Inavolisib

Inavolisib
Clinical data
Trade namesItovebi
Other namesGDC-0077, RG6114, Ro7113755
AHFS/Drugs.comMonograph
MedlinePlusa624068
License data
Routes of
administration		By mouth
Drug classPI3K inhibitor
ATC code
Legal status
Legal status
Identifiers
  • (2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
Chemical and physical data
FormulaC18H19F2N5O4
Molar mass407.378 g·mol−1
3D model (JSmol)
  • C[C@@H](C(=O)N)NC1=CC2=C(C=C1)C3=NC(=CN3CCO2)N4[C@@H](COC4=O)C(F)F
  • InChI=1S/C18H19F2N5O4/c1-9(16(21)26)22-10-2-3-11-13(6-10)28-5-4-24-7-14(23-17(11)24)25-12(15(19)20)8-29-18(25)27/h2-3,6-7,9,12,15,22H,4-5,8H2,1H3,(H2,21,26)/t9-,12-/m0/s1
  • Key:SGEUNORSOZVTOL-CABZTGNLSA-N

Inavolisib, sold under the brand name Itovebi by Genentech, a member of the Roche group, is an anti-cancer medication used for the treatment of breast cancer. It is an inhibitor and degrader of mutated phosphatidylinositol 3-kinase (PI3K) alpha (PIK3CA).

The most common adverse reactions include gastrointestinal disorders, high blood glucose, and infections.

Inavolisib was approved for medical use in the United States 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 gastrointestinal disorders (stomatitis, diarrhea, nausea, and vomiting), skin and subcutaneous tissue disorders (rash, dry skin, and alopecia), 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.

Synthesis

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

Metabolism and biotransformation

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.

Molecular mechanisms of action

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 a hydrogen 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.

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. The exact mechanism behind this mutant-specific degradation activity has not been fully elucidated.

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 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.

The results show that inavolisib doubles progression-free survival, from 7.3 months in the placebo group to 15.0 months. 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).

Society and culture

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

In May 2025, the Committee for Medicinal Products for Human Use of the European 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. The applicant for this medicinal product is Roche Registration GmbH. Inavolisib was authorized for medical use in the EU in June 2025.

Names

Inavolisib is the international nonproprietary name.

Inavolisib is sold under the brand name Itovebi.

Research

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 against alpelisib, and the treatment of solid tumors other than breast cancer.

References

  1. ↑ "Itovebi (Roche Products Pty Ltd)". Therapeutic Goods Administration (TGA). 16 April 2025. Retrieved 3 May 2025.
  2. ↑ "Summary Basis of Decision for Itovebi". Drug and Health Products Portal. 8 May 2025. Retrieved 22 June 2025.
  3. ↑ "Register of Innovative Drugs". Health Canada. 3 November 2006. Retrieved 17 April 2025.
  4. 1 2 3 "Itovebi- inavolisib tablet, film coated". DailyMed. 11 October 2024. Retrieved 11 November 2024.
  5. 1 2 3 4 "Itovebi EPAR". European Medicines Agency (EMA). 23 May 2025. Retrieved 15 June 2025. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. 1 2 "Itovebi PI". Union Register of medicinal products. 22 July 2025. Retrieved 31 July 2025.
  7. 1 2 3 4 5 6 7 8 9 "FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, advanced breast cancer". U.S. Food and Drug Administration (FDA). 10 October 2024. Archived from the original on 12 November 2024. Retrieved 11 October 2024. Public Domain This article incorporates text from this source, which is in the public domain.
  8. 1 2 Hanan 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. PMID 36455032. S2CID 254149451.
  9. 1 2 3 "Itovebi (Inavolisib) Tablets, for Oral Use" (PDF). www.accessdata.fda.gov. October 2024. p. 12. Retrieved 25 July 2025.
  10. ↑ "Drugs Trials Snapshot: Itovebi". U.S. Food and Drug Administration. 10 October 2024. Retrieved 24 June 2025. Public Domain This article incorporates text from this source, which is in the public domain.
  11. ↑ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
  12. ↑ Chen J, Lv S, Liu J, Yu Y, Wang H, Zhang H (December 2021). "An Overview of Bioactive 1,3-Oxazole-Containing Alkaloids from Marine Organisms". Pharmaceuticals. 14 (12). Basel, Switzerland: MDPI AG: 1274. doi:10.3390/ph14121274. PMC 8706051. PMID 34959674.
  13. ↑ 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. ISSN 0040-4020. S2CID 150262658.
  14. ↑ Vanhaesebroeck B, Perry MW, Brown JR, André F, Okkenhaug K (October 2021). "PI3K inhibitors are finally coming of age". Nature Reviews. Drug Discovery. 20 (10). Springer Science and Business Media LLC: 741–769. doi:10.1038/s41573-021-00209-1. PMC 9297732. PMID 34127844.
  15. ↑ Song KW, Edgar KA, Hanan EJ, Hafner M, Oeh J, Merchant M, et al. (1 January 2022). "RTK-Dependent Inducible Degradation of Mutant PI3Kα Drives GDC-0077 (Inavolisib) Efficacy". Cancer Discovery. 12 (1): 204–219. doi:10.1158/2159-8290.cd-21-0072. ISSN 2159-8274. PMC 9762331. PMID 34544753.
  16. ↑ Vanhaesebroeck B, Burke JE, Madsen RR (12 January 2022). "Precision Targeting of Mutant PI3Kα in Cancer by Selective Degradation". Cancer Discovery. 12 (1): 20–22. doi:10.1158/2159-8290.cd-21-1411. ISSN 2159-8274. PMC 7612218. PMID 35022207.
  17. ↑ Turner NC, Im SA, Saura C, Juric D, Loibl S, Kalinsky K, et al. (31 October 2024). "Inavolisib-Based Therapy in PIK3CA -Mutated Advanced Breast Cancer". New England Journal of Medicine. 391 (17): 1584–1596. doi:10.1056/NEJMoa2404625. ISSN 0028-4793. PMID 39476340.
  18. ↑ Jhaveri KL, Im SA, Saura C, Loibl S, Kalinsky K, Schmid P, et al. (10 July 2025). "Overall Survival with Inavolisib in PIK3CA -Mutated Advanced Breast Cancer". New England Journal of Medicine. 393 (2): 151–161. doi:10.1056/NEJMoa2501796. ISSN 0028-4793. PMID 40454641.
  19. ↑ "Novel Drug Approvals for 2024". U.S. Food and Drug Administration (FDA). 1 October 2024. Archived from the original on 19 April 2024. Retrieved 29 November 2024.
  20. ↑ "FDA Approves Genentech's Itovebi, a Targeted Treatment for Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer With a PIK3CA Mutation" (Press release). Genentech. 10 October 2024. Retrieved 11 October 2024 – via Business Wire.
  21. ↑ "U.S. Food and Drug Administration Approves FoundationOne Liquid CDx as a Companion Diagnostic for Itovebi (inavolisib) to Identify Patients with Hormone Receptor-Positive, HER2-Negative Breast Cancer with a PIK3CA Mutation" (Press release). Foundation Medicine. 11 October 2024. Retrieved 11 October 2024 – via Business Wire.
  22. ↑ World Health Organization (2020). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 84". WHO Drug Information. 34 (3). hdl:10665/340680.
  23. ↑ World Health Organization (2023). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 90". WHO Drug Information. 37 (3). hdl:10665/373341.
  24. ↑ Juric D, Kalinsky K, Im SA, Ciruelos E, Bianchini G, Barrios CH, et al. (June 2024). "INAVO121: Phase III study of inavolisib (INAVO) + fulvestrant (FUL) vs. alpelisib (ALP) + FUL in patients (pts) with hormone receptor-positive, HER2-negative (HR+, HER2–), PIK3CA-mutated (mut) locally advanced or metastatic breast cancer (LA/mBC)". Journal of Clinical Oncology. 42 (16_suppl) TPS1136. doi:10.1200/JCO.2024.42.16_suppl.TPS1136. ISSN 0732-183X.
  25. ↑ Swain SM, Barrios CH, Basho RK, Curigliano G, Harbeck N, Huang CS, et al. (June 2024). "INAVO122: A phase III study of maintenance inavolisib or placebo + pertuzumab + trastuzumab following induction with pertuzumab + trastuzumab + a taxane in patients (pts) with PIK3CA-mutated, HER2-positive advanced breast cancer (HER2+ aBC)". Journal of Clinical Oncology. 42 (16_suppl) TPS1124. doi:10.1200/JCO.2024.42.16_suppl.TPS1124. ISSN 0732-183X.
  26. ↑ Cortés J, Basho RK, Jhaveri K, King J, Kuemmel S, Krishnan V, et al. (1 May 2025). "408TiP INAVO123: Phase III study of first-line (1L) inavolisib/placebo + a CDK4/6 inhibitor + letrozole (INAVO/PBO + CDK4/6i + LET) in participants (pts) with PIK3CA-mutated (mut), hormone receptor-positive (HR+), HER2-negative (HER2–), endocrine-sensitive advanced breast cancer (aBC)". ESMO Open. 10 (1) 104979: 104092. doi:10.1016/j.esmoop.2025.104979. ISSN 2059-7029. PMC 11758132. PMID 39754978.
  27. ↑ Hoffmann-La Roche (7 July 2025). A Phase II, Open-Label, Multicenter Study Evaluating the Safety and Efficacy of Neoadjuvant Treatment With Inavolisib Combinations in Patients With Untreated, Early-stage, PIK3CA-Mutated Breast Cancer (Report). clinicaltrials.gov.
  28. ↑ Hoffmann-La Roche (3 July 2025). A Phase I/Ib Study Evaluating Single-Agent Inavolisib and Inavolisib Plus Atezolizumab in PIK3CA-Mutated Cancers (Report). clinicaltrials.gov.