Among these inhibitors, capivasertib and alpelisib have received approval as targeted therapies for this indication. Additionally, the review discusses key considerations for integrating these inhibitors into clinical practice, such as timing and choice of PI3K/AKT/mTOR inhibitors, and management of treatment toxicities. By examining these different aspects, this review aims to provide valuable insights into optimizing the clinical utility of PI3K/AKT/mTOR inhibitors in HR+ advanced breast cancer.

In our patient with SGC, NGS revealed a GPHN-ALK variant that allowed off-label treatment with alectinib, with a remarkable response in primary and metastatic foci. Similarly, the use of NGS in a cutaneous neoplasm in which no definitive diagnosis could be reached by pathology and which had progressed through standard of care treatment elucidated a PIK3CA mutation in which alpelisib was added and ultimately halted POD. Here, we discuss the use of NGS, future projections, and our recommendations.

P1, N=24, Active, not recruiting, National Cancer Institute (NCI) | Phase classification: P1/2 --> P1 | Trial completion date: Mar 2025 --> Jul 2025

P=N/A, N=15, Active, not recruiting, HealthPartners Institute | Recruiting --> Active, not recruiting

BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor.

P3, N=230, Recruiting, Hoffmann-La Roche | Trial completion date: Oct 2028 --> Jan 2028 | Trial primary completion date: Oct 2028 --> Oct 2026

PIK3CA gene mutations, which are often present in advanced HR+ breast cancer, can be targeted by alpelisib...The proportion of HER2-low status patients suggests potential benefits from novel HER2-targeted therapies. These findings highlight the need for routine molecular diagnostics in Chile to improve personalized treatment and address economic and access challenges.

P2, N=50, Recruiting, Murdoch Childrens Research Institute | Not yet recruiting --> Recruiting

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

P=N/A, N=435, Completed, Novartis

Comparing the rapidly-diffusing, fast target-engaging chemical probe 9 to clinical reversible PI3Kα-selective inhibitors alpelisib, inavolisib and 9r, a reversible analogue of 9, revealed 9's superior potency to inhibit growth (up to 600-fold) associated with sustained suppression of PI3Kα signaling in breast cancer cell lines. Finally, using a simple washout protocol, the utility of the highly-selective covalent PI3Kα probe 9 was demonstrated by the quantification of the coupling of insulin, EGF and CXCL12 receptors to distinct PI3K isoforms for signal transduction in response to ligand-dependent activation. Collectively, these findings along with the novel covalent chemical probes against PI3Kα provide insights into isoform-specific functions in cancer cells and highlight opportunities to achieve improved selectivity and long-lasting efficacy.

Fourteen different articles showed that the use of cytokines and cancer vaccines revealed new possibilities to treat breast cancer with antibodies against PD-1/PD-L1 (pembrolizumab), PI3K/Akt/mTOR (alpelisib and everolimus), CAR T-cell (chimeric antigen receptor), PARP (poly ADP-ribose polymerase), and CTLA4 (cytotoxic T-lymphocyte-associated protein 4), and with representative relevance of changing in tumor microenvironment. Estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) targets show also a high effectivity. In recent years, the release of new strategies has become promising, for changing the microenvironment and de-escalation of therapy based on tumor biology, novel biomarkers, and tumor spread.

We achieved a remarkable response in the metastatic lesions with minor toxicity issues. This case highlights the importance of utilizing up-to-date therapeutic agents and reactive decision-making during personalized cancer treatment.

P2/3, N=230, Recruiting, Novartis Pharmaceuticals | Trial completion date: Nov 2031 --> May 2030 | Trial primary completion date: Nov 2031 --> Oct 2027

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=40, Not yet recruiting, Faeth Therapeutics | N=120 --> 40 | Initiation date: Sep 2024 --> Dec 2024

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

Therapies targeting mutations in this pathway approved in conjunction with endocrine therapy include alpelisib, everolimus and capivasertib...She received nab-paclitaxel/atezolizumab for 4 months, letrozole and abemaciclib for 2 months, letrozole alone for 6 months, and letrozole and ribociclib for 6 weeks. Given presence of PIK3CA mutation, 4th line treatment with fulvestrant and alpelisib was planned...After progressing on capecitabine after 2 months, alpelisib with exemestane was initiated...Due to a low ejection fraction despite work with cardiooncology, she was not a candidate for trastuzumab deruxtecan. She progressed on oral cyclophosphamide and methotrexate after 2 months and Sacituzumab govitecan after 3 months...Comprehensive biomarker assessment is needed to identify patients who may benefit from sequential therapies. There is a need for trials comparing therapies that target the PI3K pathway at distinct points, potential sequencing of these therapies, and the optimal sequence strategy.

P1/2, N=0, Withdrawn, Memorial Sloan Kettering Cancer Center | N=37 --> 0 | Active, not recruiting --> Withdrawn

In patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer, inavolisib plus palbociclib-fulvestrant led to significantly longer progression-free survival than placebo plus palbociclib-fulvestrant, with a greater incidence of toxic effects. The percentage of patients who discontinued any trial agent because of adverse events was low. (Funded by F. Hoffmann-La Roche; INAVO120 ClinicalTrials.gov number, NCT04191499.).

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.

P=N/A, N=6, Completed, Bayer | Active, not recruiting --> Completed | N=50 --> 6

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.

"Foundation Medicine, Inc. today announced that it has received approval from the U.S. Food and Drug Administration (FDA) for FoundationOneLiquid CDx to be used as a companion diagnostic for Itovebi (inavolisib) in combination with palbociclib (Ibrance) and fulvestrant, a therapy developed by Genentech, a member of the Roche group, which has been contemporaneously approved for the treatment of adult patients with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy."

The PK/PD model parameters estimated from the efficacy study, combined with PBPK model-predicted human PK profiles, projected that a dose of 3 mg could lead to clinical response. Inavolisib is currently being tested in phase 3 trials.

P1/2, N=37, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting

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

P1, N=68, Completed, Otto Metzger, MD | Active, not recruiting --> Completed

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.

P1, N=6, Terminated, University of Michigan Rogel Cancer Center | N=35 --> 6 | Trial completion date: Jun 2026 --> Nov 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jun 2025 --> Nov 2023; Loss of study funding

P1, N=79, Completed, Royal Marsden NHS Foundation Trust | Unknown status --> Completed

P2, N=197, Active, not recruiting, Bryan Schneider, MD | Recruiting --> Active, not recruiting

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.

Then, an in silico docking with these lichen-derived metabolites against the PI3Kα receptor predicted these compounds has a binding affinity close to a standard PI3Kα inhibitor copanlisib. The study concludes that the extract restricts lung cancer possibly through the PI3Kα/FOXO1 axis and thus Parmelinella wallichiana represents a potential resource for anti-lung cancer drug development in future.