Expert Explains Latest Treatment Strategies in GEP-NETs

Aman Chauhan, MD

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.

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

Chauhan: 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]—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.¹ 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 ¹⁷⁷Lu-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.^2,3 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 ¹⁷⁷Lu-Dotatate, somatostatin analogues and everolimus showed radiological responses in 5% or 7% of patients. ¹⁷⁷Lu-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 JAMA Oncology 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.⁴ 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 ¹⁷⁷Lu-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.⁵ Based on our preclinical data, we [are] very optimistic that this combination might help us improve efficacy of ¹⁷⁷Lu-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 ¹⁷⁷Lu-Dotatate.

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%.⁶ 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.

References

1. 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.
2. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135. doi: 10.1056/ NEJMoa1607427.
3. 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.
4. 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. JAMA Oncol. 2017;3(10):1335-1342. doi: 10.1001/jamaoncol.2017.0589.
5. 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.
6. 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.