Results of the CLARINET FORTE study indicate that a dosing strategy of lanreotide given every 14 days may be a viable and safe option when the standard administration of every 28 days is not acceptable.
More frequent dosage of lanreotide (Somatuline) autogel in progressive pancreatic and midgut neuroendocrine tumors (NETs) resulted in an acceptable safety and efficacy profile, according to phase 2 data presented at the North American Neuroendocrine Tumor Society (NANETS) 2020 Multidisciplinary NET Medical Virtual Symposium.1,2
Results of the CLARINET FORTE (NCT02651987) study indicate that a dosing strategy of lanreotide given every 14 days may be a viable and safe option when the standard administration of every 28 days is not acceptable.
“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-Nürnberg in Germany, and co-investigators wrote in a poster presented during the meeting.
Lanreotide autogel is currently approved for the treatment of patients with unresectable pancreatic NETs.3 In the United States, the therapy is specifically indicated at a dosage of 120 mg every 4 weeks 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 the midgut, pancreas, or of unknown origin where hindgut sites of origin have been excluded in adult patients with unresectable locally advanced or metastatic disease.1,2
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 poster presented during the meeting, investigators noted that each of these treatments is linked with higher rates of toxicity than somatostatin analogs.
In the prospective, single-arm, open-label trial, investigators hypothesized that increased frequency lanreotide, administered 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 across 10 European countries to either the pancreatic NETs or midgut NETs cohorts. Lanreotide was administered at 120 mg every 14 days for 48 weeks or until centrally assessed disease progression, unacceptable toxicity, or death. Investigators could give treatment for a longer duration if fewer than 25 progressive disease or death events occurred in the pancreatic NET cohort (FIGURE).
The primary end point was PFS via independent central review. Secondary end points were disease control rate, best overall response, and duration of stable disease. Investigators examined quality of life (QOL) via questionnaires through EORTC QLQ-C30, EORTC QLQGINET21, and EQ-5D-5L. Additionally, they performed a post hoc analysis of PFS by Ki-67 index. Safety end points included treatment-emergent adverse effects (TEAEs), serious AEs (SAEs), and treatment- related AEs (TRAEs).
Pancreatic NETs cohort
The pancreatic NETs cohort (n = 48) comprised patients with somatostatin receptor type 2 (SSTR2)–positive, well-differentiated, metastatic or locally advanced, unresectable disease with or without hormone-related syndromes. Patients must have had a Ki-67 expression of 20% or less, an ECOG performance status of 0 to 2, and SSTR2–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 1.0 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 in the trial.
In the study, patients with pancreatic NETs had a median PFS of 5.6 months (95% CI, 5.5- 8.3), with rates of stable disease and progressive disease of 66.7% and 31.3%, respectively. The disease control rate (DCR) at weeks 24 and 48 were 43.8% and 22.9%, respectively.
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 stable disease was 8.3 months.
The mean age of patients 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 of 0% to 10% in 62.5% of patients. Just under half, or 45.8%, of patients had surgery of their primary tumor. Moreover, 41.7% of patients had somatostatin receptor 2 (SSTR2) heterogeneously positive tumors, and 30% of patients had lesions that were negative or weakly positive. Of those with negative or weakly positive lesions, half of patients had tumors located in the liver, the other locations being in the bone and other.
For example, the mean (standard deviation [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 investigators found to be related to treatment, were reported in 10.4% of patients and included 1 event each of spinal fracture, syncope and diarrhea, pulmonary embolism, anaphylactic reaction, and fall. TEAEs occurred in 85.4% of patients; 2 led to withdrawal. TRAEs were reported in 37.5%, with only 1 patient having grade 3 or higher TRAEs.
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. Five patients withdrew due to AEs (n = 2), withdrawal of consent (n = 2), and investigator decision (n = 1).
Midgut NETs cohort
Eligibility criteria were similar in the midgut NETs cohort (n = 51). Patients must have had SSTR2–positive, well-differentiated, metastatic or locally advanced, unresectable midgut NETs with or without hormone-related syndromes.
For patients with midgut NETs who were treated with more frequent lanreotide every 14 days, the median PFS was 8.3 months (95% CI, 5.6-11.1). Regarding best overall response, 2 partial responses (3.9%) were reported; 68.6% of patients experienced stable disease and 23.5% had disease progression. At weeks 24 and 48, the DCRs were 58.8% and 33.3%, respectively.
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 stable disease was 13.8 months.
The mean age of patients was 67.1 years and 56.9% were male. The median prior exposure to lanreotide was 1.3 years. 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 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 in the bone (42.9%), and 1 in the pancreas (14.3%).
The mean (SD) change from baseline to end of study/early withdrawal in the EQ-5D-5L index value was –0.00 (0.11), and the mean (SD) change from baseline to end of study/early withdrawal on the 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% of whom had a TEAE that led to death due to 1 incidence each of pulseless electrical activity, intestinal obstruction, and general health deterioration.
Four patients (7.8%) had a TEAE that led to withdrawal, which comprised 1 event each of upper abdominal pain, diarrhea, intestinal obstruction, and spinal cord compression. 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 were reported. Forty-six patients completed the study overall, and 5 patients withdrew due to 2 events each of AEs and locally assessed disease progression, and 1 investigator decision.
Takeaways From the Trial
In both cohorts, the increased frequency of dosing showed a safety profile that was consistent with lanreotide given at 120 mg every 28 days. These results led the investigators to conclude that this strategy is promising in patients with pancreatic and midgut NETs, especially in patients with pancreatic tumors and a Ki-67 of 10% or less.
1. Pavel M, Ćwikla JB, Lombard-Bohas C, et al. Lanreotide autogel (LAN) 120mg every 14 days in progressive pancreatic neuroendocrine tumors (pan-NETs): CLARINET FORTE study. Poster presented at: NANETS 2020 Multidisciplinary NET Medical Virtual Symposium; October 2-3, 2020. Abstract 135.
2. Pavel M, Ćwikla JB, Lombard-Bohas C, et al. Lanreotide autogel (LAN) 120 mg every 14 days in progressive midgut neuroendocrine tumors (NETs): CLARINET FORTE study. Poster presented at: NANETS 2020 Multidisciplinary NET Medical Virtual Symposium; October 2-3, 2020. Abstract 136.
3. Somatuline Depot. Prescribing information. Ipsen Biopharmaceuticals, Inc; 2019. Accessed October 19, 2020. https://bit.ly/3m0aUnS