Despite Progress, Somatostatin Analogs Remain Frontline Standard in NETs

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.

“They are basically frontline drugs, and they are [used in that setting] by virtue of their proven and very significant delay in time to progression, as well as their exceptional tolerability,” said Strosberg. “[Somatostatin analogs] are extremely low-risk drugs compared with pretty much any other drug we administer in the oncology space.”

Lanreotide (Somatuline Depot) was the first somatostatin analog to show a statistically significant improvement in progression-free (PFS). In the phase III CLARINET trial, lanreotide improved PFS by 53% compared with placebo in patients with grade 1/2 GEP-NETs.¹ Based on these data, the FDA approved the agent in December 2014 for the treatment of patients with unresectable, well or moderately differentiated, locally advanced or metastatic GEP-NETs.

However, for patients who progress on lanreotide, Lutathera (lutetium Lu 177 dotatate) has emerged as the standard second-line option when it was approved by the FDA in January 2018. In the phase III NETTER-1 trial led by Strosberg, there was a 79% reduction in the risk of progression or death with Lutathera versus octreotide in patients with unresectable, advanced GEP-NETs following progression on somatostatin analogs.²

Updated PFS data from the study showed 30 events in those who received Lutathera compared with 78 events in the patients who were treated with octreotide (HR, 0.21; 95% CI, 0.14-0.33; P <.0001).³ Time to deterioration was significantly delayed in the Lutathera arm compared with the octreotide arm for “global health” status, physical functioning, role functioning, and fatigue, according to findings presented at the 2018 ASCO Annual Meeting.

OncLive: How would you define the latest progress that has been made in NETs treatment?

How did octreotide [Sandostatin] set the stage for lanreotide?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Strosberg, an associate professor of medicine at Moffitt Cancer Center, shed light on the latest developments made in the complex treatment paradigm of GEP-NETs.Strosberg: [Although somatostatin analogs are] not exactly novel, there has been a lot of interest in the CLARINET study—especially since lanreotide was FDA approved for the treatment of patients with GEP-NETs about 2 years ago. Next, [there is] the role of capecitabine plus temozolomide in pancreatic NETs, particularly in light of the very exciting ECOG 2211 study, which showed a significant improvement in both PFS and overall survival (OS) with this combination versus temozolomide monotherapy. It was really an unprecedented PFS of nearly 2 years—that was the primary endpoint [of the trial]. Finally, [there is] the NETTER-1 study and Lutathera and its role in midgut NETs.Octreotide goes back to the early 1980s; it was the first drug to palliate the carcinoid syndrome and subsequently palliate other hormonal syndromes associated with other NETs. The drug was also shown to inhibit tumor growth. There was a lot of indication that despite low response rates, patients were having relatively long durations of time to progression. This led to the PROMID study, which was a smallish phase III study comparing octreotide LAR with placebo in patients with midgut NETs. It was a positive study—strongly positive—in terms of improvement in PFS. However, it was not a registrational study and did not lead to a change in indication. Therefore, the indication of octreotide continued to be for control of carcinoid syndrome.

Could you further discuss research evaluating capecitabine and temozolomide in this space?

Then, we saw a much larger study of lanreotide in GEP-NETs with PFS as a primary endpoint—this was the CLARINET study. This trial led to the first FDA approval of a somatostatin analog for control of tumor growth. We think octreotide and lanreotide are very similar in terms of control of tumor growth and hormonal syndromes, but lanreotide has formal approval [from the FDA].There have been quite a few small studies showing that [the combination of] capecitabine plus temozolomide has really exceptional response rates in patients with progressive pancreatic NETs. The ECOG-2211 study was the first randomized prospective study to evaluate these drugs and really try to establish whether the doublet of capecitabine and temozolomide was superior to temozolomide monotherapy. [The goal of the study] was to get information on temozolomide-based chemotherapy in the setting of a large, prospective clinical trial. It wasn't a phase III trial; it was a large, randomized phase II study with about 145 participants.

What is the role of peptide receptor radionuclide therapy (PRRT) in the treatment paradigm?

What it showed was a very significant prolongation in PFS to nearly 2 years with the combination. Remember, these were patients with progressive disease at outset. PFS with temozolomide monotherapy was about 14 months. There was also a statistically significant improvement in OS, so it was a strong indication that capecitabine and temozolomide is highly active. The confirmed response rate was about 33%, which is a little less than what we saw in the early single-arm studies.PRRT is a targeted way of delivering radiation to somatostatin receptor-expressing tumor cells. There have been quite extensive single-arm data, mostly retrospective series or prospective registries and mostly from Europe, showing high response rates and high durations of median PFS in a variety of GEP-NETs. The NETTER-1 trial was the first randomized phase III study of a radiolabeled somatostatin analog, and it compared Lutathera with high-dose octreotide in patients with progressive midgut NETs. What it showed was a very significant prolongation of PFS. At the time of primary analysis, the PFS had not been reached with Lutathera versus only 8 months with octreotide. This translates to a 79% improvement in PFS. These results led to the FDA approval of Lutathera in February of 2018, so it has been commercially available for over 1 year now. It is approved not only for [patients with] midgut NETs, but also for other GEP-NETs based on earlier, single-arm data. It is indicated for patients with progressive somatostatin expressing well-differentiated NETs.

How does the quality of life (QoL) with PRRT differ with somatostatin analogs?

Are there possible combinations that could create potential for Lutathera in the frontline setting?

What combinations are under investigation in the second-line setting?

Now, where it fits into the treatment algorithm for pancreatic NETs versus everolimus (Afinitor) or sunitinib (Sutent) has not been well established yet. For [most patients with] midgut NETs, it is the appropriate second-line systemic therapy. It is not a first-line therapy; it is indicated for patients with progressive disease.If we look at data from NETTER-1, there was a QoL analysis done based on questionnaires completed by patients. What we found is that for all clinically relevant symptoms as well as overall QoL—what they call global health—there was a significant delay in time to deterioration with Lutathera compared with high-dose octreotide. This is really the most vigorous way of analyzing QoL in a randomized clinical trial. The one exception to this was flushing, as there was really no difference between the 2 treatments. However, with respect to diarrhea, pain, physical functioning, and global health, there was a significant delay in time to deterioration with Lutathera.There are risks with Lutathera; the most notable ones are the risk for leukemia and myelodysplastic syndrome. This is rare but real, and it happens in 2% to 3% of patients. Fatigue, cytopenia, and nausea also occur. This treatment is necessary for progressive disease, but I'm not sure it will replace somatostatin analogs as a first-line treatment. Really, one of the most important things for cancer in general—especially for well-differentiated NETs—is to do no harm. These are often slow-growing tumors, and with somatostatin analogs, you can achieve very long average times to tumor growth with virtually no risk.Obviously, capecitabine and temozolomide is a combination regimen that we would like to use. There have been combinations of VEGF inhibitors and mTOR inhibitors, such as everolimus and bevacizumab (Avastin), which is actually associated with high response rates but no significant improvement in PFS. For now, we are talking mostly about sequential therapy. Over the years, there have been several combination studies. The question always is, “Even if you show improvement in PFS, does a combination approach lead to an improvement in OS?” That is extremely hard to prove with our relatively small phase III studies compared with other disease types.

References

1. Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Eng J Med. 2014;371(3):224-233. doi: 10.1056/NEJMoa1316158.
2. 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; abstr 4005).
3. 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.