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Trade names | Itovebi |
Other names | GDC-0077, RG6114, Ro7113755 |
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Routes of administration | By mouth |
Drug class | PI3K inhibitor |
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Formula | C18H19F2N5O4 |
Molar mass | 407.378 g·mol−1 |
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Inavolisib, sold under the brand name Itovebi, is an anti-cancer medication used for the treatment of breast cancer. [1] [2] It is an inhibitor and degrader of mutant phosphatidylinositol 3-kinase (PI3K) alpha. [3] 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. [4]
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. [2]
Inavolisib was approved by the US Food and Drug Administration (FDA) for treatment of PIK3CA-mutant breast cancer in October 2024. [2] [5] [6]
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. [2]
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. [2]
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. [2] 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. [2]
Inavolisib is a synthetic, organic, small compound (the full structure can be seen here). [7] 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 3.2Å 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. [3] [8]
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. [3]
Inavolisibcan be developed as a derivative of 1,3-oxazole [9] or by means of stereo-controlled N-arylation of alpha-amino acids. [10]
Inavolisib is orally administered, though there is little knowledge about its metabolism. [11] [ unreliable medical source? ] 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. [12]
Inavolisib is a selective PI3K-p110α (PIK3CA) inhibitor, which may offer antineoplastic functionality. [7] 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. [13]
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. [14] 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. [3] 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. [15] After binding to the mutant PI3Kα, inavolisib blocks phosphorylation of PIP2 to PIP3, thereby stopping downstream signalling. [16]
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. [17]
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. [18]
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. [2] [19] [20] The drug application was granted priority review and breakthrough therapy designations by the FDA. [2] [5] [21]
Inavolisib is the international nonproprietary name. [22] [23]
Inavolisib is sold under the brand name Itovebi. [2]
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. [3] [24] [16]
Fulvestrant, sold under the brand name Faslodex among others, is an antiestrogenic medication used to treat hormone receptor (HR)-positive metastatic breast cancer in postmenopausal women with disease progression as well as HR-positive, HER2-negative advanced breast cancer in combination with abemaciclib or palbociclib in women with disease progression after endocrine therapy. It is given by injection into a muscle.
Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification. Triple-negative is sometimes used as a surrogate term for basal-like.
Neratinib (INN), sold under the brand name Nerlynx, is a tyrosine kinase inhibitor anti-cancer medication used for the treatment of breast cancer.
Olaparib, sold under the brand name Lynparza, is a medication for the maintenance treatment of BRCA-mutated advanced ovarian cancer in adults. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers.
Phosphoinositide 3-kinase inhibitors are a class of medical drugs that are mainly used to treat advanced cancers. They function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes, which are part of the PI3K/AKT/mTOR pathway. This signal pathway regulates cellular functions such as growth and survival. It is strictly regulated in healthy cells, but is always active in many cancer cells, allowing the cancer cells to better survive and multiply. PI3K inhibitors block the PI3K/AKT/mTOR pathway and thus slow down cancer growth. They are examples of a targeted therapy. While PI3K inhibitors are an effective treatment, they can have very severe side effects and are therefore only used if other treatments have failed or are not suitable.
The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates AKT, localizing it in the plasma membrane. AKT can have a number of downstream effects such as activating CREB, inhibiting p27, localizing FOXO in the cytoplasm, activating PtdIns-3ps, and activating mTOR which can affect transcription of p70 or 4EBP1. There are many known factors that enhance the PI3K/AKT pathway including EGF, shh, IGF-1, insulin, and calmodulin. Both leptin and insulin recruit PI3K signalling for metabolic regulation. The pathway is antagonized by various factors including PTEN, GSK3B, and HB9.
A CDK inhibitor is any chemical that inhibits the function of CDKs. They are used to treat cancers by preventing overproliferation of cancer cells. The US FDA approved the first drug of this type, palbociclib (Ibrance), a CDK4/6 inhibitor, in February 2015, for use in postmenopausal women with breast cancer that is estrogen receptor positive and HER2 negative. While there are multiple cyclin/CDK complexes regulating the cell cycle, CDK inhibitors targeting CDK4/6 have been the most successful; four CDK4/6 inhibitors have been FDA approved. No inhibitors targeting other CDKs have been FDA approved, but several compounds are in clinical trials.
Trastuzumab emtansine, sold under the brand name Kadcyla, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the cytotoxic agent DM1. Trastuzumab alone stops growth of cancer cells by binding to the HER2 receptor, whereas trastuzumab emtansine undergoes receptor-mediated internalization into cells, is catabolized in lysosomes where DM1-containing catabolites are released and subsequently bind tubulin to cause mitotic arrest and cell death. Trastuzumab binding to HER2 prevents homodimerization or heterodimerization (HER2/HER3) of the receptor, ultimately inhibiting the activation of MAPK and PI3K/AKT cellular signalling pathways. Because the monoclonal antibody targets HER2, and HER2 is only over-expressed in cancer cells, the conjugate delivers the cytotoxic agent DM1 specifically to tumor cells. The conjugate is abbreviated T-DM1.
A MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase kinase enzymes MEK1 and/or MEK2. They can be used to affect the MAPK/ERK pathway which is often overactive in some cancers.
Palbociclib, sold under the brand name Ibrance among others, is a medication developed by Pfizer for the treatment of HR-positive and HER2-negative breast cancer. It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6. Palbociclib was the first CDK4/6 inhibitor to be approved as a cancer therapy.
Osimertinib, sold under the brand name Tagrisso, is a medication used to treat non-small-cell lung carcinomas with specific mutations. It is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor.
A selective estrogen receptor degrader or downregulator (SERD) is a type of drug that selectively binds to the estrogen receptor (ER) and induces its degradation, and thus causes its downregulation. SERDs are used in the treatment of estrogen receptor-positive breast cancer, particularly in cases where tumors have developed resistance to other forms of endocrine therapy, such as selective estrogen receptor modulators (SERMs) or aromatase inhibitors.
Abemaciclib, sold under the brand name Verzenio among others, is a medication for the treatment of advanced or metastatic breast cancers. It was developed by Eli Lilly and it acts as a CDK inhibitor selective for CDK4 and CDK6.
Ribociclib, sold under the brand name Kisqali, is a medication used for the treatment of certain kinds of breast cancer. Ribociclib is a kinase inhibitor. It was developed by Novartis and Astex Pharmaceuticals.
Alpelisib, sold under the brand name Piqray among others, is a medication used to treat certain types of breast cancer. It is used together with fulvestrant. It is taken by mouth. It is marketed by Novartis.
Elacestrant, sold under the brand name Orserdu, is a selective estrogen receptor degrader (SERD) used in the treatment of breast cancer. It is taken by mouth.
Gedatolisib (PF-05212384) is an experimental drug for treatment of cancer in development by Celcuity, Inc. The mechanism of action is accomplished by binding the different p110 catalytic subunit isoforms of PI3K and the kinase site of mTOR.
Endocrine therapy is a common treatment for estrogen receptor positive breast cancer. However, resistance to this therapy can develop, leading to relapse and progression of disease. This highlights the need for new strategies to combat this resistance.
Capivasertib, sold under the brand name Truqap, is an anti-cancer medication used for the treatment of breast cancer. It is taken by mouth.
Giredestrant is an investigational oral selective estrogen receptor degrader (SERD) being developed for the treatment of estrogen receptor-positive (ER+) breast cancer. It is a potent, nonsteroidal compound that antagonizes estrogen effects by competitively binding to both wild-type and mutant estrogen receptors with nanomolar potency. Giredestrant works by inducing an inactive conformation of the estrogen receptor ligand-binding domain and promoting proteasome-mediated degradation of the receptor protein.