Pegvisomant and Pasireotide LAR as second line therapy in acromegaly: clinical effectiveness and predictors of response

Abstract

Background: The treatment of acromegaly resistant to first generation somatostatin receptor ligands (SRLs) is often difficult. Pegvisomant and Pasireotide LAR are mostly used in these subset of patients, as second line therapies. Choice of the type of second line therapies is difficult, since predictors of response are still unclear, impairing personalized therapy. We aimed to investigate predictors of response to Pegvisomant and Pasireotide LAR. Methods: Seventy-four acromegaly patients entered this observational, cross-sectional and retrospective study if (1) resistant to high dose first generation SRLs and (2) treated with Pegvisomant and Pasireotide LAR for at least 12 consecutive months. Patients treated with radiotherapy in the previous 10 years were excluded. Results: Fourty-one patients were treated with Pegvisomant and 33 with Pasireotide LAR. At the end of the study, acromegaly was controlled in 35 patients treated with Pegvisomant (85.4 %) and in 23 treated with Pasireotide LAR (69.7%). In this cohort, a poor Pegvisomant response and a shorter progression free time were observed in cases with tumor extension to the third ventricle (p=0.004, HR:1.6, 95%CI:1.2-4.6), with a Ki67-Li>4% (p=0.004, HR:3.49, 95%CI:1.4-3.9) and with pre-treatment IGF-I>3.3xULN (p=0.03, HR:1.3, 95%CI:1.1-6.0). A poor Pasireotide Lar response and a shorter progression free time were observed in cases with tumor extension to the third ventricle (p=0.025, HR:1.6 95%CI:1.4-3.4), pre-treatment IGF-I>2.3xULN (p=0.049, HR:2.4, 95%CI:1.4-8.0), SST5 membranous expression (p=0.023 HR:5.6 95%CI:1.3-6.4) and in patients carried the d3-delated GHR isoform (p=0.005, HR:11.37, 95%CI:1.3-20.0). Conclusion: Molecular and clinical biomarkers can be useful in predicting the responsiveness to Pegvisomant and Pasireotide LAR

More than a decade of real-world experience of pegvisomant for acromegaly: ACROSTUDY

“…Reasons for the decrease of PEGV in combination with SRL/DA over time are likely multifactorial and varied due to treatment practices across countries and centres, but could be due to toleration issues, patient preference, cost of the combination therapy, radiation, and optimization of biochemical control. Use of combination treatment in acromegaly patients may benefit patients with aggressive acromegaly ( 6 ), particularly those partially resistant to first-generation SRLs and with large/invasive tumours ( 41 ), similar to those treated with PEGV and pasireotide ( 42 , 43 ). A recent study showed that low-dose SRL plus weekly PEGV represents a potential novel dosing option for achieving cost-effective, optimal biochemical control in patients with uncontrolled acromegaly requiring combination therapy ( 44 ).…”

Glucose metabolism outcomes in acromegaly patients on treatment with pasireotide-LAR or pasireotide-LAR plus Pegvisomant

“…Taken together, these findings suggest that the higher dose of PAS-LAR needed to control a more biochemically active disease may have contributed to a greater glucose metabolism alteration. In fact, it is already known that in the presence of a more active disease at baseline, it is more difficult to obtain biochemical control of acromegaly [39]. Moreover, PAS-LAR has been shown to decrease insulin secretion acting at pancreatic beta cell level and to also decrease GlP and GLP-1 secretion [24].…”

Pasireotide in the Personalized Treatment of Acromegaly

“…Pasireotide shows the highest affinity for SST5, followed by SST2, SST3, and SST1 ( 79 ), although it has a slightly lower affinity -but still important- to SST2 than first-generation SRLs. In recent studies ( 15 , 80 , 81 ), it has been shown that in somatotropinomas depicting a SST5 immunohistochemical score of 2 or 3, a positive response to pasireotide is observed in about 50% of the cases resistant to first-generation SRLs; SST3 and AIP expression did not influence the response to pasireotide, while sparsely granulated adenomas responded better compared to densely granulated. However, in most of the tumors of unselected patients, pasireotide seems to exert its biological effects predominantly through SST2 ( 82 ).…”

“…Besides the different receptor binding affinity, pasireotide exhibits different functional properties compared to first-generation SRLs when binding to SST5, and particularly SST2. However, in one of the recently published studies, high expression of SST5 was controversially associated with pasireotide resistance in some cases ( 81 ). Also, AIP low expression tumors may be pasireotide-responsive, indicating that this pathway is not exclusively implicated in the biological response to pasireotide, in opposition to what happens with first-generation SRLs, in which it plays an important role; this has been recently described in AIP mutated acromegaly patients ( 84 ).…”

“…GH receptor (GHR) polymorphisms, and particularly d3-GHR have been involved in different sensitivity to GH and to the different necessity of pegvisomant dosage to get hormonal control during acromegaly treatment ( 88 ). Surprisingly, d3-GHR has been linked to resistance to pasireotide treatment in a retrospective study ( 81 ). Although no explanation is so far available, a worse response to first-generation SRLs was described in patients carrying d3-GHR genotype ( 89 ).…”