Alpelisib administration reduced lymphatic malformations in a mouse model and in patients

Delestre, Fabienne; Venot, Quitterie; Bayard, Charles; Fraissenon, Antoine; Ladraa, Sophia; Hoguin, Clément; Chapelle, Célia; Yamaguchi, Junna; Cassaca, Rubina; Zerbib, Lola; Magassa, Sato; Morin, G; Asnafi, Vahid; Villarèse, Patrick; Kaltenbach, Sophie; Fraïtag, Sylvie; Duong, Jean-Paul; Broissand, Christine; Boccara, O.; Soupre, V.; Bonnotte, Bernard; Chopinet, Caroline; Mirault, Tristan; Legendre, Christophe; Guibaud, Laurent; Canaud, Guillaume

doi:10.1126/scitranslmed.abg0809

Cited by 50 publications

(61 citation statements)

References 29 publications

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“…Alpelisib treatment-induced clinical responses in all patients, including improvement of cardiac EF as seen in our index patient. Of note, alpelisib-induced responses in patients who did not respond to prior treatment with mTOR inhibitors, such as rapamycin, similar to observations in KRAS -mutant oncology patients ( Di Nicolantonio et al, 2010 ), similar to the recent findings of Delestre et al ( Delestre et al, 2021 ). Small clinical series have shown that mTOR inhibition can induce responses in a subset of unselected advanced LMs, with observed response rates of ~50–60% ( Freixo et al, 2020 ).…”

Section: Discussionsupporting

confidence: 86%

Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial

Shaheen

Tse

Sokol

et al. 2022

eLife

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Background:Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases.Methods:We examined the genomic landscape of a patient cohort of LMs (n = 30 cases) that underwent comprehensive genomic profiling using a large-panel next-generation sequencing assay. Immunohistochemical analyses were completed in parallel.Results:These LMs had low mutational burden with hotspot PIK3CA mutations (n = 20) and NRAS (n = 5) mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal LM harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable radiologic complete response, as defined in RECIST1.1, to the PI3Kα inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive to alpelisib treatment in vitro, which was demonstrated by a concentration-dependent drop in measurable impedance, an assessment of cell status.Conclusions:Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations.Funding:R.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953.Clinical trial number:NCT03941782

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Section: Discussionsupporting

confidence: 86%

Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial

Shaheen

Tse

Sokol

et al. 2022

eLife

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“…In a recent proof‐of‐concept study, Delestre et al 19 demonstrated the efficacy of alpelisib in a genetic mouse model. Based on these very promising results, they decided to administer the drug to three children and three adults with severe lymphatic malformations secondary to a PIK3CA mutation.…”

Section: Figurementioning

confidence: 99%

Alpelisib to treat CLOVES syndrome, a member of the PIK3CA‐related overgrowth syndrome spectrum

Fontelles

Pastor

Moreillo

2022

Brit J Clinical Pharma

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CLOVES syndrome is a rare congenital overgrowth disorder caused by mutations in the phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) gene. It is part of the PIK3CA-related overgrowth syndrome (PROS) spectrum and its treatment is challenging. PROS malformations have traditionally been treated by surgery, but research into pharmacological treatments capable of blocking the PIK/AKT/mTOR pathway has increased over the past decade. The results have been promising and suggest that compassionate use of these treatments in patients with PROS disorders could have clinical benefits. Another promising drug is alpelisib (BYL719), which is a selective inhibitor that competitively binds to the p110a subunit of PIK3 in the intracellular PI3K/AKT signalling pathway. Compassionate use of low-dose alpelisib had striking effects in an uncontrolled case series of 19 PROS patients, several with lifethreatening complications. Moreover, there were few adverse effects and the treatment did not impair linear growth, despite the young age of many of the patients.We present the case of a patient with CLOVES syndrome who was started on compassionate treatment with alpelisib after surgical debulking of a cystic lymphangioma and treatment with sirolimus. This promising drug significantly reduced the size of the lymphangioma and prevented progression of the tissue overgrowth in the gluteal region. This case suggests that low-dose PI3K inhibition may provide collateral benefits that extend beyond mitigation of disease-specific features of PROS.

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“…We present the rst AUC and primary PK parameters in children. Currently, alpelisib dosing in pediatrics is based on a xed-dosing strategy irrespective of weight and age (2-18 years old: 50 mg daily oral dose) (13,14). As weight represents the main determinant of drug exposure in children( 16), weight-adjusted dosing was chosen.…”

Section: Discussionmentioning

confidence: 99%

Repurposing alpelisib, an anti-cancer drug, for the treatment of severe TIE2-mutated venous malformations: preliminary pharmacokinetics and pharmacodynamic data

Kleiber

Remy

Tran

et al. 2022

Preprint

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Extensive venous malformations (VM) involving limbs severely impact quality of life, mostly due to chronic pain and functional limitations. Patients can also display coagulopathy with associated risks of life-threatening thromboembolism and bleeding. Current pharmacological VM treatments (e.g. sirolimus) are not universally effective as 10% of patients present intractable debilitating and/or critical disease. Novel therapies are therefore highly needed for treatment-resistant VM. Over 70% of sporadic VM are attributed to activating mutations in the TEK gene, encoding the receptor tyrosine kinase TIE2 expressed by venous endothelial cells. Despite in vitro studies showing the superiority of alpelisib over sirolimus in inhibiting TIE2 signalling pathway and vein remodelling, there are currently no clinical reports of alpelisib use in VM. Our aim was therefore to assess the effect of alpelisib in TIE-2 mutated VM and to assess its pharmacokinetics. Three patients with a VM harboring the TEK L914F mutations were treated with alpelisib in an open-label compassionate use study. All patients experienced significant improvement. Pain was controlled, gait improved, size of the abnormal venous network decreased, and coagulopathy showed dramatic improvement. Drug exposure was highly variable despite similar weight-adjusted doses, suggesting that alpelisib dosing should be individualized to patient’s characteristics and guided by therapeutic drug monitoring to improve clinical response.

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Alpelisib administration reduced lymphatic malformations in a mouse model and in patients

Abstract: Alplesib exerts therapeutic effects in a mouse model of lymphatic anomalies and in six patients with lymphatic malformations over 6 months’ treatment.

Cited by 50 publications

References 29 publications

Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial

Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial

Alpelisib to treat CLOVES syndrome, a member of the PIK3CA‐related overgrowth syndrome spectrum

Repurposing alpelisib, an anti-cancer drug, for the treatment of severe TIE2-mutated venous malformations: preliminary pharmacokinetics and pharmacodynamic data

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