Journal: The Breast : Official Journal of the European Society of Mastology

Article Title: Development of novel agents for the treatment of early estrogen receptor positive breast cancer ☆

doi: 10.1016/j.breast.2021.11.007

Figure Lengend Snippet:

Article Snippet: Taselisib [ ] , Genentech, Inc., SOLTI Breast Cancer Research Group, Breast International Group, Austrian Breast and Colorectal Cancer Group , NCT02273973 , II , Neoadjuvant; post menopausal, cT1-3 , Taselisib + Letrozole vs. Placebo + Letrozole , Complete , 334 , mRECIST, ORR, pCR , ORR: all; 39% (placebo) vs. 50% (taselisib) OR = 1·55, (95%CI 1·00–2·38; p = 0·049); PIK3CA-mutant:38% (placebo) vs. 56% (taselisib) OR 2·03, (95%CI 1·06–3·88; p = 0·033) pCR: low, no difference.

Techniques: Expressing, Mutagenesis, Adjuvant

Journal: International Journal of Molecular Sciences

Article Title: PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects

doi: 10.3390/ijms22073464

Figure Lengend Snippet: Summary of trials, outcomes and adverse events associated with isoform-specific PI3K inhibitors in various phases of clinical studies.

Article Snippet: Taselisib in combination with anti-androgen therapy, Enzalutamide (Enz) in AR+ metastatic TNBC patients [ ] , Active, not recruiting , Vanderbilt-Ingram Cancer Center in collaboration with NCI, Translational Breast Cancer Research Consortium, Conquer Cancer Foundation and Genentech, Inc. , I/II, NCT02457910 , Arm A: Patients received Taselisib (4 mg) orally once daily on days 1 to 28 and Enz (160 mg) PO QD on days 9 to 28 of cycle 1 and days 1 to 28 of subsequent cycles. Arm B: Patients received 160 mg Enz PO QD on days 1 to 28. Cycles were repeated after 28 days. The combination was safe, well tolerated and increased the CBR in these patients ( n = 30). The CBR was 35.7% including 4 patients with SD and 1 patient with PR. The median PFS was 3.4 months with median PFS for ER+ patients (7.2 months) being substantially higher than that for TNBC patients (2.1 months). There was no difference in PFS across groups receiving drug combinations or Enz only. There was no difference in PFS or CBR with the PIK3CA status. However, better CBR was reported in TNBC patients with LAR subtype tumors versus other subtypes (75% vs. 12.5%; p = 0.06) along with better median PFS of 4.6 months vs. other subtypes (PFS = 2 months). LAR subtype tumors demonstrated a decrease in proliferation and AR target gene expression post-treatment with combination. Mutational landscape assessment of tumors suggested that LAR tumors were enriched GATA3 and FOXA1 genes. TP53 mutations were frequent across all subtypes. In contrast, non-LAR tumors were enriched in RB1 , S82X , R467X (deleterious mutations in cell-cycle) as well as ESCO1,BRCA1 , BRACA2 , BAP1 and FANCE (DNA repair genes) along with activating mutations in MAPK pathway and growth factor receptors. Two potential oncogenic gene fusions FGFR2-TACC2 and FGFR2-TAOK1 were identified which represent a mechanism by which LAR tumors activated the PI3K pathway. Pathways associated with complement and innate immunity were augmented post-treatment. Treatment with Taselisib and Enz specifically increased T-cell and NK cell markers. AR splice variants might contribute to Enz resistance. The MTD was not reached and the trial was terminated early. The RP2D was achieved at 4 mg daily dose of Taselisib with 160 mg Enz/day. 13 patients were enrolled in the phase I and 17 patients (Enz; n = 5 and Enz + Taselisib; n = 12) in phase II trial. , Hyperglycemia, rash, increased AST/ALT, anemia, neutropenia, fever, fatigue, nausea, vomiting and pruritus..

Techniques: Mutagenesis, Activity Assay, Amplification, Expressing, Incubation, Staining, Inhibition, Transformation Assay, Infection, Modification, Concentration Assay, Marker

Journal: Cancer discovery

Article Title: Phase I Dose Escalation Study of Taselisib (GDC-0032), an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors

doi: 10.1158/2159-8290.CD-16-1080

Figure Lengend Snippet: In vivo efficacy of taselisib in the KPL-4 PIK3CA-mutant breast cancer xenograft model. Taselisib was dosed orally and daily at the doses indicated for 21 days as indicated by treatment period (Rx). Control tumor bearing mice were treated with 0.5% methylcellulose/0.2% Tween-80 (vehicle). Tumor volumes were measured and calculated as described in Materials and Methods.

Article Snippet: Taselisib (Genentech, Inc.) was taken on an empty stomach as a single dose (powder-in-capsule formulation) at the same time of day +/- 2 hours ( 33 ).

Techniques: In Vivo, Mutagenesis, Control

Journal: Cancer discovery

Article Title: Phase I Dose Escalation Study of Taselisib (GDC-0032), an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors

doi: 10.1158/2159-8290.CD-16-1080

Figure Lengend Snippet: Pharmacokinetic Parameters of Taselisib (GDC-0032)

Article Snippet: Taselisib (Genentech, Inc.) was taken on an empty stomach as a single dose (powder-in-capsule formulation) at the same time of day +/- 2 hours ( 33 ).

Techniques:

Journal: Cancer discovery

Article Title: Phase I Dose Escalation Study of Taselisib (GDC-0032), an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors

doi: 10.1158/2159-8290.CD-16-1080

Figure Lengend Snippet: Pharmacodynamic modulation of the PI3K pathway. Needle core tumor biopsies obtained from patients at baseline and at steady state (cycle 1, between days 15-21) were fixed and evaluated by reverse phase protein array for PI3K-Akt pathway markers. Decreases of > 60% in pAkt and pS6, and up-phosphorylation of BIM (pro-apoptopic protein) were demonstrated in comparison to baseline for (A) patient 1 on 3 mg QD taselisib with paired biopsies from right endobronchial mass and (B) patient 2 on 16 mg QD taselisib with paired biopsies from right upper anterior thigh mass.

Article Snippet: Taselisib (Genentech, Inc.) was taken on an empty stomach as a single dose (powder-in-capsule formulation) at the same time of day +/- 2 hours ( 33 ).

Techniques: Protein Array, Phospho-proteomics, Comparison