeted agent in this particular setting.

The MTKI sunitinib is approved for the treatment of progressive, well-differentiated pNETs in patients with unresectable locally advanced or metastatic disease.

 Although data on sunitinib are limited, the therapy has demonstrated an increase in PFS for progressive, metastatic, welldifferentiated pNETs in phase III and phase IV clinical trials.

A substantial need still exists for novel therapies in the treatment of GEP-NETs to improve efficacy and reduce radiation and toxic adverse effects. Once patients have exhausted appropriate treatment options, clinicians often encourage participation in clinical trials of new therapies. Multiple trials are currently being conducted to explore the therapeutic effects of immunotherapies for NETs; while data are currently limited, immunotherapies have demonstrated safety and efficacy in the treatment of other cancers.29,30 Immunotherapies are sometimes used in clinical practice for high-grade, poorly differentiated GEP-NETs. Well-differentiated, low-grade GEPNETs are not immunogenic, so clinicians hesitate to administer immunotherapy to this population.

Treatment combinations—including triplet combinations&mdash; are also being explored through preclinical and clinical trials. Initial results have been positive; however, large randomized trials are needed to generate strong evidence that supports their safety and efficacy. The primary limitations to combination therapies are sensitization and toxicity.

Sequencing Strategies and Personalized Medicine

The expanding targeted treatment options increase the need for national guidelines on therapy strategy and sequencing, which have not yet been established. The 2019 NCCN Guidelines state that no data currently support a specific sequence of regional versus systemic therapy or a sequence for systemic therapies.

 As stated previously, surgery is typically first-line treatment for localized tumors, and SSAs often serve as first-line options for systemic treatment.

 PRRT is often initiated once patients progress on an SSA,

 and mTOR inhibitors, chemotherapy (such as CAPTEM), MTKI, and novel therapies may be used as well to address symptoms and slow progression. Although many institutions have generated their own treatment guidelines for internal use, these approaches can vary considerably.

When selecting and sequencing therapies, clinicians must consider patient preferences, finances, and quality of life in addition to tumor grade, tumor burden, and timing of disease progression. Every patient presents with the disease differently, running the gamut from being asymptomatic to experiencing symptoms from the primary disease to having stage IV metastatic disease with liver symptomatology. Some tumors may be more hepatic than others, and some tumors are refractory to PRRT from the start. Each patient requires a unique treatment approach, and clinicians continue to grapple with identifying the optimal therapeutic regimen at the individual level, because of a lack of both treatment guidelines and data to help guide decision making. Because most clinical trials on therapies for GEP-NETs involve a heterogenous group of patients not separated by WHO classification for tumor grade (because of difficulties with proper stratification during trials), clinicians do not have data on the efficacy of a drug in patients with a specific tumor grade. It is difficult to predict how a grade 1 tumor versus a grade 2 tumor will respond to a therapy.

All available therapies for GEP-NETs, whether as monotherapy or in combination, are currently leveraged to treat this complex, diverse population of patients, yet no treatment has maintained PFS indefinitely. Clinicians acknowledge that many aspects of GEP-NETs are still unknown, and substantial efforts must be made to better understand the disease while advancing treatment options. There is a particular need for phase II and III clinical trials to gain insight into treatment for grade 3 tumors, which have received less attention in the past because of grade 3 tumor rarity and poor pathology.

Research efforts are pushing toward improvements in therapies; patients with GEP-NETs as well as clinicians who treat the disease are invested in understanding the disease and improving outcomes. Patients actively engage in online discussions, and many clinicians refer appropriate patients to participate in clinical trials for novel therapies that may advance safety and efficacy. The number of such trials is on the rise as the healthcare community recognizes opportunities to improve GEP-NET treatment. Investigators are also working to identify additional biomarkers for improved diagnosis, prognosis, and therapy response.

Nonetheless, GEP-NETs currently remain difficult to treat, and it is not possible to apply a single set of treatment principles to all patients. Although building treatment sequencing guidelines for patients can be helpful, assessing the response in each patient is most important for determining the most promising course of therapy. The therapeutic approach also involves deciding when to re-treat (eg, choosing whether to administer CAPTEM for either 12 months consecutively or 6 months with a subsequent break before reinitiating therapy). Until GEP-NETs and therapeutic approaches are more fully understood, clinicians may find support in their quest to determine the right treatment courses for their patients by creating and participating in community forums with other oncologists to learn as much as possible about the various approaches and outcomes.

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Although the data from these clinical trials on PRRT are valuable for guiding treatment decisions, additional trials are necessary that decouple SSAs from PRRT and generate evidence for the efficacy and safety of PRRT monotherapy. Clinicians generally feel comfortable combining SSAs with PRRT, but some question whether the SSA-PRRT combination (versus PRRT monotherapy) is ultimately necessary. Some clinicians prefer to treat according to methods from clinical trials and guidelines from NCCN, and they combine an SSA with PRRT to account for potential factors regarding PRRT that are not yet understood. However, others prefer to go off label and administer PRRT as a monotherapy to patients who are asymptomatic. Currently, PRRT as a monotherapy for GEP-NETs is being evaluated in the phase III, randomized, controlled COMPETE trial, with the experimental group receiving 177Lu-edotreotide and the control group receiving everolimus. The primary outcome is to demonstrate the efficacy of 177Lu-edotreotide in prolonging PFS in patients with progressive, inoperable, somatostatin receptor—positive GEP-NETs, and the secondary outcome is overall survival (OS) for these patients. Estimated primary completion date for this trial is December 2023.

During an OncLive® scientific interchange, panelists discussed the current treatment landscape for patients with gastroenteropancreatic-neuroendocrine tumors and the need for improved novel therapies.

Current and Emerging Treatments for Gastroenteropancreatic Neuroendocrine Tumors

Thomas Hope, MD, an associate professor of radiology at University of California, San Francisco (UCSF), discusses considerations when making sequencing decisions for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

There is no answer to the optimal sequence of treatments for patients with GEP-NETs, because there are no data to support an order to the available treatments, explains Hope. The decision regarding what therapy to give a patient depends on their disease and comorbidities, including liver failure, renal failure, bone marrow injury, diabetes, infections, and more, according to Hope.

Additionally, the location of the disease impacts whether patients should receive liver-directed therapy or surgical resection. Hope suggests physicians consider the patient, extent of disease, type of tumor, aggressiveness of tumor, and tumor grade when deciding what therapy to administer.

The decision how to sequence therapy for each patient often falls to multidisciplinary tumor boards, says Hope. At UCSF, the tumor boards involve radiology, nuclear medicine, medical oncology, surgery, and pathology, concludes Hope.

Videos

Thomas Hope, MD, discusses considerations when making sequencing decisions for patients with gastroenteropancreatic neuroendocrine tumors.

Dr. Hope on Sequencing Considerations for GEP-NETs

Thomas Hope, MD, an associate professor of radiology at University of California, San Francisco, discusses treatment options for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

Treatment strategies for patients with GEP-NETs are typically split into 2 categories: small bowel NETs and pancreatic NETs. The treatment methodology for patients is based on the primary origin of the tumor.

Patients with small bowel NETs will typically receive treatment with somatostatin analogs. After progression, patients may consider peptide receptor radionuclide therapy (PRRT) or everolimus (Afinitor), depending on the pace and extent of disease.

Pancreatic NETs have a higher Ki-67 score and patients may, depending on the aggressiveness and extent of tumor presentation, start with capecitabine (Xeloda) plus temozolomide or a somatostatin analog. Other approved therapies to treat patients with pancreatic NETs include sunitinib (Sutent), everolimus, or PRRT.

The sequencing of treatments for both diseases is unclear. Other treatment options include surgery and liver-directed therapy. However, with multiple options and an unclear sequencing strategy, the choice is complex, concludes Hope.

Thomas Hope, MD, discusses treatment options for patients with gastroenteropancreatic neuroendocrine tumors.

Dr. Hope on Treatment Options for GEP-NETs

Hagen F. Kennecke, MD, MHA, FRCPC, a medical oncologist at Virginia Mason Medical Center, discusses the treatments available for patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

When patients have advanced disease, they should always consider surgery first and then get staged with Gallium-68 dotatate (Netspot) PET/CT scans, explains Kennecke. If surgery is not possible, patients receive liver-directed therapy followed by targeted treatment, such as Lutetium-177-PSMA-617 plus chemotherapy or targeted therapy with everolimus (Afinitor), says Kennecke.

Sequencing, according to Kennecke, is less important compared with how urgently patients need therapy and how they react to treatment. If patients require debulking surgery, then surgery, liver-directed therapy, or chemotherapy will be most effective. When a patient has more indolent disease that is positive for receptors, they may be eligible for targeted and radiopeptide therapies, concludes Kennecke.

Hagen F. Kennecke, MD, MHA, FRCPC, discusses the treatments available for patients with advanced gastroenteropancreatic neuroendocrine tumors.

Dr. Kennecke on Available Treatments for GEP-NETs

Hagen F. Kennecke, MD, MHA, FRCPC, a medical oncologist at Virginia Mason Medical Center, discusses multidisciplinary interactions within Virginia Mason Medical Center for patients with gastroenteropancreatic neuroendocrine tumors.

At a weekly tumor board, Kennecke will present a patient’s history, provide their background, and sequentially review pathology. Pathology must be analyzed to ensure the tumor grade is assessed with Ki-67 differentiation. After, imaging is conducted and repeat imaging is ordered if multi-phase CT scans are not completed, says Kennecke.

Then, the Gallium-68 dotatate (Netspot) PET/CT scan is reviewed and a Krenning score is assigned to all patients, grading to tumors from 0 to 4, according to Kennecke. From this evaluation of the patient, the tumor board decides what the best strategy is before discussing with the patients, he concludes.

Hagen F. Kennecke, MD, MHA, FRCPC, discusses multidisciplinary interactions within Virginia Mason Medical Center for patients with gastroenteropancreatic neuroendocrine tumors.

Dr. Kennecke on Suggested Multidisciplinary Actions for GEP-NETs

Aman Chauhan, MD, a medical oncologist at University of Kentucky, discusses sequencing decisions when treating patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

Currently, sequencing for patients with GEP-NETs is largely dictated by the presentation or degree of tumor progression. Patients with metastatic disease, especially bone metastases who are symptomatic, would likely be treated with peptide receptor radionuclide therapy upfront, according to Chauhan.

In asymptomatic patients with slow-growing tumors or low-bulk metastatic disease, Chauhan recommends somatostatin analogs and potentially a mTOR inhibitor afterwards before the patient is exposed to radionuclide therapy. Chauhan continues to search for conclusive data to guide sequencing decisions for patients with GEP-NETs.

Aman Chauhan, MD, discusses sequencing decisions when treating patients with gastroenteropancreatic neuroendocrine tumors.

Dr. Chauhan on Sequencing Therapies for GEP-NETs

Aman Chauhan, MD, a medical oncologist at University of Kentucky, discusses the role of somatostatin analogs in treating patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

Somatostatin analogs form the backbone of treatment for patients with GEP-NETs and changed the way these are managed, explains Chauhan. Somatostatin analogs are often used for frontline treatment of patients with GEP-NETs and work well for those with functional and nonfunctional NETs, evident through the randomized CLARINET study, says Chauhan. This phase III study examined lanreotide (Somatuline Depot) versus placebo in patients with metastatic GEP-NETs.

In addition to being effective in treating patients with GEP-NETs, somatostatin analogs are well tolerated with a better safety profile than traditional chemotherapy, targeted therapy, or radiation-based therapy, concludes Chauhan.

Aman Chauhan, MD, discusses the role of somatostatin analogs in treating patients with gastroenteropancreatic neuroendocrine tumors.

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