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Novel Therapies Lower Symptom Burden, Improve Survival in NETs

Caroline Seymour
Published: Wednesday, Apr 03, 2019

Kunal C. Kadakia, MD

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.

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