Inavolisib

Inavolisib, sold under the brand name Itovebi, is an anti-cancer medication used for the treatment of breast cancer. It is a inhibitor and degrader of mutant phosphatidylinositol 3-kinase (PI3K) alpha. The PI3K-mediated signalling pathway has shown to play an important role in the development of tumours as dysregulation is commonly associated with tumour growth and resistance to antineoplastic agents and radiotherapy.

The most common adverse reactions include decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased ALT, nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache.

Inavolisib was approved by the US Food and Drug Administration (FDA) for treatment of PIK3CA-mutant breast cancer in October 2024.

Medical uses

Inavolisib is indicated in combination with palbociclib and fulvestrant 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.

Side effects

The most common adverse reactions include decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased ALT, nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache.

History

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. Primary endocrine resistance was defined as relapse while on the first two years of adjuvant endocrine therapy (ET) and secondary endocrine resistance was defined as relapse while on adjuvant ET after at least two years or relapse within twelve months of completing adjuvant ET.

Structure, reactivity, and synthesis

Inavolisib is a synthetic, organic, small compound (the full structure can be see
here
. When binding to phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (p110α), inavolisib’s carbonyl group can accept a hydrogen bond from the Tyr836 (conserved) in p110α. The difluoromethyl group can interact with the hydroxyl group presented on Ser774 (conserved) in p110α, which is 3.2 Å nearer than of which on 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.

Compared to similar PI3K inhibiting compounds, inavolisib has a higher thermodynamic aqueous solubility that proved advantageous in the formulation process and aiding greater consistency in predictions of absorption.

Inavolisibcan be developed as a derivative of 1,3-oxazole or by means of stereo-controlled N-arylation of alpha-amino acids.

Metabolism and biotransformation

Inavolisib is orally administered, though there is little knowledge about its metabolism. However, absorption, metabolism, and excretion data of taselisib, a molecule with a related chemical scaffold, suggest moderately slow absorption into the systemic circulation, metabolism to play a minor role in drug clearance, and biliary excretion to be the main route of excretion.

Molecular mechanisms of action

Inavolisib is a selective PI3K-p110α ( PIK3CA) inhibitor, which may offer antineoplastic functionality. Therefore, it may serve as a new addition to combination therapy with conventional cancer treatment, such as chemotherapy. Combining inavolisib with palbociclib and fulvestrant might improve treatment of breast cancer.

Next to its inhibitory enzymatic ability, it is suggested that inavolisib binds to - and activates degradation of - mutated forms of p110α. Members of the PI3K family regulate cellular processes such as cell growth and proliferation, survival, remodelling, and intracellular transport of organelles. PI3K also plays an essential role for the immune system.

The class I isoform PI3K alpha (PI3Kα) is often times expressed in solid tumours through gene amplification or activated mutations. Mutations in PI3Kα can often be found in cancer cells, especially HR+ breast cancer, which causes a disruption of the PI3K pathway. This leads to increased tumour growth and metastasis. One of the most common mutations can be found in ''PIK3CA'', which plays a significant role in tumour cell proliferation.

In preclinical studies, inavolisib has shown to specifically initiate the degradation of this p110α oncogene with the help of proteasomes. After binding to the mutant PI3Kα, inavolisib blocks phosphorylation of PIP₂ to PIP₃, thereby stopping downstream signalling.

Consequently, biomarkers in the PI3K pathway are reduced, cell proliferation inhibited, and the rate of ''PIK3CA''-mutant breast cancer apoptosis increased (in comparison to the wild type). The exact mechanism of action of inhibitors like inavolisib on mutated PI3Kα and the inhibitors' influence on mutant structures are still unknown.

Toxicity

Inavolisib is able to induce a cytotoxic response but this is directed towards tumour cells that contain the PI3K mutation, thereby inhibiting further tumour growth and leading to cell loss.

Society and culture

Legal status

In October 2024, the US Food and Drug Administration FDA approved inavolisib for the treatment of PIK3CA-mutant breast cancer based on the results from the INAVO120 trial. The drug application was granted priority review and breakthrough therapy designations by the FDA.

Names

Inavolisib is the international nonproprietary name.

Inavolisib is sold under the brand name Itovebi.

Research

Due to inavolisib’s ability to inhibit the PI3K pathway through HER2-dependent degradation, it is undergoing clinical trials to potentially make use of it as an antineoplastic (anti-cancer) drug to treat breast cancer.

References

External links

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Antineoplastic drugs
Phosphoinositide 3-kinase inhibitors
Acetamides
Benzoxazepines
Difluoromethyl compounds
Oxazolidinones
Drugs developed by Genentech
Drugs developed by Hoffmann-La Roche