Piqray (alpelisib)

Activating mutations in PIK3CA are frequently found in estrogen-receptor-positive (ER+) breast cancer, and the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib with anti-ER inhibitors is approved for therapy...Together, our findings uncover a regulatory crosstalk between post-translational modifications that fine-tunes KMT2D function at the chromatin. This provides a rationale for the use of SMYD2 inhibitors in combination with PI3Kα/AKT inhibitors in the treatment of ER+/PIK3CA mutant breast cancer.

The most commonly used methodologies were next-generation sequencing and mutation-/allele-specific qualitative polymerase-chain-reaction-based assays. In summary, this recurrent PIK3CA EQA proved to be a suitable approach for quality assessment in predictive molecular biomarker testing, to obtain an international overview of methods used for PIK3CA mutation analysis and to identify the strengths and weaknesses of individual methods.

Furthermore, 5,7,4'-trimethoxyflavone was verified to bind to LRPPRC, STAT3, and CDK1, dissociating LRPPRC-JAK2-STAT3 and JAK2-STAT3-CDK1 interaction, leading to impaired tumorigenesis in 4-Nitroquinoline N-oxide induced ESCC mouse models and suppressed tumor growth in ESCC patient derived xenograft mouse models. In summary, this study suggests regulation of m6A modification by LRPPRC, and identifies a novel triplex target compound, suggesting that targeting LRPPRC-mediated JAK2/STAT3/MYC axis may overcome JAK2/STAT3/MYC dependent tumor therapeutic dilemma.

Curcumin alone led to dose-dependent responses and when combined with BYL719, positive effects were revealed, as they were when it was combined with MK-1775 or PD-0332991, suggesting a potential use of some of these combinations for HPV+ OPSCC.

In HR+/HER2-/PIK3CA-mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia. Novartis Pharmaceuticals.

Finally, the combination of VTP50469, an inhibitor of the Menin-MLL interaction, and alpelisib synergistically represses PDX tumors harboring PIK3CA mutations. Together, these findings unveil the metabolic link between PIK3CA mutant tumor cells and the IECs, highlighting AA as the potential target for the treatment of patients with CRC harboring PIK3CA mutations.

P3, N=27, Active, not recruiting, Spanish Breast Cancer Research Group | Recruiting --> Active, not recruiting | N=300 --> 27 | Trial completion date: Sep 2026 --> Nov 2024 | Trial primary completion date: Jun 2026 --> Nov 2024

P1, N=32, Recruiting, Columbia University

Body composition measures, specifically SMD and VAT may provide an opportunity to identify patients at higher risk for severe alpelisib related hyperglycemia, and cutaneous toxicity. These findings suggest the potential use of body composition assessment to caution toxicity risk, allowing for personalized therapeutic observation and intervention.

Anaplastic thyroid cancer (ATC), a rare and aggressive malignancy with a poor prognosis, has shown promise with the approved dabrafenib/trametinib combination for BRAFV600E mutation. The combination of trametinib and alpelisib showed promise as a strategy for treating ATC with co-mutations in BRAF and PI3KCA, both in vitro and in vivo. This combination offers insights into overcoming resistance to BRAF-targeted treatments in ATC with mutations in BRAF and PI3KCA.

Approvals for oestrogen receptor-positive advanced breast cancer include the PI3K inhibitor alpelisib for PIK3CA-mutated tumours, the AKT inhibitor capivasertib for tumours with alterations in PIK3CA, AKT1, or PTEN, and the mTOR inhibitor everolimus, which is used irrespective of mutation status. The availability of different inhibitors leaves physicians with a potentially challenging decision over which of these therapies should be used for individual patients and when. In this Review, we present a comprehensive summary of our current understanding of the pathways and the three inhibitors and discuss strategies for the optimal sequencing of therapies in the clinic, particularly after progression on a CDK4/6 inhibitor.

P1, N=500, Active, not recruiting, Eli Lilly and Company | Phase classification: P1a/1b --> P1

Alpelisib represents an active treatment option in patients with recurrent gynecological cancers harboring a PIK3CA mutation. These findings support the need of biomarker-driven randomized trials of PI3K inhibitors in gynecological cancers.

P4, N=100, Recruiting, Novartis Pharmaceuticals | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

Furthermore, differences in AEs emerged between patients with PIK3CA-mutated breast cancer and those with PROS. This study provides vital insights for healthcare professionals to navigate AEs in clinical practice and informs future research for enhancing alpelisib 's safety profile.

Of these, nine received treatment with a molecular target drug: eight patients with a mutation of the PIK3CA gene were treated with alpelisib and fulvestrant; one patient with FGFR1/2 amplifications received TAS120. The growing number of detectable mutations and increased accessibility of the test may lead to a greater number of potential therapeutic implications for the NGS assay. Perspectives suggest that NGS analysis can be implemented in daily clinical practice, particularly in contexts where a Molecular Tumor Board (MTB) is active.

P=N/A, N=60, Recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2024 --> Jun 2024 | Trial primary completion date: Dec 2024 --> Jun 2024

P2, N=69, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=135 --> 69

P1/2; Phase classification: P2 --> P1/2

A risk model using 5 clinically relevant baseline characteristics was able to identify patients at higher or lower probability for developing alpelisib-induced hyperglycemia. Early identification of patients who may be at higher risk for hyperglycemia may improve management (including monitoring and early intervention) and potentially lead to improved outcomes.

However, following the breast cancer-specific FDA approvals of alpelisib+fulvestrant for PIK3CA-mutant disease in 2019 and elacestrant for ESR1-mutant disease in 2023, a significant shift in Level 1 actionability was observed between EUR (45%) and AFR (34%) attributed in part to the paucity of PIK3CA (26.3% vs. 36.2% in EUR) and ESR1 (4.1% vs. 7.5% in EUR) oncogenic alterations in AFR.We further observed AFR with CRC to have lower prevalence of MSI-H (5.8% vs.10.7% in EUR), TMB (12.5% vs. 18.8% in EUR) and BRAF V600E (5.1% vs. 9% in EUR). Correspondingly, in 2023, 16.4% of AFR with CRC have Level 1 alterations compared to 25.4% of EUR. Moreover, while AFR have higher rates of KRAS mutations (57.2% vs. 42.6% in EUR), they have a lower prevalence of the standard care biomarker KRAS G12C (3.4% vs. 7% of KRAS-mutant CRC in EUR) further exacerbating the disparities in CRC clinical actionability.Taken together, here we demonstrate that a significant disparity exists in the clinical actionability landscape of AFR with cancer compared to EUR, largely due to differences in relative mutational frequencies of Level 1 genomic alterations.

P1/2, N=52, Recruiting, SynDevRx, Inc. | Phase classification: P1b/2 --> P1/2

Tumors with PIK3CA mutation found in either tumor and/or plasma are candidates for PI3K inhibitor (eg. Alpelisib) by applying PCR based method- or sequencing...Another recent phase lll trial randomizing patients to switch to fulvestrant + CDK4/6i from aromatase inhibitor + CDK4/6i at time of plasma ESR1 mutation positive or stay on AI + CDK4/6i, reported longer progression survival for early switch to fulvestrant...AKT inhibitor (eg.Capivasertib) has recently been approved for patients with PI3K/AKT/PTEN pathway alteration including PTEN loss, AKT activating mutation and the renown PI3KCA mutations...While liquid biopsy technology holds promise for both advanced and early breast cancers for its ability to potentially identify patients and guide decisions, it is crucial to select appropriate method for each clinical setting and purposes. With limited number of studies investigating the relevant correlation/comparison between each methods and pipelines, clinicians should bear in mind to deeply understand each methodology selected for each clinical trials before bringing them into real patients.

P3, N=234, Recruiting, Novartis Pharmaceuticals | Trial completion date: Sep 2026 --> Aug 2027 | Trial primary completion date: Aug 2026 --> Aug 2025

P3, N=20, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Apr 2024 --> Sep 2024 | Trial primary completion date: Apr 2024 --> Sep 2024

P2, N=15, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=106 --> 15

A radiosensitizing effect can be confirmed after treatment with AZD0156, Afatinib or Alpelisib in three organoid lines using this assay so far. Establishment of HNSCC organoids was successful using our workflow. These 3D models can be used to screen for potential radiosensitizers. For validation, we established an organoid formation assay to determine the clonogenic survival as an important endpoint in radiobiology.

P2, N=51, Recruiting, GOG Foundation | Not yet recruiting --> Recruiting

We focused on assessing whether pretreating cells with inhibitors for phosphatidylinositol 3-kinase (PI3K) and mammalian target for rapamycin (mTOR) could enhance the antiproliferative effects of lanreotide...Additionally, combination treatment consisting of BYL719 and everolimus plus lanreotide tested in NCI-H720 and NCI-H727 led to diminished cell proliferation in a dose-dependent manner...Interestingly, SSTR expression reinduction could be exploited in therapeutic and diagnostic applications. The overall results of this study support the evaluation of combination-based therapies using lanreotide in preclinical studies to further increase its antiproliferative effect and ultimately facilitate its use in high-grade tumors.

Binding affinities predicted via thermodynamic integration (TI) are in good agreement with previously reported IC50s. Yet, computationally demanding techniques such as TI might not always be the most efficient approach for affinity prediction, as in our case study, fast high-throughput techniques were capable of classifying compounds as active or inactive, and one docking approach showed accuracy comparable to TI.

P3, N=358, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=50, Not yet recruiting, Murdoch Childrens Research Institute | N=30 --> 50 | Trial completion date: Sep 2028 --> Nov 2026 | Initiation date: Sep 2023 --> Apr 2024 | Trial primary completion date: Sep 2026 --> Jun 2026

P3, N=287, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

Liquid biopsy holds significant promise for improving precision treatment and tumor prognosis in colorectal cancer patients. The combination of biomarker-based drug prediction with organoid-based functional drug sensitivity assay may lead to more effective cancer treatment.

The mechanistic studies in dynamic mode further endorsed the potential of identified hits in blocking the ATP-binding site of the receptor with higher binding affinities than the native inhibitor, alpelisib (BYL-719), particularly the compounds 1, 2, and 11. These outcomes support the reliability of the developed classification model and the devised computational strategy for identifying new isoform-selective drug candidates for PI3Kα inhibition.

We used combination of PI3K inhibitor- Alpelisib (BYL719) and ICA-1 (a PKC-ι-specific 5-amino-1-2,3-dihydroxy-4-(methylcyclopentyl)-1H-imidazole-4-carboxamide). The decreased level of N-cadherin, p-vimentin, and vimentin and the increased level of E-cadherin confirm reduced malignancy. Therefore, implementing a combination of Alpelisib and a PKC-ι inhibitor is an effective approach to reducing cell proliferation, and invasion that eventually induces apoptosis and may be considered as a potential therapeutic option in ccRCC.

Here, we investigated the radiochemosensitizing potential and adaptation mechanisms of four PI3K inhibitors, Alpelisib, Copanlisib, AZD8186, and Idelalisib in eight HNSCC models grown under physiological, three-dimensional matrix conditions. Finally, we demonstrate that targeting of the cell adhesion molecule β1 integrin on top of Alpelisib sensitizes non-responders to radiochemotherapy. Taken together, our study demonstrates the sensitizing potential of Alpelisib and other PI3K inhibitors in HNSCC models and uncovers a novel β1 integrin-dependent mechanism that may prove useful in overcoming resistance to PI3K inhibitors.

Importantly, targeted inhibition of the check-point inhibitor CHK1 with MK-8776 effectively caused death of p21-high T47D cells, thus establishing a new vulnerability of BYL719-resistant breast cancer cells. Together, our integrated studies uncover hidden molecular mediators causing resistance to PI3Kα inhibition and provide a framework to prioritize combination therapies for PI3K-mutant breast cancer.

Progressive vascular malformations in the pediatric population can be hard to diagnose and treat and are thought to arise from somatic mutations. Our case highlights a patient with progressive malformation despite multiple surgical resections who was successfully treated with targeted immunotherapy after proper identification of genetic mutation.

P1, N=0, Withdrawn, OHSU Knight Cancer Institute | N=25 --> 0 | Not yet recruiting --> Withdrawn

This study reveals the prevalence, clinicopathology, and molecular features of HPV-ind CCs and emphasizes the importance of PIK3CA mutations and PI3K pathway activation in tumorigenesis, which suggests the potential significance of PI3Kα inhibitors in HPV-ind CC patients.

Background: PIK3CA mutations occur in ~40% of HR-positive breast cancers, where alpelisib, an orthosteric PI3Kα inhibitor, is FDA-approved in combination with fulvestrant... To identify on-target and off-target alterations potentially mediating resistance to PI3Kα inhibitors, we used a targeted next-generation sequencing assay (Guardant360; Guardant Health) to analyze ctDNA in serially collected plasma samples from 32 patients with PIK3CA-mutated advanced HR-positive, HER2-negative breast cancer treated with alpelisib and inavolisib...Some mutations had differential effects on PI3Kaselective vs. pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Ka-inhibitor RLY-2608... In one of the largest patient cohorts analyzed to date, this study defines the clinical landscape of acquired resistance to PI3Ka inhibitors. Genomic alterations within the PI3K pathway represent a major mode of resistance and identify a novel class of secondary PIK3CA resistance mutations that can be overcome by an allosteric PI3Ka inhibitor. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers.