Novel Therapies Lower Symptom Burden, Improve Survival in NETs

Kunal C. Kadakia, MD

In recent years, positive data from 7 randomized phase III clinical trials have been reported in the field of neuroendocrine tumors (NETs), among which the PROMID, CLARINET, and NETTER-1 trials have demonstrated the greatest impact on the space.

In a presentation during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Kunal C. Kadakia, MD, a hematologist/medical oncologist at Levine Cancer Institute, Atrium Health, highlighted key takeaways from these trials and explained how their findings have been applied to clinical practice.

In 1986, Mayo Clinic published the first study in NETs, results of which demonstrated a reduction in the symptomatic burden (eg, flushing and diarrhea) of carcinoid syndrome with somatostatin analogs. Subsequent to the FDA approval of octreotide (Sandostatin) in 1988, antitumor activity was reported. However, it was not until 25 years later that data from the first randomized phase III trial demonstrating the activity of octreotide LAR was published.

In the phase III PROMID trial, 85 patients with well-differentiated midgut NETs who had not received prior systemic therapy were randomized to receive either 30 mg of octreotide every 28 days or placebo. The majority of patients had metastatic disease, a Ki-67 index <3%, and a positive OctreoScan, said Kadakia.

Although only 1 partial response was reported, investigators noted a clinically significant improvement in time to progression.¹ Results indicated a doubling in the progression-free survival (PFS) at 14.3 months in the octreotide arm versus 6.0 months in the placebo arm (HR, 0.34; P = .000072), confirming the antiproliferative effects of somatostatin analogs beyond hormonal control.

Five years after PROMID was published, the second-generation somatostatin analog lanreotide (Somatuline Depot) was tested in the phase III CLARINET trial. Similarly, 204 patients with well-differentiated tumors, the majority of whom had low-grade tumors and had not received prior systemic therapy, were randomized to receive either 120 mg of lanreotide or placebo.

Notably, the study included patients with nonfunctional pancreatic, midgut, and hindgut tumors, said Kadakia. Moreover, 40% of patients had pancreatic NETs, thus representing a more heterogeneous population compared with those included in the PROMID trial. At the time of the analysis, the median PFS was not reached in the lanreotide arm versus 18 months in the placebo arm, reflecting a 53% reduction in the risk of progression or death with lanreotide (P <.001).²

Despite the improvement in time to progression seen with lanreotide, Kadakia explained that the 18-month PFS in treatment-naïve patients suggests that “a period of observation is probably reasonable for a subset of patients with nonfunctional, asymptomatic, low-volume disease.”

Investigators also reported a similar hazard ratio among patients with nonpancreatic NETs (HR, 0.35; 95% CI, 0.16-0.80; P = .009), further supporting the use of these agents in patients with midgut NETs. In patients with pancreatic NETs, the risk reduction was more modest at 42% (HR, 0.58; 95% CI, 0.32-1.04; P = .06).

“We know that based on these 2 studies, as well as a number of retrospective series, that these agents have efficacy in several different NETs, although they appear to be most effective in midgut tumors,” added Kadakia.

Taken collectively, these data suggest that somatostatin analogs stand as the preferred frontline therapy in the majority of well-differentiated, low- to intermediate-grade functioning and nonfunctioning NETs.

For patients who progress on somatostatin analogs, peptide receptor radionuclide therapy (PRRT) has become a novel therapeutic option for patients who have strong somatostatin receptor expression on functional imaging, said Kadakia. PRRT consists of a radionuclide isotope—most commonly octreotide or octreotate—and a chelator that binds the somatostatin analog to the isotope, allowing for selective delivery of radiation to somatostatin receptor-expressing cells.

Initial constructs used Indium-111 and Yttrium-90 isotopes, but due to inadequate and overreaching cytotoxicity of the target tumor, they were discontinued in development. Most recently, Lutathera (lutetium Lu 177 dotatate) has emerged, showing a tissue penetration of 2 mm and a longer half-life than prior constructs.

Aside from several retrospective trials on PRRT, the NETTER-1 trial was the first prospective, randomized controlled trial to examine Lutathera. Eligible patients included those with well-differentiated midgut NETs who had progressed on 30 mg of octreotide within 3 years of randomization. The majority of patients had a Ki-67 index ≤3%.

“The median time from diagnosis to metastasis was 3 to 5 years, so we’re talking about a relatively indolent group of patients compared with some of the patients we see in the clinic,” said Kadakia.

Patients were randomized to receive either Lutathera (n = 115) at a fixed dose of 200 millicuries for four 8-week cycles followed by a somatostatin analog 4 to 24 hours after each dose of Lutathera or 60 mg of high-dose octreotide (n = 115) every 4 weeks.

PFS among the intent-to-treat population (n = 229), as assessed by blinded independent central review, was not reached in the Lutathera arm versus 8.4 months in the high-dose octreotide arm, resulting in a 79% reduction in the risk of progression or death (HR, 0.21; 95% CI, 0.129-0.338; P <.001).

In addition to the estimated 40-month PFS in the Lutathera arm, investigators reported an 18% objective response rate (ORR) in the PRRT arm versus 3% in the high-dose octreotide arm.

“In comparison, everolimus (Afinitor) and sunitinib (Sutent) have ORRs of less than 5%, despite their relative efficacy in pancreatic NETs,” said Kadakia.

At the interim analysis, investigators reported a 60% reduction in the risk of death with Lutathera compared with high-dose octreotide (HR, 0.4; 95% CI, 0.21-0.77; P = .0043).³ Although encouraging, these data are immature, said Kadakia; a greater statistical threshold is required to prove significance.

Although the trial was limited to patients with midgut NETs, nonrandomized data suggest the activity of PRRT in non-midgut NETs, he added.

“The ORRs in, albeit, retrospective series appear to be higher in pancreatic NETs,” said Kadakia.

In terms of sequencing, it remains unclear where to place the therapy upon progression of a somatostatin analog, especially in patients with non-midgut NETs, for whom there are other approved agents.

In terms of tolerability, 77% of patients completed all 4 cycles of Lutathera in the NETTER-1 trial. The most common adverse events in the trial were grade 1/2 nausea and vomiting, likely related to the amino acid infusion. Overall, the therapy was observed to be well tolerated in the trial as well as at Levine Cancer Institute, since its inception, said Kadakia. Moreover, updated data from the 2018 ASCO Annual Meeting seemed to favor Lutathera in terms of quality of life compared with high-dose octreotide.⁴

Although myelosuppression is of concern, the rate of grade 3/4 myelosuppression was <10% in the trial. A potential concern with this treatment, said Kadakia, is the rate of severe myelodysplastic syndrome or acute leukemia, which hovers around 1% to 2%.

References

1. Rinke A, Mu&#776;ller HH, Schade-Brittinger C, et al; PROMID Study Group. 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.
2. Caplin ME, Pavel M, &#262;wikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Eng J Med. 2014;371(3):224-233. doi: 10.1056/NEJMoa1316158.
3. 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.
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.