Systemic Treatments for NETs: Whom to Treat and How to Sequence

Jonathan Strosberg, MD

Although novel therapeutic strategies have shown potential in recent clinical trials, somatostatin analogs are still the frontline standard of care for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), said Jonathan R. Strosberg, MD.

Although several recently approved systemic treatments are helping to improve outcomes for patients with neuroendocrine tumors (NETs), a highly heterogeneous tumor type that historically has had few treatment options, these agents have led to the conundrum of how to optimally sequence treatments. During a recent OncLive Peer Exchange^® discussion, NET experts Simron Singh, MD, MPH, and Jonathan R. Strosberg, MD, provided insight on which patients are the best candidates for these approved treatments and how to sequence therapy to optimize outcomes. They also discussed data for several agents under investigation, including various immunotherapies and the novel targeted agent lenvatinib (Lenvima).

NETs are rare, making up <3% of all malignancies.¹ In the United States, the prevalence is <200,000 cases, with an estimated 12,000 new NETs diagnosed annually.^1,2 However, data from the Surveillance, Epidemiology, and End Results program suggest that incidence and prevalence of NETs are steadily rising.³ Between 1973 and 2012, the age-adjusted incidence rate was observed to increase 6.4-fold, from 1.09 per 100,000 to 6.98 per 100,000, respectively.³ This increase was observed across all sites, stages, and grades but was most prevalent in early-stage disease. The study investigators attributed the increased incidence and prevalence to better detection of early-stage disease and improved overall survival (OS) from recent treatment advances, particularly for distant-stage gastrointestinal (GI) and pancreatic NETs.³

Singh, agreed. “I speculate it’s probably due to better classification and a better understanding of the disease,” he said. Regardless of the cause, the result is more healthcare providers encountering patients with NETs, making a good understanding of these complex tumors and their treatments essential.

A key challenge with managing NETs has been the complexity of these diverse tumors, which originate in the hormone-producing cells of the diffuse endocrine system and, subsequently, can affect numerous sites in the body. The most common sites include the GI tract (ie, stomach, small intestine, appendix, rectum), pancreas, lungs, bronchi, and thymus.⁴ Furthermore, even when NETs have the same site of origin, there can be significant differences in mutation burden, presence or absence of hormone-related symptoms (ie, functional vs nonfunctional tumors, respectively), tumor differentiation (ie, well-differentiated vs poorly differentiated), and grade (ie, low, intermediate, or high), all of which affect treatment decision making and outcomes.

“One of the things that is important to emphasize is the value of trying to understand the different characteristics that define each patient’s neuroendocrine tumor. We need to treat each patient as an individual and understand that no 2 neuroendocrine tumors may be quite alike. We have to tailor our treatment accordingly to get the results that we want,” Singh said, noting that this is an exciting time in neuroendocrine cancer because there are more approved treatments and agents under investigation than ever before.

Oldies but Goodies: SSAs

Somatostatin analogues (SSAs) have been used since the late 1980s in patients with functional NETs to relieve symptoms such as skin flushing, diarrhea, and wheezing from carcinoid syndrome and other hormonal hypersecretion syndromes.⁵ These agents work by inhibiting the secretion of serotonin, growth hormone, and peptide hormones. Two that are primarily used for gastric, pancreatic, and lung NETS are octreotide (Sandostatin) and lanreotide (Somatuline). Over the past decade, 2 studies have also shown these agents to have antitumor effects in both functional and nonfunctional NETs: PROMID, which assessed octreotide in patients with midgut NETs, and CLARINET, which assessed lanreotide for patients with enteropancreatic NETs (Table 1). In both studies, the SSA led to significant improvements in progression-free survival (PFS) compared with placebo.^6,7

Table 1. Somatostatin Analogues Demonstrate Antitumor Effect in NETs

“We know that somatostatin analogues not only control hormonal symptoms in the large majority of cases but also significantly inhibit tumor growth. They’re not going to actually shrink tumors, but they can significantly delay time to progression,” Strosberg said, noting that these agents are primarily a first-line treatment for somatostatinreceptor— positive tumors, which applies to most midgut NETs. Singh and Strosberg agreed that octreotide and lanreotide are very similar, although there are no head-to-head studies comparing them. “If you look at the hazard ratio for midgut NETs in the CLARINET study, it’s virtually identical to what was seen in the PROMID study,” Strosberg said, adding that these agents target the same somatostatin receptor subtypes. Subsequently, he said, there is unlikely to be an advantage to switching from one to the other at the time of disease progression. However, a change in dose or dosing schedule might be beneficial in such situations when the goal is symptom control, he noted. “These drugs are extremely well tolerated. Therefore, we want to make sure that we’re using them to their maximum advantage before we move on to potentially more toxic agents,” Singh said.

Targeted Therapies: Everolimus and Sunitinib

Table 2. Everolimus and Sunitinib Outperform Placebo in NETs^8,9

Two targeted agents that have been approved for patients with NETs include everolimus (Afinitor) and sunitinib (Sutent), both of which are taken orally. Everolimus is an mTOR inhibitor approved for advanced pancreatic NETs and progressive, nonfunctional GI and lung NETs, whereas sunitinib is a multitargeted tyrosine kinase inhibitor approved for advanced, well-differentiated pancreatic NETs. “[Everolimus is] probably the most studied targeted agent we have in the neuroendocrine tumor field today,” Singh said. He cited the phase III RADIANT-3 and RADIANT-4 studies, which showed a PFS benefit in patients receiving everolimus versus placebo (Table 2).^8,9

Based on RADIANT-4 data, everolimus became the only approved therapy for lung neuroendocrine cancers, Singh noted. This is as opposed to GI and pancreas NETs, for which there are other options, he said.

Unlike SSAs, which Strosberg referred to earlier in the discussion as “probably the least risky drugs used in the entire oncology sphere,” everolimus is associated with significant toxicities, including mucositis, fatigue, diarrhea, endocrine abnormalities such as hyperglycemia, cholesterol and lipid abnormalities, and rare adverse effects such as fibrosis in the lungs, Singh explained. As a result, patients taking everolimus require more careful monitoring for toxicities, and other second-line treatments might be preferable in patients with midgut NETs, who have more options available. Nevertheless, Singh said, these agents should be considered a part of the armamentarium for all NETs, even midgut tumors.

Data for sunitinib are sparse, although data for metastatic pancreatic NETs have shown outcomes comparable with everolimus treatment (Table 2),10 Singh noted. As with everolimus, some toxicities need to be considered, including fatigue, hypertension, and hand-foot syndrome. In patients with pancreatic NETs, who have a choice of everolimus or sunitinib, factoring in comorbidities might help oncologists choose between these agents. “For patients with diabetes, you may want to consider sunitinib, [and] for patients who have a history of cardiovascular disease, hypertension, or bleeding diathesis you may want to consider everolimus,” Strosberg said.

The Power of Radiopeptides: ¹⁷⁷Lu-Dotatate and Beyond

Peptide receptor radionuclide therapy (PRRT) combines radioisotopes with SSAs to create radiopeptides, which enable a targeted dose of radiation to be delivered directly to the NET once the radiopeptides bind to the somatostatin receptors on tumor cells. Thus, patients eligible for this therapy need to have somatostatin receptor—expressing tumors.

“Results have shown fairly high response rates ranging from about 20% in midgut NETs to about 40% in pancreatic NETs,” Strosberg said. He proceeded to discuss the phase III NETTER-1 study, for which he was an investigator and that helped lead to the approval of the PRRT lutetium-177 (177Lu)—dotatate (Lutathera) for gastroenteropancreatic NETs, including foregut, midgut, and hindgut NETs, in adults in the United States and Europe.

Table 3. Temozolomide/Capecitabine Combination Shows Advantage Over Cytotoxic Monotherapy in Advanced Pancreatic NETs¹⁴

NETTER-1 randomly assigned 229 patients with well-differentiated, metastatic midgut NETs who progressed on first-line SSA therapy to receive 177Lu—dotatate at a dose of 7.4 GBq every 8 weeks plus repeatable octreotide LAR 30 mg (n = 116) or high-dose octreotide LAR alone, administered at a dose of 60 mg every 4 weeks (n = 113; control group).¹¹ “The study showed a very significant improvement in [PFS]. It was 8 months with high-dose octreotide. It was not reached at the time of analysis with 177Lu—dotatate. The hazard ratio was 0.21. This was obviously very statistically significant,” Strosberg said. He noted that preliminary analysis of OS data also revealed an advantage, with almost twice as many deaths in the control arm versus the PRRT arm, but Strosberg noted that the main OS analysis has yet to be undertaken. Although PRRT may be tempting to use as a first-line therapy, Strosberg said it should be considered as a second- or subsequent-line treatment for most patients who are eligible. This is because the treatment is more toxic than SSAs alone. “There’s a roughly 2% risk of long-term bone marrow damage, myelodysplastic syndrome, or leukemia,” he said.

There has also been some question of whether patients starting PRRT should be continued on SSAs during and after PRRT; the concern has been that the SSAs might compete with the radiolabeled SSAs for occupying the somatostatin receptor on the neuroendocrine cancer cells. Although there are no definitive answers yet, Strosberg said, somatostatin receptor scintigraphy has not shown SSAs to have a significant impact on tumoral uptake of radiolabeled somatostatin, even when given shortly before the scan, suggesting that SSAs could likely be given shortly before each PRRT treatment without compromising efficacy. He said that for patients with functional tumors, he continues SSAs during and after PRRT. However, for patients with nonfunctional tumors, he may provide some concomitant SSA therapy if patients progress relatively slowly while on first-line SSA therapy, but that he stops it altogether if patients progress quickly.

Currently, 177Lu-dotatate is the only radiopeptide approved to treat NETs, but others are being assessed. The phase III COMPETE study is evaluating the safety and efficacy of 177Lu—edotreotide PRRT versus everolimus in patients with inoperable, progressive, somatostatin receptor-positive, gastroenteric or pancreatic NETs.12 “This will be a good study to give us early indications of how to potentially sequence treatments. We really haven’t had too many studies, if any, in the neuroendocrine field comparing 2 active drugs,” Strosberg said.

A Role for Chemotherapy: Temozolomide

In the 1980s and 1990s, the alkylating agent streptozocin (Zanosar) was extensively studied and found to be particularly active in metastatic pancreatic NETS; however, over the past decade, temozolomide (Temodar) has emerged as a more tolerable and convenient oral alternative for patients with these tumors based on safety and efficacy data from small subsets of patients in phase II studies and retrospective series.¹³ Recently, data were reported from the Eastern Cooperative Oncology Group (ECOG) E2211 study, which was the first randomized controlled prospective trial comparing temozolomide alone and with capecitabine (Xeloda) in patients with advanced pancreatic NETs (Table 3).¹⁴

“This study showed that there was a benefit with the use of a temozolomide and capecitabine combination over temozolomide alone. But I think the real key to that study was that it really showed that temozolomide was an effective agent,” Singh said.

E2211 validated the use of temozolomide in combination with capecitabine for patients with advanced pancreatic NETs, but Singh and Strosberg noted that the role of this combination for other NETs remains unclear. Anecdotal information in lung and midgut NETs has not indicated it to be effective, although this may be the result of not having biomarkers available to improve patient selection. However, this may soon change: Singh said that expression of the methylated DNA— protein-cysteine methyltransferase (MGMT) enzyme has shown promise in predicting response to temozolomide treatment in patients with NETs and that further studies are needed to determine its role.

Until better information on treatment sequencing is available, decisions should be made on an individual patient basis, Singh and Strosberg said. This requires careful consideration of long-term toxicities and potential interactions between treatments, such as the risk of bone marrow toxicity with both chemotherapy and PRRT.

“The only thing I would say with a relative level of confidence is that if you’re dealing with a relatively aggressive high tumor burden, chemotherapy is probably a good option for pancreatic NETs. For midgut NETs, I’d say PRRT is probably the appropriate second-line systemic therapy for most patients, although for patients with liver-dominant disease, I still think liver embolization can be quite effective,” Strosberg said.

Immunotherapy and Targeted Agents

Immunotherapy has revolutionized the treatment of many solid tumors, but not for NETs, Singh and Strosberg said. In the KEYNOTE- 158 basket trial, pembrolizumab (Keytruda) showed limited antitumor activity in patients with previously treated advanced NETs, with only 4 partial responses (3 pancreatic and 1 GI) and no complete responses among the 107 study patients.¹⁵ Another checkpoint inhibitor, spartalizumab (PDR001), has thus far also shown only modest benefit in patients with NETs.¹⁶ “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,” Strosberg said.

However, at the 2019 American Association for Cancer Research Annual Meeting 2019, which took place in March, more promising immunotherapy data were reported from the phase II DART trial, which showed a 44% response rate with the immune checkpoint inhibitor combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with high-grade NETs and 0% in low- and intermediate- grade disease.¹⁷

“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,” Singh said.

Singh and Strosberg ended their discussion of novel emerging therapies with a quick review of lenvatinib, a targeted agent that has shown the most promise in treating pancreatic NETs. Lenvatinib is an oral inhibitor of multiple receptor tyrosine kinases, including VEGFR 1-3, fibroblast growth factor receptor 1-4, platelet growth factor receptor, RET, and KIT.¹⁸

In the international phase II TALENT trial, lenvatinib had a 29.2% overall response rate (ORR), which is the highest ORR by central radiology assessment with a targeted agent in advanced NETs. Patients with pancreatic NETS had an ORR of 40.4% (95% CI, 27.3%- 54.9%), whereas patients with GI NETs had an ORR of 18.5% (95% CI, 9.7%-31.9%). All ORRs were partial responses. Although patients with pancreatic NETs had a better ORR, patients with GI NETs had a longer median PFS (14.2 months vs 17.6 months, respectively).¹⁸

“It’s hard to know what to make of [PFS] 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,” Strosberg said.

References

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