Piqray (alpelisib)

P2, N=24, Active, not recruiting, Novartis Pharmaceuticals | Trial primary completion date: Jan 2025 --> Jul 2025

P2, N=69, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Feb 2025 --> Aug 2025

Mutational hotspots are a recurrent feature in both genes which, due to positive selection during tumorigenesis, can be potentially exploited by targeted treatments, as has been demonstrated by the US Food and Drug Administration (FDA)-approved PI3K inhibitor alpelisib in advanced hormone-receptor positive (HR+) breast cancer... The AGENA ClearSEEK PIK3CA and TP53 Panels combine low hands-on time requirements with accurate data assessment, and provide a reliable tool for clinical trial evaluation of known actionable PIK3CA mutations and response to PI3K inhibitors in breast cancer, as well as for investigating the oncogenic activities of TP53 hotspot mutations and patient selection e.g., for cell cycle targeting therapies.

P2, N=15, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

P2, N=44, Recruiting, Marina N Sharifi | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Sep 2024 --> Sep 2025

By comparing eribulin-resistant breast cancer cell lines, we confirmed that BYL-719 could effectively overcome drug resistance. Finally, we believe that drug resistance can be overcome by targeting the BCSCs. Conjugation of BYL-719 with other anti-neoplastic agents may be a promising treatment for this in clinic.

Targeting this pathway has been approved as a therapeutic option for breast cancer and lymphoma (e.g. alpelisib, idelalisib), and there are several clinical trials underway in additional types of cancer...We report the case of a 53-year-old female with metastatic breast cancer who developed acute grade 3 hyperglycemia from a novel PI3K inhibitor, inavolisib...All patients treated with PI3K inhibitors should receive pre-treatment screening for hyperglycemia, lifestyle advice, and a glucometer to measure fasting BGL and 2-h post-dinner BGL levels twice per week for at least the first 30 days of treatment. Insulin or insulin secretagogues (e.g. sulfonylurea) may inhibit the anti-tumor activity of PI3K inhibitors, and thus treatment of PI3K inhibitor-associated hyperglycemia should prefer alternative approaches such as a low carbohydrate diet, metformin, SGLT2i, or dose reduction of the PI3K inhibitor.

Alpelisib (ALP) is a novel phosphoinositide-3-kinase (PI3K) inhibitor recently approved for human receptor-positive, human epidermal growth factor receptor 2-negative, PIK3CA-mutated metastatic breast cancer in combination with fulvestrant. The environmental impact of both methods was assessed using AGREE software and scores for CE and HPLC were calculated to be 0.74 and 0.51, respectively. Because of equally reliable analytical performance and greener analysis, CE should be considered as an alternative technique to HPLC in the analysis of ALP pharmaceutical dosage forms.

Our findings support that targeting PLK1 and PI3Kα with onvansertib and alpelisib, respectively, may be a promising strategy for patients with PIK3CA-mutant HR+ breast cancer failing ET + CDK4/6i therapies and warrant clinical evaluation.

Our findings highlight the potential of this innovative therapeutic combination, suggesting a need for further investigations in this setting.

P1, N=155, Recruiting, Olema Pharmaceuticals, Inc. | N=90 --> 155 | Trial completion date: Aug 2024 --> Jun 2026 | Trial primary completion date: Aug 2024 --> May 2026

P1/2, N=255, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2024 --> Jun 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

Compounds 3b and 3e were further evaluated for their in vitro inhibitory activities against PI3Kα and mTOR compared to alpelisib and dactolisib, respectively as reference drugs. Molecular docking experiments provided additional explanation for these results by demonstrating the ability of these derivatives to form a network of key interactions, known to be essential for PI3Kα/mTOR inhibitors. All these experimental results suggested that 3b and 3e are potential PI3Kα/mTOR dual inhibitors and could be considered promising lead compounds for the development of anticancer agents.

This study provides pre-clinical evidence that AKT inhibitors combined with PI3K inhibitors, cisplatin, or vincristine exhibit additive/synergistic anti-MB activity, and lower doses could be used. The latter also applied to one MB line grown as spheroids, further supporting their future potential use.

P3, N=19, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

Our findings expand the understanding of the molecular profile of the HER2L subgroup and comparison to the classically defined breast cancer subgroups. Genomic risk assessments after progression on novel therapeutics can be assessed to better define implications for mechanisms of resistance.

This research systematically identified biomarkers related to NB prognosis and developed a reliable prognostic model applying WGCNA and multiple bioinformatics methods. The model has important application value in predicting patients' prognosis, evaluating drug sensitivity and immunotherapy effect, and provides new ideas and directions for precise treatment of neuroblastoma.

Herein, we investigated combined blockade of the CDK4/6 and PI3K signaling with palbociclib, alpelisib, and capivasertib, which inhibit CDK4/6, PI3Kα, and AKT1-3, respectively...The AR antagonist enzalutamide was inactive against MDA-MB-453, MFM-223, and CAL148 cells and did not enhance the efficacy of either combination...Finally, treatment with palbociclib and the PDGFR inhibitor CP637451 arrested growth of MDA-MB-453 and MFM-223 cells to the same degree as palbociclib/capivasertib. These findings support testing the combination of CDK4/6 and AKT inhibitors in patients with LAR TNBC, and further investigation of PDGFR antagonists in this breast cancer subtype.

Imlunestrant, as monotherapy or in combination with targeted therapy, had a manageable safety profile with evidence of preliminary antitumor activity in ER+/HER2- ABC.

P2, N=24, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jan 2025 --> Jul 2025

This study provides safety data for an oral combination therapy of alpelisib-capecitabine and defines tolerable doses for further study.

P3, N=234, Recruiting, Novartis Pharmaceuticals | Trial completion date: Aug 2027 --> Dec 2027 | Trial primary completion date: Aug 2025 --> Dec 2025

These data suggest adding an SGLT2i can effectively manage hyperglycemia, resulting in fewer alpelisib dose modifications and discontinuations in patients with PIK3CA-mutated HR+ /HER2- ABC (SOLAR-1: NCT02437318; BYLieve: NCT03056755).

The first orally active PI3K inhibitor, Alpelisib (BYL-719) in fulvestrant combination, was approved for treating HR+/ HER2- metastatic BC. Therefore, utilizing PI3K/mTOR/AKT inhibitors in combination with currently available strategies could be an optimistic approach to overcoming drug resistance and resensitizing drug-resistant tumor cells of BC. Here, in this perspective, BC cancer therapies related to drug resistance, the involvement of PI3K/AKT/mTOR pathway in drug resistance and multi-drug resistance, and the role of PI3K/AKT/mTOR inhibitors in getting rid of drug resistance have been illuminated.

P2, N=1, Terminated, Memorial Sloan Kettering Cancer Center | N=63 --> 1 | Trial completion date: Jul 2026 --> Aug 2024 | Recruiting --> Terminated | Trial primary completion date: Jul 2026 --> Aug 2024; Limited amount of eligible participants

P=N/A, N=60, Completed, Novartis Pharmaceuticals | Recruiting --> Completed

P1/2, N=50, Not yet recruiting, M.D. Anderson Cancer Center

Our data indicate that combination of TUC and IR could be more effective than single treatment strategies for BC. Thereby, treatment sequence seems to be an important factor. The lower sensitivity to TUC in NSCLC and particularly in CRC (compared to BC) implicates, that tumor promotion there might be less HER2-related. Combination with inhibitors of other driver mutations may aid in overcoming partial TUC resistance. These findings are of high relevance to improve long-time prognosis especially in brain-metastasized situations given the intracranial activity of TUC.

P1, N=25, Recruiting, Assistance Publique Hopitaux De Marseille | Unknown status --> Recruiting | Trial completion date: Sep 2022 --> Jan 2026 | Trial primary completion date: Sep 2022 --> Jan 2026

Using a combination of functional and metabolic assays, we evaluated a panel of PC cell lines with different PTEN/PIK3CA status for their sensitivity to multi-node PAM inhibitors (PI3K/mTOR: gedatolisib, samotolisib) and single-node PAM inhibitors (PI3Kα: alpelisib; AKT: capivasertib; mTOR: everolimus). Gedatolisib, as a single agent and in combination with other therapies, reported promising preliminary efficacy and safety in various solid tumor types. Gedatolisib is currently being evaluated in a Phase 1/2 clinical trial in combination with darolutamide in patients with mCRPC previously treated with an AR inhibitor, and in a Phase 3 clinical trial in combination with palbociclib and fulvestrant in patients with HR+/HER2- advanced breast cancer.

She was subsequently started on Alpelisib with Fulvestrant, however, Alpelisib was discontinued due to hyperglycemia. Arimidex was also started but was eventually discontinued due to worsening lung nodules on PET/CT...She was started on Venetoclax and Azacitidine, her pancytopenia improved, however, has overall poor prognosis...Gemcitabine's anti-AML activity and short-term exposure for other treatments make them unlikely to trigger t-AML. This report encourages analysis of long-term genotoxic side-effects of Palbociclib in breast cancer management and bone marrow biopsy is crucial when prolonged pancytopenia exists post treatment.

Alpelisib (inhibiting PI3Kα), copanlisib (inhibiting PI3Kα andPI3Kδ), duvelisib (inhibiting PI3Kδ and PI3Kγ), and idelalisib (inhibitingPI3Kδ) were developed to target the PI3K pathway...The safety profiles of the five PI3K inhibitorsvary concerning adverse events. These findings could guide drug selection andinform future prospective research.

P3, N=137, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Sep 2024 --> Jan 2025

There were no clinically relevant drug-drug interactions observed between alpelisib and capecitabine. The combination of alpelisib and capecitabine is generally tolerated, without pharmacokinetic interactions, and shows antitumor activity in patients with PIK3CA mutant advanced cancers.

P1, N=46, Active, not recruiting, Vanderbilt-Ingram Cancer Center | Trial completion date: May 2024 --> Feb 2025

In addition, antibacterial activity showed that compounds 11 and 12 were the most active against Staphylococcus aureus. Compound 6a is a promising molecule that could be a lead candidate for further studies.

P2, N=19, Active, not recruiting, Stanford University | Recruiting --> Active, not recruiting | N=150 --> 19

Although anti-HER2 therapy has made significant strides in reducing metastasis and relapse in HER2-positive breast cancer, resistance to agents like trastuzumab, pertuzumab, and lapatinib frequently develops in patients undergoing treatment...Furthermore, the efficacy of PI3K PROTAC surpassed that of Alpelisib, a selective PI3K-p110α kinase inhibitor in clinic. The superior performance of PI3K PROTAC was also confirmed in lapatinib-resistant breast cancer xenograft tumors and patient-derived breast cancer organoids (PDOs). In conclusion, this study reveals that the novel PI3K PROTAC we synthesized could serve as an effective agent to overcome lapatinib resistance.

P2/3, N=230, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jan 2030 --> Nov 2031 | Trial primary completion date: Jan 2030 --> Nov 2031

Mutational hotspots are a recurrent feature in both genes which, due to positive selection during tumorigenesis, can be potentially exploited by targeted treatments, as has been demonstrated by the FDA-approved PI3K inhibitor alpelisib in advanced hormone-receptor positive (HR+) breast cancer... The Agena ClearSEEK PIK3CA and TP53 Panels combine low hands-on time requirements with accurate data assessment and provide a reliable tool for clinical trial evaluation of known actionable PIK3CA mutations and response to PI3K inhibitors in breast cancer, as well as for investigating the oncogenic activities of TP53 hotspot mutations and patient selection, e.g., for cell cycle targeting therapies.

Among the PIK3CA mutations, 78% were canonical (included in the alpelisib companion diagnostic non-NGS test), while the remaining 22% were characterized as non-canonical mutations (identifiable only by NGS test)...We describe the genomic landscape of Brazilian patients with ER+/HER2- MBC, in which the somatic mutation profile is comparable to what is described in the literature globally. These data are important for developing precision medicine strategies in this scenario, as well as for health systems management and research initiatives.

Although multiple compounds have been developed, at present, there are just three inhibitors approved to target this pathway in patients with advanced ER-positive, HER2-negative breast cancer: everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor). Herein, we review the common mechanisms of resistance to agents that target the PI3K/AKT/mTOR signalling pathway, elaborate on current management approaches, and discuss ongoing clinical trials attempting to mitigate this significant issue. We highlight the need for additional studies into AKT1 inhibitor resistance in particular.