Increased Lanreotride Autogel Dosing Shows Encouraging Antitumor Activity in Progressive Pancreatic, Midguts NETs

Increasing the dosage of lanreotide (Somatulin) autogel from every 28 days to every 14 days led to encouraging progression-free survival (PFS) outcomes in patients with progressive pancreatic and midgut neuroendocrine tumors (NETs), according to findings from the CLARINET FORTE trial (NCT02651987) that were presented during the 2020 NANETS Virtual Symposium.^1,2

In patients with pancreatic NETs, the median PFS was 5.6 months (95% CI, 5.5-8.3), with a 66.7% stable disease (SD) rate; 31.3% of patients had progressive disease. The disease control rate (DCR) at weeks 24 and 48 were 43.8% and 22.9%, respectively.

For patients with midgut NETs, the median PFS was 8.3 months (95% CI, 5.6-11.1) with the increased dosing. Regarding best overall response, 2 partial responses (3.9%) were reported; 68.6% of patients experienced SD and 23.5% had disease progression. At weeks 24 and 48, the DCRs were 58.8% and 33.3%, respectively.

In both cohorts, the increased frequency of dosing showed a safety profile that was consistent with lanreotide given at 120 mg every 28 days.

“Increasing lanreotide dosing frequency may be a consideration before switching to an alternative, less tolerable therapy in preselected patients,” Marianne Pavel, MD, of Friedrich Alexander University Erlangen-Nümberg in Germany, and co-investigators wrote in one of the posters that were presented during the meeting.

Lanreotide autogel is currently approved for the treatment of patients with unresectable pancreatic NETs. Specifically, in the United States, the therapy is indicated at a 120-mg dose for the treatment of patients with unresectable, well- or moderately differentiated, locally advanced or metastatic gastroenteropancreatic (GEP)-NETs. In Europe, the dosage is approved for the treatment of patients with grade 1, and a subset of grade 2, GEP-NETs of midgut, pancreatic, or unknown origin where hindgut sites of origin have been excluded in adult patients with unresectable locally advanced or metastatic disease.

Upon progression of lanreotide autogel at 120 mg every 28 days, patients can receive treatment with sunitinib (Sutent), everolimus (Afinitor), peptide receptor radionuclide therapy, or chemotherapy. However, in the posters that were presented during the NANETs meeting, investigators noted that each of these treatments are linked with higher rates of toxicity than somatostatin analogs.

In the international, prospective, single-arm, open-label, exploratory, phase 2 CLARINET FORTE study, investigators hypothesized that increasing the frequency of lanreotide dosing from every 28 days to every 14 days could regain tumor stabilization in patients with progressive pancreatic or midgut NETs, as well as delay the time and/or need to use alternative, less tolerable therapies. Patients were enrolled between November 2015 and October 2019 from 19 centers and 23 centers across 10 European countries in the pancreatic NETs and midgut NETs cohorts, respectively.

The pancreatic NETs cohort (n = 48) was comprised of patients with somatostatin receptor type 2–positive, well-differentiated, metastatic or locally advanced, unresectable disease, with or without hormone-related syndromes. Patients must have had a Ki-67 of 20% or less, an ECOG performance status of 0 to 2, and somatostatin receptor type 2–positive lesions, as assessed by imaging in the organs of target lesions. Moreover, patients must have had disease progression per independent central review in accordance with RECIST v1.0 criteria, while on frontline lanreotide at 120 mg every 28 days for at least 24 weeks. Disease progression must have occurred within 24 months prior to enrollment.

Eligibility criteria were similar in the midgut NETs cohort (n = 51). Here, patients must have had somatostatin receptor type 2–positive, well-differentiated, metastatic or locally advanced, unresectable midgut NETs, with or without hormone-related syndromes.

Lanreotide was administered at 120 mg every 14 days for 48 weeks or until centrally assessed disease progression, unacceptable toxicity, or death, or longer if fewer than 25 progressive disease or death events occurred in the pancreatic NET cohort. The agent was given at 120 mg every 14 days for 96 weeks in the midgut NETs cohort.

The primary end point was PFS via independent central review; secondary end points were disease control rate, best overall response, and duration of SD. Quality of life (QoL) was examined via QoL questionnaires through EORTC QLQ-C30, QLQ‑GINET.21, and EQ-5D-5L. Additionally, a post-hoc analysis of PFS by Ki-67 index was also performed.

Safety end points included treatment-emergent adverse effects (TEAEs), serious adverse effects (SAEs), and treatment-related AE (TRAEs).

In the pancreatic NETs cohort, 79 patients were screened, and 48 patients were enrolled and included in the FAS. Five patients withdrew due to AEs (n = 2), withdrawal of consent (n = 2), and investigator decision (n = 1).

The mean age was 63.3 years, and 41.7% of patients were male. The median prior exposure to lanreotide was 1.8 years. Additionally, 75% of patients had a grade 2 tumor, with a grade 4 Krenning score occurring in 58.3% of patients, a Ki-67 index of 10% or lower in 89.6% of patients, and a hepatic tumor load from 0% to 10% in 62.5% of patients. Just under half, or 45.8%, of patients had prior surgery of their primary tumor. Moreover, 41.7% of patients had SSTR2 heterogeneously–positive tumors, and 30% of patients had lesions that were negative or weakly positive. Half of patients had tumor location in the liver, the rest being in the bone (33.3%) and other (33.3%).

Additional results showed that, in the post-hoc analysis of PFS by Ki-67 index, the median PFS was 5.6 months in patients whose Ki-67 was at least 2% (n = 12) and in those whose Ki-67 was at least 5% (n = 33). The median PFS was 8.0 months and 2.8 months in those with a Ki-67 of 10% or lower (n = 43) and higher than 10% (n = 5), respectively. The median duration of SD was 8.3 months.

Regarding safety, diarrhea and flushing symptoms incidence did not worsen over time, and no deterioration of QoL was reported in either the pancreatic or the midgut NETs cohorts.

For example, the mean (SD) change from baseline to end of study/early withdrawal in EQ-5D-5L index value was ‒0.04 (0.12), and the mean (SD) change from baseline to end of study/early withdrawal in EQ-5D-5L visual analog scale was ‒1.90 (14.8).

SAEs, none of which were found to be related to treatment, were reported in 10.4% of patients and included spinal fracture, syncope and diarrhea, pulmonary embolism, anaphylactic reaction, and fall (n = 1 each). TEAEs occurred in 85.4% of patients; 2 led to withdrawal due to liver injury (n = 1) and fatigue, abdominal pain, and diarrhea (n = 1). No TEAEs led to death. TRAEs were reported in 37.5% of patients; 1 patient experienced a grade 3 or higher TRAE. Gastrointestinal disorders occurred in 25% of patients and were the most common class of TRAEs; 1 patient had hyperglycemia and no patients experienced bile duct stones or steatorrhea as a TRAE.

In the midgut NETs cohort, 79 patients were screened and 51 were enrolled and included in the FAS. Forty-six patients completed the study overall, and 5 patients withdrew due to AEs (n = 2), locally assessed disease progression (n = 2), and investigator decision (n = 1).

The mean age was 67.1 years and 56.9% of patients were male. The median prior exposure to lanreotide was 1.3 years, and more than half of patients (56.9%) had a grade 1 tumor and 44.7% had a grade 4 Krenning score. Ninety-two percent of patients had a Ki-67 index of 10% or lower, and 64.7% of patients had a hepatic tumor load between 0% and 10%. Additionally, 23.5% of patients had prior surgery of their primary tumor, and 43.1% had SSTR2 heterogeneously–positive disease; 31.8% of patients had some negative or weakly positive lesions. Four patients each had disease in the liver (57.1%) and other (57.1%), followed by 3 (42.9%) in the bone, and 1 (14.3%) in the pancreas.

Additional findings showed that the median PFS was 8.4 months, 8.7 months, 8.6 months, and 5.5 months in patients whose Ki-67 was 2% or lower, 5% or lower, 10% or lower, and greater than 10%, respectively. The median duration of SD was 13.8 months.

The SD change from baseline to end of study/early withdrawal in the EQ-5D-5L index value was ‒0.00 (0.11), and the SD change from baseline to end of study/early withdrawal in EQ-5D-5L visual analog scale was ‒1.76 (9.34).

Moreover, 25.5% of patients reported SAEs, but none were related to therapy. However, TEAEs occurred in 94.1% of patients, 5.9% (n = 3) of whom had a TEAE that led to death due to pulseless electrical activity, intestinal obstruction, and general health deterioration (n = 1 each). Four patients (7.8%) had a TEAE that led to withdrawal, which comprised upper abdominal pain, diarrhea, intestinal obstruction, and spinal cord compression (n = 1 each). Three patients with TEAEs died.

Fifty-one percent of patients had a TRAE, the most common of which were gastrointestinal disorders (37.3%) and general disorders or administration-site conditions (13.7%). Hyperglycemia, bile duct stones, and steatorrhea occurred in 1 patient each and were reported as TRAEs. However, no grade 3 to 5 TRAEs reported.

References

1. Pavel M, Ćwikla JB, Lombard-Bohas C, et al. Lanreotide autogel 120 mg every 14 days in progressive pancreatic neuroendocrine tumors: CLARINET FORTE study. Presented at: 2020 NANETS Symposium; October 2-3, 2020; Virtual. Abstract C-8.
2. Pavel M, Ćwikla JB, Lombard-Bohas C, et al. Lanreotide autogel 120 mg every 14 days in progressive midgut neuroendocrine tumors: CLARINET FORTE study. Presented at: 2020 NANETS Symposium; October 2-3, 2020; Virtual. Abstract C-9.