Barr Bridges Past and Present Treatment of Neuroendocrine Tumors

Jodie Barr, DO

In the treatment of patients with neuroendocrine tumors (NETs), researchers have made significant strides that can be augmented by the use and development of genetic sequencing and biomarkers, said Jodie Barr, DO, a hematologist/oncologist at Lawrence Memorial Hospital.

“There is a lot we don’t know about the biology of the tumors; they’re very heterogenous,” she explained. “Trying to figure out what is going on genetically with these tumors will help us figure out how to sequence treatment prognostically and really help tailor treatment for...patients.”

In January 2018, the FDA approved Lutathera (lutetium Lu 177 dotatate) for the treatment of patients with somatostatin receptor—positive gastroenteropancreatic tumors following the results of the phase III NETTER-1 trial.

In the trial, patients with midgut NETs were randomized to Lutathera (n = 116) or high-dose octreotide (n = 113) after progressing on 30 mg of octreotide. These patients received 4 doses of Lutathera at 7.4GBq every 8 weeks in combination with 30 mg of octreotide. Patients in the control arm received 60 mg of octreotide long-acting release every 4 weeks.

The combination reflected a 79% decrease in the risk of progression or death compared with octreotide, and the overall response rate was 13% with Lutathera and 4% with octreotide (P <.0148). The interim analysis of overall survival (OS), which was presented at the 2018 ASCO Annual Meeting, demonstrated that the median OS was not reached in the Lutathera arm and was 27.4 months in the octreotide arm (HR, 0.536; 95% CI, 23.1-not estimable).¹

The combination of capecitabine and temozolomide has also shown encouraging signals in the randomized, two-arm, phase II E2211 trial in patients with advanced pancreatic NETs. The trial compared 200 mg/m² of oral temozolomide once daily (PO QD) on days 1 to 5 with 200 mg/m² of oral temozolomide daily on days 10 to 14 and 750 mg/m² of oral capecitabine daily on days 1 to 14.

The median progression-free survival (PFS) was 22.7 months with the combination versus 14.4 months with temozolomide monotherapy (HR, 0.58; P = .023).² The median OS had not yet been reached in the combination arm versus 38.0 months with temozolomide (HR, 0.41, P = .012) at a follow-up of 29 months.

OncLive: What are the available and emerging treatments for patients with NETs that you discussed in your talk?

In an interview during the 2018 OncLive^® State of the Science Summit™ on A Summer of Progress: Highlights from ASCO 2018, Barr discussed the evolution of treatment of patients with NETs and the need for biomarkers.Barr: Some of our available options for NETs have really been limited. The 2018 ASCO Annual Meeting was fairly exciting because there are some updated treatment options for these patients. My talk focused on systemic treatment.

The E2211 study looked at capecitabine and temozolomide compared with temozolomide in pancreatic NETs. That was exciting because we now have a foundation for some confirmatory studies, especially for those patients who have more aggressive disease.

The NETTER-1 study came out, which looked at Lutathera. This [was] initially studied in midgut NETs and showed a fairly significant response rate. Approximately 79% of those patients had a decreased risk of death.

There is also some symptom control with telotristat ethyl (Xermelo), which helps patients with refractory diarrhea as well.

What do we know about the biology of NETs?

What were the design and findings of the E2211 trial with capecitabine and temozolomide?

Finally, [we spoke about] looking at the genetic sequencing of these tumors [because] we want to personalize medicine. Trying to figure out what is going on genetically with these tumors [will] help [us] figure out how to sequence treatment prognostically and help tailor treatment for those patients.They’re a very heterogeneous group. There are very slowgrowing tumors; these are patients who are asymptomatic. There are also very aggressive tumors; these are patients who have a lot of symptoms. There’s a big variety. Hopefully, trying to figure out the genetics of those tumors [will help us figure out] what is going on and how to better [help patients].The trial randomized patients to temozolomide and capecitabine or temozolomide alone. The idea was that adding in capecitabine potentially [induced] a synergistic effect in depleting O6-methylguanine-DNA-methyltransferase.

How has Lutathera impacted the treatment paradigm?

Is there rationale to explore immunotherapy in patients with NETs?

Where does telotristat fit into practice?

How has NET treatment evolved over the past 5 years?

What are some factors that you take into consideration when deciding the optimal sequence?

These were grade 1/2 NETs. The study was not blinded; that’s the one bias with the study. These patients received 1 of those 2 arms, and they looked at the endpoint of PFS. The study showed significant benefit and met the endpoint. The interim analysis showed some potential OS benefit as well.It’s a way for us to do a better targeted treatment. It’s essentially taking this isotope and using a chelator to attach it to the somatostatin analogue, so we can selectively target those tumor cells. It’s a more selective treatment with hopefully less toxicity than oral or intravenous chemotherapy.I have not seen any data for immunotherapy at this time, but I’m sure at some point we’ll have data for that. [We’ll have to] look at biomarkers and the genetic profile of the tumor.[Telotristat works for] patients who are failing somatostatin analogues. This is just focused on diarrhea, not the other parts of carcinoid syndrome. The trial randomized patients who failed [somatostatin analogues to] either telotristat at 2 different doses or placebo. The trial showed that those patients had fewer bowel movements as well as less 5-hydroxyindoleacetic excretion in their urine.Initially, all we had were somatostatin analogues. We now have several oral chemotherapies, everolimus (Afinitor), sunitinib (Sutent), and more targeted treatment such as liver-directed therapy. We’re seeing more selected treatment for these patients.We don’t know [the optimal sequence]. We’re hoping that genetic sequencing as well as finding a biomarker can help us figure out how to sequence [therapies for] those patients. We just don’t know what the best sequence is when we get to the second-line setting. In the first-line setting, we use somatostatin analogues, but the second-line setting is still in question

References

1. Strosberg JR, Wolin EM, Chasen BA. First update on overall survival, progression- free survival, and health-related time-to-deterioration quality of life from the NETTER-1 study: 177Lu-Dotatate vs. high dose octreotide in progressive midgut neuroendocrine tumors. J Clin Oncol. 2018;36(suppl; abstr 4099).
2. Kunz PL, Catalano PJ, Nimeiri H, et al. A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: a trial of the ECOG-ACRIN Cancer Research Group (E2211). J Clin Oncol. 2018;36 (suppl; abstr 4004).