Inavolisib isindicated in combination withpalbociclib andfulvestrant for the treatment of adults with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy.[7]
The most common adverse reactions include gastrointestinal disorders (stomatitis,diarrhea,nausea, andvomiting), skin and subcutaneous tissue disorders (rash, dry skin, andalopecia), infections, and laboratory abnormalities, the most notable of which is increased fasting blood glucose. 6% of those treated with inavolisib in the INAVO120 trial had to discontinue treatment due to adverse effects.[7][9]
Inavolisib has an oral bioavailability of 76%, which is not significantly affected by diet. After absorption, inavolisib is extensively distributed (155 L) and is primarily metabolized through hydrolysis. 49% of a single dose of inavolisib is excreted in urine, 48% in feces, and only a minority of the dose is excreted unchanged.[9]
Inavolisib is a PI3Kα inhibitor with a high degree of selectivity over beta-, gamma-, and delta-isoforms of PI3K. When binding to the catalytic portion of PI3K alpha, p110α, inavolisib's carbonyl group forms ahydrogen bond with Tyr836 (conserved) in p110α. The difluoromethyl group can interact with the hydroxyl group presented on Ser774 (conserved) in p110α, which is 3.2Å nearer than that of the equivalent residue Ser754 in p110δ. Additionally, the amide group can interact with Gln859 (non-conserved). This results in a very high selectivity regarding PI3Kα isoforms. Inhibition of PI3Kα reduces the proliferation and increases apoptosis of cancer cell lines that are dependent on PI3Kα activity.[8][14]
In addition to its kinase inhibitory ability, clinically relevant concentrations of inavolisib have been shown to specifically degrade the mutated forms of p110α in a manner that is dependent on receptor tyrosine kinase activity. Such ability prevents the activation of downstream signalling pathways, even with rebound upstream RTK activity.[15] The exact mechanism behind this mutant-specific degradation activity has not been fully elucidated.[16]
Efficacy was evaluated in INAVO120 (NCT04191499), a randomized, double-blind, placebo-controlled, multicenter trial in 325 participants with endocrine-resistant, PIK3CA-mutated HR-positive, HER2-negative locally advanced or metastatic breast cancer whose disease progressed during or within twelve months of completing adjuvant endocrine therapy and who had not received prior systemic therapy for locally advanced or metastatic disease.[7] Primary endocrine resistance was defined as relapse during the first two years of adjuvant endocrine therapy. Secondary endocrine resistance was defined as relapse while on adjuvant endocrine therapy after at least two years or relapse within twelve months of completing adjuvant endocrine therapy.[7]
The results show that inavolisib doubles progression-free survival, from 7.3 months in the placebo group to 15.0 months.[17] Inavolisib was also shown to extend overall survival by 7 months (27.0 months in the placebo group vs 34.0 months in the inavolisib group).[18]
In May 2025, theCommittee for Medicinal Products for Human Use of theEuropean Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Itovebi, intended for the treatment of adults with PIK3CA-mutated, estrogen receptor (ER)-positive, HER2-negative locally advanced and metastatic breast cancer.[5] The applicant for this medicinal product is Roche Registration GmbH.[5] Inavolisib was authorized for medical use in the EU in June 2025.[5][6]
Inavolisib is being studied in multiple settings and in combination with other molecules, including the treatment of advanced/metastatic breast cancer, one of which is a head-to-head trial againstalpelisib, and the treatment of solid tumors other than breast cancer.[24][25][26][27][28]
^abcd"Itovebi EPAR".European Medicines Agency (EMA). 23 May 2025. Retrieved15 June 2025. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ab"Itovebi PI".Union Register of medicinal products. 22 July 2025. Retrieved31 July 2025.
^abHanan EJ, Braun MG, Heald RA, MacLeod C, Chan C, Clausen S, et al. (December 2022). "Discovery of GDC-0077 (Inavolisib), a Highly Selective Inhibitor and Degrader of Mutant PI3Kα".Journal of Medicinal Chemistry.65 (24). American Chemical Society (ACS):16589–16621.doi:10.1021/acs.jmedchem.2c01422.PMID36455032.S2CID254149451.
^"Drugs Trials Snapshot: Itovebi".U.S. Food and Drug Administration. 10 October 2024. Retrieved24 June 2025. This article incorporates text from this source, which is in thepublic domain.
^Han C, Kelly SM, Cravillion T, Savage SJ, Nguyen T, Gosselin F (2019). "Synthesis of PI3K inhibitor GDC-0077 via a stereocontrolled N-arylation of α-amino acids".Tetrahedron.75 (32). Elsevier BV:4351–4357.doi:10.1016/j.tet.2019.04.057.ISSN0040-4020.S2CID150262658.
^World Health Organization (2020). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 84".WHO Drug Information.34 (3).hdl:10665/340680.
^World Health Organization (2023). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 90".WHO Drug Information.37 (3).hdl:10665/373341.
Clinical trial numberNCT04191499 for "A Study Evaluating the Efficacy and Safety of Inavolisib + Palbociclib + Fulvestrant vs Placebo + Palbociclib + Fulvestrant in Patients With PIK3CA-Mutant, Hormone Receptor-Positive, Her2-Negative, Locally Advanced or Metastatic Breast Cancer (INAVO120)" atClinicalTrials.gov
This article incorporates text from this source, which is in thepublic domain.