Clinician Handout

 

 

 

Medscape: What is our current understanding of the heterogeneity and biology of gastroenteropancreatic neuroendocrine tumors (GEP-NETs)?

Dr Vikas Prasad: Neuroendocrine neoplasia is a highly heterogenous group of diseases that can be divided into neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). NETs are typically well-differentiated and have a proliferation rate ranging from 1% to approximately 55% to 60%. These tumors are heterogeneous not only in terms of clinical presentation, but also tumor biology. Even within a single patient there can be considerable variability, making it challenging to define appropriate diagnostic and therapeutic approaches.^[1]

Diagnosis and prognostication are largely dependent upon tumor grade, extent of disease, and clonal evolution in patients with GEP-NETs. Ki67 is a marker for cell proliferation and is important in the assessment of disease aggressiveness and risk, with Ki67 index of < 3% corresponding to grade 1, 3% to 20% to grade 2, and > 20% to grade 3 disease. Disease stage and tumor grade are generally measured from a single point biopsy to inform decisions on treatment, which may not be representative of the heterogeneity of the entire tumor.^[1] This reinforces the importance of integrating every available diagnostic parameter into disease assessment and treatment decisions.

Somatostatin receptor (SSTR) expression density is another feature of NETs that can vary widely between patients and within individual patients. Different GEP-NET disease clones may be present within a single primary tumor or between multiple tumor metastases, leading to significant heterogeneity.^[2] In tumors with a low proliferation rate, SSTR heterogeneity is often low, while those with high proliferation rates generally have more heterogeneous SSTR expression. Studies have now shown SSTR heterogeneity to be an independent prognostic and predictive factor in patients with progressive NETs.^[3]

Beyond Ki67 and SSTR expression, there are limited biomarkers to inform treatment decisions in patients with GEP-NETs. This underscores the importance of understanding the biology of GEP-NETs and discussing all available diagnostic and prognostic factors. Whenever possible, these factors should be discussed extensively in the forum of a multidisciplinary tumor board to provide a personalized treatment approach.^[1] A NET tumor board should ideally include pathologists, surgeons, radiologists, nuclear medicine physicians, and an oncologist/gastroenterologist/endocrinologist, each providing unique perspectives on treatment selection and sequencing.

Medscape: What are the current systemic treatment approaches for patients with GEP-NETs?

Dr Prasad: If you look at the evolution of treatment options available for patients with GEP-NETs, the last 5 to 10 years have witnessed the emergence of important new treatment approaches.^[4-14] Currently available therapies for patients with advanced and/or metastatic disease include somatostatin analogues (SSAs), peptide receptor radionuclide therapy (PRRT), interferon α (IFNα), chemotherapy, and targeted agents.^[1] Standard first-line therapy for functional NETs typically consists of SSAs, including octreotide or lanreotide. SSAs have long-acting release (LAR) formulations and an excellent safety profile, offering patients good tumor control, functional control, and minimal side effects (Table 1).^[4-6] Interferon α or the oral tryptophan hydroxylase inhibitor telotristat ethyl can also be used for symptom control in functional NETs. Telotristat ethyl can reduce diarrhea in patients with NETs and carcinoid syndrome and can be added to SSA therapy in patients with poorly controlled symptoms.^[1]

Chemotherapy has been used for several decades in patients with GEP-NETs, primarily in patients with pancreatic NETs or highly proliferative NETs elsewhere in the body. Chemotherapy generally consists of monotherapy or doublet combinations of agents such as streptozotocin, 5-fluorouracil, capecitabine, temozolomide, or platinum-based regimens. Although response rates are moderate to high, particularly for NECs, the side effects associated with chemotherapy, depending upon the regimen, can sometimes be substantial. Thus, the benefit/risk ratio should be carefully discussed with patients when considering treatment options.^[1]

Targeted therapies currently approved for treatment of GEP-NETs include the mammalian target of rapamycin (mTOR) inhibitor everolimus and the multi-targeted tyrosine kinase inhibitor (TKI) sunitinib.^[1] Everolimus is recommended for patients with advanced progressive pancreatic NETs and non-functional, progressive gastrointestinal (GI) NETs based on efficacy demonstrated in the RADIANT-3 and RADIANT-4 studies, respectively. Compared with placebo, everolimus significantly reduced the risk of disease progression or death by 65% in advanced pancreatic NETs and 52% in non-functional GI NETs, leading to regulatory approval for these disease subtypes. Tolerability is an important consideration, with everolimus most commonly associated with stomatitis, diarrhea, fatigue, infections, rash, and peripheral edema.^[1,7,8]

Sunitinib is recommended for patients with advanced progressive pancreatic NETs based on efficacy demonstrated in a randomized phase 3 study. In patients with advanced, well-differentiated pancreatic NETs, sunitinib more than doubled median progression-free survival (PFS) compared with placebo in patients with unresectable disease.^[9] This TKI also showed a nonsignificant numerical improvement in median overall survival (OS), which may have been impacted by a crossover rate of 69% in the control arm to sunitinib.^[10] Side effects associated with sunitinib appear to be modest and include diarrhea, nausea, asthenia, vomiting, and fatigue.^[9]

Table 1. Select Randomized Clinical Trial Data for Systemic Therapies in GEP-NETs

NR = not reported; TTP = time to progression.

Medscape: What is the current role for PRRT in patients with GEP-NETs?

Dr Prasad: PRRT is currently recommended for patients with progressive NETs with high SSTR expression, albeit without any consideration of the heterogeneity of SSTR expression. This should change in the future. The peptides most often used for PRRT are DOTATATE and DOTATOC and the radionuclide ¹⁷⁷Lu is preferred due to reduced renal toxicity.^[1] The first randomized clinical trial to investigate PRRT in patients with GEP-NETs was the phase 3 NETTER-1 trial, which directly compared ¹⁷⁷Lu-DOTATATE plus best supportive care (including octreotide-LAR) to high-dose octreotide-LAR alone in patients with metastatic, well-differentiated, SSTR-positive midgut NETs. All patients had prior SSA treatment and progressive disease within the last 3 years. The primary analysis showed that, compared with control, ¹⁷⁷Lu-DOTATATE significantly improved median PFS (not reached vs 8.4 months, HR 0.21; P < .001) and response rate (18% vs 3%; P = .001), with interim analysis of OS demonstrating preliminary benefit (HR 0.40; P = .004).^[11] A recent updated analysis with median follow-up of > 6.3 years showed no significant difference in median OS between the 2 arms (48.0 months vs 36.3 months for octreotide alone, HR 0.84; P = .30), which may have been impacted by a high rate of cross-over (36%) to PRRT-based therapy in the control arm.^[12]

¹⁷⁷Lu-DOTATATE has a favorable safety profile, with transient grade 3/4 hematologic events occurring in approximately 12% of patients. The most common low-grade events included nausea and vomiting, fatigue, abdominal pain, and diarrhea.^[11] A total of 1.8% of patients developed myelodysplastic syndrome. Nephrotoxicity was primarily low-grade, with high grade (grade ≥ 3) occurring in only 5.4% of patients.^{[12] 177}Lu-DOTATATE also maintains patient quality of life longer than octreotide alone in this study, improving patient-reported outcomes related to overall function, fatigue, pain, and diarrhea.^[13]

The NETTER-R retrospective registry study evaluated ¹⁷⁷Lu-DOTATATE in patients with advanced, well-differentiated, SSTR-positive pancreatic NETs. Recently presented data included a median PFS of 24.8 months, median TTP of 29.5 months, median OS of 41.4 months, and response rate of 40.3%, suggesting consistent benefit in pancreatic NETs. The safety profile was similar to that observed in the NETTER-1 study, including hematologic and renal toxicities, although no treatment discontinuations were related to treatment-emergent adverse events.^[14]

The efficacy and favorable safety profile of this therapeutic approach led to inclusion in the current European Society of Medical Oncology (ESMO) guidelines as an important option for the second-line treatment of patients with grade 1 or grade 2 GEP-NETs, as well as third-line therapy for grade 3 pancreatic NETs (Figure 1).^[1]

Figure 1. ESMO Guidelines For Systemic Treatment of GEP-NETs^[1]

 

Reprinted from Annals of Oncology, 31(7), Pavel, M., et al., Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, pp. 844-860, Copyright 2020, with permission from Elsevier.

5-FU = 5-fluorouracil; CAP = capecitabine; CAPTEM = capecitabine and temozolomide; EVE = everolimus; FOLFIRI = 5-fluorouracil/leucovorin/irinotecan; FOLFOX = 5-fluorouracil/leucovorin/oxaliplatin; Pan-NET = pancreatic neuroendocrine tumor; SI-NET = small intestinal neuroendocrine tumor; STZ = streptozotocin; SUN = sunitinib; TEM = temozolomide.

Studies have also demonstrated efficacy for PRRT as salvage therapy, including re-treatment after disease progression in patients who already received prior PRRT therapy.^[15] A meta-analysis of 13 studies showed that re-treatment of progressive disease in patients with NETs previously treated with PRRT produced a median PFS of 12.52 months, median OS of 26.78 months, and disease control rate (DCR) of 71%.^[16]

Medscape: What challenges exist regarding identification and management of progressive disease after standard therapy?

Dr Prasad: Identification of progressive GEP-NETs using stand-alone computed tomography (CT) or magnetic resonance imaging (MRI) is challenging in clinical practice. PRRT can be associated with delayed responses that might happen up to 1 to 3 years after therapy begins. In addition, a small percentage of patients may experience pseudo-progression early during PRRT therapy, so early staging could mistakenly look like disease progression.^[17] SSTR positron emission tomography (PET)-CT (or PET-MRI) should be strongly considered to improve disease response assessment in patients receiving PRRT. In addition, it is time to validate and integrate serum-based biomarkers to chalk out composite end points for PRRT response.

Management of progressive GEP-NETs remains an important clinical challenge. There are a number of available therapies in the second-line and third-line setting, with current ESMO guidelines separating treatment recommendations according to disease location, tumor grade, Ki67 expression, and SSTR expression (Figure 1). The ESMO guidelines provide valuable delineation of disease risk based on a Ki67 cutoff of < 10% vs 10% to 15%, allowing better identification of optimal therapy.^[1] Therapeutic options should be carefully discussed within the multidisciplinary tumor board and with patients, taking into account performance status, response to prior therapies, overall quality of life, and goals of therapy. Treatment selection and sequencing should be firmly based on available clinical trial data and treatment guidelines, individualizing decisions according to the patient's needs. Management of progressive NETs becomes even more complicated once standard treatment options are exhausted, reinforcing the need for continued investigation of novel therapies.

Medscape: What novel approaches are showing the most promise in improving personalized care for GEP-NETs?

Dr Prasad: A number of exciting advances are under investigation for patients with pancreatic and GI NETs (Figure 2).^[18] The novel multi-targeted TKI surufatinib recently demonstrated significant efficacy in the phase 3 SANET-p and SANET-ep trials in patients with advanced pancreatic or extrapancreatic NETs, respectively.^[19,20] In patients with progressive pancreatic NET after ≤ 2 prior systemic regimens, surufatinib significantly improved median PFS compared with placebo (10.9 vs 3.7 months, HR 0.49; P = .0011).^[19] Similarly, surufatinib significantly prolonged median PFS compared to placebo in the SANET-ep trial in patients with extrapancreatic NETs after ≤ 2 prior systemic regimens (9.2 vs 3.8 months, HR 0.33; P < .0001).^[20] In both studies, surufatinib had a manageable safety profile and was most commonly associated with hypertension and proteinuria.^[19,20]

Several other multi-targeted TKIs are also under investigation in patients with advanced GEP-NETs, including cabozantinib, axitinib, nintedanib, famitinib, regorafenib, and anlotinib. In addition, immune checkpoint inhibitors such as pembrolizumab, spartalizumab, and nivolumab have also been evaluated in pancreatic and extrapancreatic NETs, with some demonstrating promising activity in advanced disease.^[18]

Figure 2. Molecular Targets of Novel TKIs Under Investigation in NETs^[18]

 

Future directions for PRRT include novel alpha emitters and SSTR antagonists (instead of agonists), as well as the potential use of PRRT in the first-line setting either alone or in combination with SSAs.^[18] PRRT is associated with few side effects compared with other systemic options, suggesting it may be a good frontline option for carefully selected patients with high tumor burden, higher proliferation rate, and low to moderate tumor growth rate. Retrospective analyses demonstrated efficacy for PRRT as first-line therapy in advanced inoperable or metastatic NETs, including a response rate of 30%, DCR of 85%, and median PFS of 48 months.^[21] The ongoing phase 3 NETTER-2 study is comparing ¹⁷⁷Lu-DOTATATE to long-acting octreotide as frontline therapy in patients with highly proliferative GEP-NETs (grade 2 or 3). Patients can be SSA naive or have no disease progression while receiving initial SSA therapy.^[22] Additionally, the ongoing phase 2 NeoLuPaNET trial is evaluating ¹⁷⁷Lu-DOTATATE as neoadjuvant therapy in patients with resectable non-functioning pancreatic NETs at high risk for recurrence.^[23]

PRRT is also under investigation in combination with other agents, including phase 2 studies with telotristat in patients with well-differentiated NETs or in combination with the immune checkpoint inhibitor nivolumab in patients with grade 3 NET or NEC.^[24,25] The ongoing phase 2 CONTROL NET study is evaluating ¹⁷⁷Lu-Octreotate with capecitabine and temozolomide (CAPTEM) in patients with low to intermediate-grade pancreatic and midgut NETs.^[26] Patients receiving combinations of PRRT with other systemic therapies should be closely monitored for potential adverse events, including combined hematologic toxicity or neurotoxicity. One primary concern with such combination therapies is the delayed onset of life-threatening hematological toxicities (eg, myelodysplastic syndrome or leukemia). Several ongoing clinical trials will hopefully continue to expand the treatment landscape for GEP-NETs by improving long-term patient outcomes (primarily overall survival) and quality of life for patients with these heterogeneous malignancies.

This transcript has been edited for style and clarity.