Lanreotide Demonstrates Confirmed Efficacy in Advanced Bronchopulmonary NETs

Lanreotide autogel/depot (Somatuline Depot) administered at 120 mg every 28 days may be an appropriate treatment for patients with advanced bronchopulmonary (BP) neuroendocrine tumors (NETs), according to results of the phase 3 SPINET trial (NCT02683941) that were presented during the 2021 NANETS Annual Symposium.¹

Results showed that lanreotide demonstrated a median progression-free survival (PFS) of 16.6 months (95% CI, 12.8-21.9) in patients who were randomized to lanreotide during the double-blind and open-label treatment phase of the phase 3 study. When patients were stratified based on typical carcinoid or atypical carcinoid disease, the median PFS was 21.9 months (95% CI, 12.8—not calculable [NC]) and 14.1 months (95% CI, 5.6-16.6), respectively.

“The SPINET trial is the largest prospective study to date with a somatostatin analog in somatostatin receptor–positive bronchopulmonary NETs—both typical and atypical NETs—despite the poor target enrollment [of the trial],” lead study author Diane Reidy-Lagunes, MD, said in a virtual presentation during the conference. “The safety profile of lanreotide was favorable and consistent with its known profile in gastroenteropancreatic [GEP]-NETs.”

Lanreotide is approved by the FDA for the treatment of adult patients with unresectable, well- or moderately differentiated, locally advanced or metastatic GEP-NETs, as well as for the treatment of adults with carcinoid syndrome. It is also indicated for use as long-term treatment of acromegalic patients who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy.

Well-differentiated BP-NETs comprise approximately 20% to 25% of all NETs. Moreover, metastatic typical and atypical carcinoids express high levels of somatostatin receptors, and first-line antiproliferative treatment with somatostatin analogs are already recommended for patients with advanced unresectable somatostatin receptor–positive typical and atypical carcinoids, as per guidelines issued by the European Neuroendocrine Tumor Society, the National Comprehensive Cancer Network, and ESMO.

In the double-blind, placebo-controlled SPINET trial, investigators sought to evaluate the efficacy and safety of lanreotide in patients with advanced somatostatin receptor–positive typical and atypical carcinoid BP-NETs. Patients were randomized 2:1 to receive lanreotide at 120 mg every 28 days plus best supportive care (BSC) or placebo with BSC, before moving into an optional open-label treatment phase where lanreotide was given again at 120 mg every 28 days for 18 months after the last patient randomization.

Patients were stratified by tumor type (atypical vs typical carcinoid) and prior chemotherapy (yes vs no).

To be eligible for enrollment, patients at least 18 years old had to have metastatic and/or unresectable well-differentiated BP-NETs (either typical or atypical carcinoid), a mitotic index of less than 2 mitoses/2 mm3 (typical carcinoid) or 10 or fewer mitoses/2 mm3 and/or foci of necrosis (atypical carcinoid), positive somatostatin receptor imaging, and an ECOG performance status of 0 or 1. Those who previously received a somatostatin analog or received prior therapy with at least 2 lines of chemotherapy for BP-NETs were excluded.

Enrollment to SPINET was stopped due to slow accrual; once this occurred, patients whose disease had not progressed during the double-blind phase were then switched to open-label lanreotide.

“It was challenging to accrue in part because of the aforementioned fact that these therapies are already on most of the NET guidelines, so unfortunately, the study had to be held because of poor accrual and the protocol needed to be amended,” Reidy-Lagunes explained. “As a result, the protocol amendment included an amendment to the primary end point.”

The adapted primary end point was median PFS, which was centrally assessed via RECIST v1.1 criteria during the double-blind and open-label phases in patients randomized to lanreotide. Secondary end points included PFS, objective response rate (ORR), and time to treatment failure (TTF) in the lanreotide and placebo groups in the double-blind phase, as well as safety.

Baseline characteristics were similar between the lanreotide (n = 51) and placebo (n = 26) arms. The mean age was 66.1 years; 54.3% of patients were male and 70.9% of patients were White. The median time since diagnosis was 7.7 months, and more than half of patients had typical carcinoid BP-NETs (59.2%). Patients had a Ki-67 proliferation index of 0 to <3% (22.4%), ≥3% to <10% (39.7%), ≥10% to <20% (19.4%), or ≥20% (9.7%). Nearly 8% of patients received prior chemotherapy.

Additionally, 62.2% of patients had metastatic disease, which was in the lung (31.4%), liver (56.1%), bone (39.1%), or the brain (6.3%). Notably, most patients (92.3%) had a hepatic tumor load of 25% or lower. Patients had a Krenning scale score of 2 (35.9%), 3 (45.9%), or 4 (18.4%).

Further findings showed that the median PFS in the double-blind phase in all patients showed that the median PFS was 16.6 months (95% CI, 11.3-21.9) in the lanreotide arm vs 13.6 months (95% CI, 8.3-NC) for those who were randomized to placebo (HR, 0.90; 95% CI, 0.46-1.88; P = .769).

For patients with typical carcinoid, the median PFS in the double-blind phase was 21.9 months (95% CI, 13.8-NC) and 13.9 months (95% CI, 13.4-NC) for lanreotide and placebo, respectively. The PFS benefit was smaller in the atypical carcinoid subset at 13.8 months (95% CI, 5.6-16.6) for lanreotide and 11.0 months (95% CI, 2.8-16.9) for placebo.

The ORR in the intent-to-treat population with lanreotide was 14.0% and 0% with placebo, providing a 14.0–point difference (95% CI, –10.97-37.86). Additionally, TTF was 13.3 months (95% CI, 5.6-14.1) with lanreotide and 9.8 months (95% CI, 5.4-13.6) with placebo (HR, 0.86; 95% CI, 0.50-1.50; P = .582).

Regarding safety in the double-blind phase, treatment-related adverse events (TRAEs) occurred in 74.5% and 53.8% of lanreotide- vs placebo-treated patients, respectively. Most treatment-emergent adverse events (TEAEs) were grade 1 (86.3% vs 88.5%, respectively) and 2 (72.5% vs 73.1%).

Two TEAEs led to treatment withdrawal with lanreotide vs 3 with placebo. Serious TEAEs occurred in 19.6% and 26.9% of lanreotide- and placebo-treated patients, respectively; 2 of these on lanreotide and 1 on placebo were considered treatment related.

The most common TEAEs in the double-blind phase were diarrhea (62.7% with lanreotide vs 30.8% with placebo), fatigue (255% vs 38.5%, respectively), asthenia (21.6% vs 19.2%), and abdominal pain (21.6% vs 23.1%).

In the open-label phase, lanreotide was linked with any-grade TEAEs in 65.0% of patients with a 32.5% rate of TREAs. TEAEs were mostly grade 1 (62.5%) and grade 2 (35.0%). There was 1 serious AE, but this was not related to treatment. The most common TEAEs were diarrhea (22.5%), abdominal pain (10.0%), and headache (10.0%).

Reference

1. Reidy-Lagunes D, Hörsch D, Singh S, et al. Lanreotide autogel/depot in patients with advanced bronchopulmonary neuroendocrine tumors: results from the phase 3 SPINET study. Presented at: 2021 NANETS Virtual Symposium; November 3-6, 2021; virtual. Abstract 126.