Skip To Main Content

Inavolisib (PI3K alpha inhibitor)

(RG6114)

Breast

Phase III

A Study Evaluating the Efficacy and Safety of GDC-0077 + Palbociclib + Fulvestrant vs Placebo + Palbociclib + Fulvestrant in Patients With PIK3CA-Mutant, Hormone Receptor-Positive, Her2-Negative, Locally Advanced or Metastatic Breast Cancer (INAVO120)

NCT04191499

Phase I

To Evaluate the Safety, Tolerability, and Pharmacokinetics of GDC-0077 Single Agent in Participants With Solid Tumors and in Combination With Endocrine and Targeted Therapies in Participants With Breast Cancer 

NCT03006172

Solid Tumor

Phase I

To Evaluate the Safety, Tolerability, and Pharmacokinetics of GDC-0077 Single Agent in Participants With Solid Tumors and in Combination With Endocrine and Targeted Therapies in Participants With Breast Cancer 

NCT03006172

This compound and its uses are investigational and have not been approved by the US Food and Drug Administration. Efficacy and safety have not been established. The information presented should not be construed as a recommendation for use. The relevance of findings in preclinical studies to humans is currently being evaluated.

A selective PI3Kα-mutant inhibitor and degrader1-3

1. PI3K pathway in HR+ breast cancer

The PI3K pathway is frequently dysregulated in HR+ breast cancer—promoting tumor growth, disease progression, and resistance to endocrine treatment. Dysregulation is typically caused by mutations in the genes coding for pathway enzymes, including PI3K. The PI3K family of proteins comprises a variety of isoforms, and mutations in the PI3Kα isoform gene—PIK3CA—have been implicated in HR+ breast cancer.1,4-10

GDC-0077 PI3K pathway signaling

2. GDC-0077: a selective PI3Kα-mutant inhibitor and degrader

GDC-0077 is an investigational small molecule designed to selectively inhibit mutant PI3Kα. This molecule is thought to be >300-fold more selective for PI3Kα over other class I PI3K isoforms, including PI3Kδ. GDC-0077 binds to the ATP-binding site of PI3Kα, thereby blocking phosphorylation of PIP2 to PIP3 and preventing downstream signaling as shown in preclinical models. Moreover, GDC-0077 specifically degrades the mutant form of PI3Kα, resulting in reduction of pathway activity. The biochemical features of GDC-0077 are designed to optimize its cellular therapeutic index through reduced off-target cytotoxicity.1-3,11

GDC-0077 inhibiting PI3Ka

GDC-0077 resulted in tumor regressions and induction of apoptosis in breast cancer xenograft models

PIK3CA-mutant human breast cancer xenograft models demonstrated that GDC-0077 results in tumor regression, induction of apoptosis, and a reduction of pathway activity biomarkers (pAKT, pPRAS40, and pS6RP). Also, in a PIK3CA-mutant human breast cancer xenograft model, the combination of GDC-0077 with selective estrogen receptor degradation or CDK4/6 inhibition improved antitumor activity compared with the individual modalities.1,3

Breast cancer cells

ATP=adenosine triphosphate; CDK=cyclin-dependent kinase; HR=hormone receptor; pAKT=phosphorylated AKT; PI3K=phosphatidylinositol 3-kinase; PIK3CA=phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha; PIP2=phosphatidylinositol 4,5-bisphosphate; PIP3=phosphatidylinositol 3,4,5-trisphosphate; pPRAS40=phosphorylated proline-rich AKT substrate of 40 kDa; pS6RP=phosphorylated S6 ribosomal protein; PTEN=phosphatase and tensin homolog; RTK=receptor tyrosine kinase.

    • Hong R, Edgar K, Song K, et al. Cancer Res. 2018;78:PD4-14.

      Hong R, Edgar K, Song K, et al. Cancer Res. 2018;78:PD4-14.

    • Jones LH. Cell Chem Biol. 2018;25:30-35. PMID: 29174540

      Jones LH. Cell Chem Biol. 2018;25:30-35. PMID: 29174540

    • Edgar K, Hanan E, Staben S, et al. Cancer Res. 2017;77:156.

      Edgar K, Hanan E, Staben S, et al. Cancer Res. 2017;77:156.

    • LoRusso PM. J Clin Oncol. 2016;34:3803-3815. PMID: 27621407

      LoRusso PM. J Clin Oncol. 2016;34:3803-3815. PMID: 27621407

    • Miller TW, Rexer BN, Garrett JT, Arteaga CL. Breast Cancer Res. 2011;13:224. PMID: 22114931

      Miller TW, Rexer BN, Garrett JT, Arteaga CL. Breast Cancer Res. 2011;13:224. PMID: 22114931

    • Mukohara T. Breast Cancer (Dove Med Press). 2015;7:111-123. PMID: 26028978

      Mukohara T. Breast Cancer (Dove Med Press). 2015;7:111-123. PMID: 26028978

    • Sabine VS, Crozier C, Brookes CL, et al. J Clin Oncol. 2014;32:2951-2958. PMID: 25071141

      Sabine VS, Crozier C, Brookes CL, et al. J Clin Oncol. 2014;32:2951-2958. PMID: 25071141

    • Thorpe LM, Yuzugullu H, Zhao JJ. Nat Rev Cancer. 2015;15:7-24. PMID: 25533673

      Thorpe LM, Yuzugullu H, Zhao JJ. Nat Rev Cancer. 2015;15:7-24. PMID: 25533673

    • Miller TW, Hennessy BT, Gonzalez-Angulo AM, et al. J Clin Invest. 2010;120:2406-2413. PMID: 20530877

      Miller TW, Hennessy BT, Gonzalez-Angulo AM, et al. J Clin Invest. 2010;120:2406-2413. PMID: 20530877

    • Qin H, Liu L, Sun S, et al. PeerJ. 2018;6:e5092. PMID: 29942710

      Qin H, Liu L, Sun S, et al. PeerJ. 2018;6:e5092. PMID: 29942710

    • Cintas C, Guillermet-Guibert J. Front Oncol. 2018;7:330. PMID: 29404273

      Cintas C, Guillermet-Guibert J. Front Oncol. 2018;7:330. PMID: 29404273