Piqray (alpelisib)

The discovery that the non-selective beta-blocker propranolol induces rapid regression of proliferating IHs established the first widely adopted systemic pharmacologic therapy in vascular anomaly care and provided a clinical proof-of-concept that targeting lesion-specific endothelial biology can alter disease course. In parallel, recurrent somatic variants affecting PI3K/AKT/mTOR (e.g., PIK3CA, TEK/TIE2, AKT1) and RAS/MAPK (e.g., KRAS, NRAS) signalling have reframed many malformations as mosaic disorders amenable to targeted inhibition with agents such as sirolimus, alpelisib, AKT inhibitors and MEK inhibitors. This review synthesizes translational mechanisms, clinical evidence and safety considerations for beta-blockers and emerging targeted therapies, emphasizing lesion phenotype, timing of intervention and molecular stratification as determinants of response. We highlight current limitations, including toxicity, durability and pathway escape, and outline future directions for precision therapy and genotype-guided trial design in vascular anomalies.

P2, N=69, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2026 --> Jan 2027 | Trial primary completion date: Mar 2026 --> Jan 2027

P2, N=39, Recruiting, Peking Union Medical College | Trial primary completion date: Jul 2026 --> Jul 2028

This prospective real-world analysis shows slightly shorter median PFS and OS times compared with the pivotal trials. Patients in our analyses received alpelisib in later therapy lines, which may explain the poorer outcome.

P2/3, N=232, Recruiting, Novartis Pharmaceuticals | N=158 --> 232

P3, N=137, Terminated, Novartis Pharmaceuticals | Trial completion date: Jan 2027 --> Feb 2026 | Active, not recruiting --> Terminated; The study was terminated following a strategic decision to halt recruitment due to persistently slow enrollment. This decision was not driven by any new or unexpected safety concerns.

Global sensitivity analysis identified compensatory feedback, tumor proliferation rate, and PI3K-mTOR crosstalk as key determinants of tumor response. This novel QSP application exemplifies an innovative bottom-up modeling approach to support patient selection and dosing strategies for future clinical studies.

P1/2, N=40, Active, not recruiting, Criterium, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Aug 2024 --> Mar 2026

These findings may facilitate the development of traditional medicinebased therapeutic strategies and provide insights for potential lead optimization in breast cancer drug discovery.

P3, N=358, Terminated, Novartis Pharmaceuticals | Active, not recruiting --> Terminated; Sponsor Decision

P2, N=51, Active, not recruiting, GOG Foundation | Recruiting --> Active, not recruiting | Trial completion date: Apr 2026 --> Nov 2028 | Trial primary completion date: Apr 2025 --> May 2028

Using mouse models of ER+BC (FVB/N mice, TC11 tumor model), we show reduced growth of SEMA7A+ tumors with PI3K inhibitors (GCT-007:10 mg/kg daily, alpelisib: 20mg/kg daily), alone or in combination with tamoxifen (0.5mg/100uL, every 3rd day). Combination of an anti-SEMA7A antibody (SmAbH1) (100-250 ug/100uL, every other day) and fulvestrant (83 mg/kg, every 5 days) also revealed that direct inhibition of SEMA7A via SmAbH1 significantly reduces tumor growth of SEMA7A-expressing tumors, and that the efficacy of SmAbH1 is not diminished by the standard of care, fulvestrant. Overall, our studies suggest that patients with ER+SEMA7A+ tumors should be candidates for PI3K-targeted therapies or anti-SEMA7A-based therapy.