taselisib (GDC-0032)

P2, N=70, Active, not recruiting, National Cancer Institute (NCI)

By investigating the Genomics of Drug Sensitivity in Cancer (GDSC) database, we identified axitinib and taselisib as candidate compounds that could potentially target the KISS-high myeloblasts. Altogether, our findings suggest that KISS holds the potential to improve the current prognostic scheme of MDS and inform novel therapeutic opportunities.

P1, N=68, Active, not recruiting, Otto Metzger, MD | Trial completion date: Dec 2023 --> May 2024

Additionally, the high-risk group exhibited higher sensitivity to Afatinib, Fulvestrant, Gefitinib, Osimertinib, Sapitinib, and Taselisib. In conclusion, our study highlighted the potential utility of the constructed DRLPS in the prognosis prediction of HCC patients, which demonstrated promising clinical application value.

5-Fluorouracil_1073 and Taselisib_1561 were predicted as potential treatment options for GBM patients, while ABT737_1910 and Wnt_C59-1622 exhibited superior response in GBM patients of the HR group. We presented a novel prognostic model for patients with GBM, based on histone modification-related genes. In addition, we identified the crucial role of the TMEM176A in the regulation of GBM carcinogenic phenotypes for the first time.

These findings suggest that targeting the PI3K/AKT/mTOR pathway may have therapeutic potential in PDAC, and distinct pathway states, immune modulation and tumor microenvironments have prognostic value.

In the chemotherapy drug sensitivity analysis, we found that the high Risk Score group might be more suitable for treatment with PI3K inhibitors Taselisib and Pictilisib. In addition, we found that patients in the low-risk group responded better to immunotherapy. Risk Score of 9-gene composition of PCD signature possesses promising clinical potential in OV prognosis, immunotherapy, immune microenvironment activity, and chemotherapeutic drug selection, and our study provides the basis for an in-depth investigation of the PCD mechanism in OV.

The profile of MEN1611 and its antitumoral activity suggest an improved profile as compared to pan-inhibitors, which are limited by a less than ideal safety profile, and isoform selective molecules, which may potentially promote development of resistance mechanisms. The compelling antitumor activity in combination with trastuzumab in HER2 + trastuzumab-resistant, PIK3CA mutated breast cancer models is at the basis of the ongoing B-Precise clinical trial (NCT03767335).

Our study establishes clonal multiple PIK3CAmut as an important molecular determinant of response to p110α inhibition and provides rationale for further clinical investigation of p110α inhibitors alone or with rationally-selected therapies in breast cancer and potentially other solid tumor types.

Elevated expression of CCNE2 has been associated with poor outcome in ER-positive breast cancer, and has been identified as part of gene signatures that predict disease progression in tamoxifen-resistant breast cancer or advanced breast cancer. Our analysis revealed an association between high CCNE2 expression and worse PFS in patients that received PBO + FUL. Further, this association was not observed in the patients that received the combination of TAS+FUL, which may inform future rational combination strategies for the clinical development of PI3K inhibitors in ER+/HER2- PIK3CAmut aBC.

Broadly, alterations in estrogen receptor (ER), PI3K, and p53 pathway genes were associated with resistance to taselisib+fulvestrant in participants with PIK3CAmut ctDNA. Altogether, we demonstrated the impact of genomic (co-)alterations on outcomes with one of the largest clinico-genomic datasets of ER+, HER2-, PIK3CAmut breast cancer patients treated with a PI3K inhibitor.

P1, N=68, Active, not recruiting, Otto Metzger, MD | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2020 --> Dec 2022

P2, N=6452, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

The PI3K inhibitors which are under clinical trial studies include GDC-0032, INK1117 for PI3K-α, and AZD8186 for PI3K-β. This review primarily focuses on the structural insights and structure anticancer activity relationship studies of recent PI3K inhibitors including their clinical stages of development and therapeutic values.

Through drug sensitivity analysis, Trifluridine, PD407824, and Taselisib were shown to be effective drugs for METTL2A-positive BRCA patients. Overall, our research conducts a holistic view of the expression level and prognostic signature of m3C-related genes with multiple malignancies. Importantly, METTL2A has been intensely explored as a potential oncogene in BRCA, to aid the development of potential drug agents for precision therapy in breast cancer patients.

P2, N=189, Completed, The Netherlands Cancer Institute | Suspended --> Completed | N=290 --> 189 | Trial completion date: Dec 2022 --> May 2022

Results Combining LOXO-783 with either fulvestrant (FUL; CI at 50% inhibition = 0.28) or imlunestrant (CI at 50% inhibition = 0.43) showed increased efficacy in cell proliferation assays using the HR+, HER2-, PI3Kα H1047R- mutant T47D model...Similar results were observed in a T47D model engineered to express ESR1 D538G, as well as in an HR+, HER2- PI3Kα double in-cis mutant model (H1047R/D350G) also harboring ESR1 D538G and derived from a patient who had progressed on prior letrozole plus taselisib...Extending these studies to additional treatment settings, LOXO-783 was similarly efficacious as a single agent in abemaciclib-resistant and abemaciclib/FUL double-resistant models, and was additive in combination with paclitaxel in a triple negative breast cancer model in vitro and in vivo...LOXO-783 is also efficacious in ESR1 mutant as well as in abemaciclib and abemaciclib/FUL double-resistant models. A phase 1 trial of LOXO-783 alone or in combination with anticancer therapies is ongoing (PIKASSO-01; NCT05307705).

P1/2, N=30, Terminated, Vanderbilt-Ingram Cancer Center | Active, not recruiting --> Terminated; Interim analysis - toxicity

P3; Completed --> Terminated; The Sponsor discontinued the manufacturing and development of taselisib due to modest clinical benefit and limited tolerability.

These data suggest that inhibition of authophagy with CQ could overcome mechanism of drug resistance to PI3K/AKT inhibitors plus paclitaxel in TNBC making the evaluation of such combinations in clinical trials warranted.

P=N/A, N=1864, Completed, Southwest Oncology Group | Active, not recruiting --> Completed

In this study, taselisib monotherapy had very limited activity in a heterogeneous cohort of heavily pretreated cancer patients with PIK3CA-mutated tumors; the presence of a PIK3CA mutation alone does not appear to be a sufficient predictor of taselisib activity.

These yielded several candidates, including axtinib, GDC-0032, GSK-690693, and SGX-523. The combination regimen of trametinib and AXL/MET/VEGFR inhibitor glesatinib showed initial efficacy both in vitro and in vivo (92% reduction in tumor volume)...Furthermore, resistant cell lines showed a compensatory mechanism via increases in MAPK and non-MAPK pathway proteins that may represent targets for future combination regimens. Intrinsic-targeted options have potential to address paucity of medical treatment options for HNSCC cancer patients, enhance response to extrinsic targeted agents, and/or reduce morbidity as neoadjuvant to surgical treatments.

P1, N=68, Active, not recruiting, Otto Metzger | Trial completion date: Dec 2021 --> Dec 2022

P2, N=290, Suspended, The Netherlands Cancer Institute | Trial completion date: Jul 2022 --> Dec 2022 | Trial primary completion date: Jan 2022 --> Jul 2022

We report that the most frequently mutated genes identified are consistent with previous studies in pts with ER+, HER2- aBC. This analysis shows that alterations in TP53 and PTEN were associated with poor prognosis in both tx arms, and FGFR1 alterations were associated with a poor prognosis in TAS+FUL treated pts. Further, NF1 alterations were associated with a poor prognosis in PBO+FUL treated pts, an association that was not observed with TAS+FUL.

New cell cycle inhibitors are under development (SHR6390). New combinations are also being evaluated, notably palbociclib with SAR439859 (a new selective estrogen receptor degrader: SERD). Targeting of the Phosphoinositide 3-kinases (PI3K) pathway by taselisib, in hormone-resistant disease with a Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) mutation, modestly improves progression-free survival but with a non-negligible toxicity of the treatment.

P2, N=6452, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2022 --> Dec 2025 | Trial primary completion date: Jun 2022 --> Dec 2025

P1/2, N=30, Active, not recruiting, Vanderbilt-Ingram Cancer Center | Trial completion date: Dec 2021 --> Jul 2022

PIK3CA, which encodes the p110α catalytic subunit of PI3Kα, is one of the most frequently genetically activated kinases in solid tumors. In this issue of Cancer Discovery, Song and colleagues report that the related PI3Kα inhibitors taselisib and inavolisib trigger receptor tyrosine kinase (RTK)-dependent degradation of the mutant p110α protein in breast cancer cells that are positive for HER2 RTK, limiting feedback-mediated drug resistance and potentially widening the therapeutic index of PI3Kα inhibition.See related article by Song et al., p. 204.

The PI3K inhibitors which are under clinical trial studies include GDC-0032, INK1117 for PI3K-α, and AZD8186 for PI3K-β. This review primarily focuses on the structural insights and structure anticancer activity relationship studies of recent PI3K inhibitors including their clinical stages of development and therapeutic values.

P2, N=70, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Nov 2021 --> Mar 2022

P2, N=290, Suspended, The Netherlands Cancer Institute | Trial primary completion date: Jul 2021 --> Jan 2022

Here we discover that GDC-0077 and taselisib more potently inhibit mutant PI3K pathway signaling and cell viability through unique HER2-dependent mutant p110a degradation. Both are more effective than other PI3K inhibitors at maintaining prolonged pathway suppression. This study establishes a new strategy for identifying inhibitors that specifically target mutant tumors by selective degradation of the mutant oncoprotein and provide a strong rationale for pursuing PI3Kα degraders in patients with HER2-positive breast cancer.

P1/2, N=686, Completed, Genentech, Inc. | Active, not recruiting --> Completed

P3, N=631, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

Here, we delineate the molecular mechanisms of the acquisition of resistance to two isoform-selective inhibitors of PI3K (isiPI3K), alpelisib (BYL719) and taselisib (GDC0032), in HNC cell lines...Knocking-down IGF2 with siRNA, or blocking IGF1R with AEW541, resulted in superior anti-tumor activity of isiPI3K in vitro and ex vivo. In vivo, the combination of isiPI3K and IGF1R inhibitor induced stable disease in mice bearing either tumors generated by the HNC UM-SCC47 cell line or HPV+ patient-derived xenografts. These findings indicate that IGF2 and the IGF2/IGF1R pathway may constitute new targets for combination therapies to enhance the efficacy of PI3K inhibitors for the treatment of HNC.

P1, N=68, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Feb 2021 --> Dec 2021

P2, N=70, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Nov 2020 --> Nov 2021

The pan-PI3K inhibitor, buparlisib and the beta-isoform-sparing PI3K inhibitor, taselisib, met efficacy endpoints in clinical trials, but pictilisib did not; moreover, poor tolerability of these three drugs abrogated further clinical trials. With appropriate toxicity management and patient selection using validated testing methods, all eligible patients can potentially benefit from this new treatment. Further clinical trials to assess combinations of hormone therapy with PI3K, AKT, mTOR, or CDK 4/6 inhibitors, or studies in men and women with other breast subtypes are ongoing.

P2, N=70, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: May 2020 --> Nov 2020

P1/2, N=30, Active, not recruiting, Vanderbilt-Ingram Cancer Center | Trial completion date: Dec 2020 --> Dec 2021