Following Encouraging Therapeutic Advances, Focus in NETs Turns to Sequencing

Ana Maria Cristina De Jesus-Acosta, MD

Despite the activity of peptide receptor radionucleotide therapy (PRRT), somatostatin analogs remain the recommended frontline treatment for patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs), after which sequencing becomes less clear, explained Ana Maria Cristina De Jesus-Acosta, MD.

In 2014, lanreotide (Somatuline Depot) became the first somatostatin analog to receive FDA approval for the treatment of patients with advanced GEP-NETs. The approval was based on positive data from the phase III CLARINET trial, in which patients were randomized to receive 120 mg of lanreotide or placebo every 28 days. Investigators noted a 53% reduction in the risk of disease progression within 96 weeks with lanreotide versus placebo.¹

To date, lanreotide is the only somatostatin analog that has received regulatory approval. However, octreotide LAR was the first analog to demonstrate an improved time to progression compared with placebo in the phase III PROMID trial in patients with treatment-naïve midgut NETs.² Taken collectively, these trials show that somatostatin analogs are effective in controlling symptoms and delaying progression—2 critical endpoints in this patient population, explained De Jesus-Acosta.

Subsequent findings from the phase III NETTER-1 trial showed a 79% reduction in the risk of progression or death with Lutathera (lutetium Lu 177 dotatate) versus single-agent octreotide in patients with unresectable, advanced GEP-NETs following progression on somatostatin analogs.³ These data, in conjunction with data showing a superior PFS and objective response rate, served as the basis for the January 2018 FDA approval of the therapy. Further, in June 2018, updated data presented at the 2018 ASCO Annual Meeting showed that the median overall survival (OS) had yet to be reached in patients randomized to Lutathera.⁴

According to its label, Lutathera can be used as second-line therapy or reserved for third-line therapy, although there are no data to suggest a superior sequence. Sequencing of available treatments for patients with NETs remains an active area of debate, explained De Jesus-Acosta, especially in light of emerging data that suggest enhanced response rates with Lutathera in combination with other agents, including lanreotide and everolimus (Afinitor).^5,6 Moreover, due to its efficacy and safety profile, there is rationale to investigate its use as frontline therapy.

“There is interest on improving outcomes with PRRT either by moving it upfront as first-line therapy or combining it with other agents,” said De Jesus-Acosta. “Sequencing is going to be very important, as well. The challenge will be trying to understand how to sequence all of these different drugs and identify appropriate biomarkers to help us select the best treatment options for patients upfront.”

OncLive^®: Could you discuss the key data with somatostatin analogs?

Are somatostatin analogs used in patients with all types of NETs?

Could you discuss the data that led to the approval of Lutathera?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, De Jesus-Acosta, assistant professor of oncology at Johns Hopkins Medicine, discussed somatostatin analogs and PRRT, and spoke to the discussion regarding the optimal sequence of therapy in patients with NETs. De Jesus-Acosta: The data are based on the CLARINET study. Somatostatin analogs have been used for decades to control the symptoms of hormone secretion in patients with NETs. By 2009, the PROMID study was published, which demonstrated an antiproliferative effect by controlling PFS in patients with NETs. Subsequently, the phase III CLARINET clinical trial with lanreotide showed improved PFS compared with placebo. That is a huge advance because we want to be able to control disease burden and delay progression, so we can delay their symptoms.They are used for all types of NETs when patients have functional symptoms of carcinoid syndrome such as flushing and diarrhea. Based on the PROMID and CLARINET studies these agents can be used to control their time to progression. They’re usually the first-line therapy that is provided to patients. The NETTER-1 trial was the first prospective phase III clinical trial that evaluated PRRT in patients with GEP-NETs. In that study, patients were randomized to receive PRRT in combination with best supportive care—which was octreotide—versus higher-dose octreotide injections. The patients who were treated with PRRT received 4 infusions.

Where does that leave the role of surgery and chemotherapy?

Is there rationale for its use in the frontline setting?

Is there a standard sequencing?

Where do the results of the KEYNOTE-158 trial leave potential for immunotherapy?

The primary outcome was PFS. The study demonstrated that the PFS was better in patients who were treated with PRRT versus those in the control arm. There were also more response rates in the group of patients treated with PRRT versus those who were treated with octreotide only. For patients who have resectable or locoregional disease, surgery is still offered as a curative intent. In patients who have advanced unresectable or metastatic disease, we prefer somatostatin analogs first. In patients with high disease burden or when immediate response is needed chemotherapy may be preferred. For PRRT, as of now, the FDA indication is as a second-line therapy or beyond for patients with advanced GEP-NETs. It’s not approved as a first-line treatment. There is rationale for its use as frontline therapy. The treatment is certainly well tolerated. It needs to be tested in clinical trials, but it is an area of investigation.It varies; we still don't know the optimal sequence. There is a lot of discussion and debate in that regard. As of now, the indication is following failure on somatostatin analogs in patients with somatostatin receptor expression. In practice, most physicians are using PRRT either in the second-line setting or the third-line setting. There's still a lot of variation in that regard. It’s also a new approved therapy in the United States, so we still have to see how it pans out over time in terms of physicians’ preference as a second-line therapy versus other types of treatments. It still doesn't take out the role of immunotherapy in patients with NETs. The clinical trials that have been presented so far have been with checkpoint inhibitors. We still need to better understand the tumor microenvironment in patients with NETs to see whether there is a potential for enhanced efficacy in combination with other agents. The results are certainly somewhat disappointing, but it still warrants further investigation.

References

1. Ipsen’s Somatuline^® Depot^® Is the First Therapy Approved by the FDA in the United States for the Treatment of Patients With Locally Advanced or Metastatic Gastroenteropancreatic Neuroendocrine Tumors. Ipsen. Published December 16, 2014. https://bit.ly/2GMdkpJ. Accessed February 26, 2019.
2. A Rinke, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27(28):4656-4663. doi: 10.1200/JCO.2009.22.8510.
3. Strosberg JR, Wolin EM, Chasen B, et al. NETTER-1 phase III: Efficacy and safety results in patients with midgut neuroendocrine tumors treated with ¹⁷⁷Lu-DOTATATE. J Clin Oncol. 2016;34 (suppl 15; abstr 4005). doi: 10.1200/JCO.2016.34.15_suppl.4005.
4. Strosberg JR, Wolin EM, Chasen BA, et al. 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 15; abstr 4099). doi: 10.1200/JCO.2018.36.15_suppl.4099.
5. Yordanova A, Wicharz MM, Mayer K, et al. The role of adding somatostatin analogues to peptide receptor radionuclide therapy as a combination and maintenance therapy. Clin Cancer Res. 2018. doi: 10.1158/1078-0432.CCR-18-0947.
6. Aljubran AH, Alrowaili M, Raef H, et al. Combination of everolimus and lu-177 PRRT in treatment of G1-2 neuroendocrine tumors (NET): phase 1-2 study. J Clin Oncol. 2019;37 (suppl 4; abstr 386). doi: 10.1200/JCO.2019.37.4_suppl.386.