Piqray (alpelisib) / Novartis - LARVOL DELTA

Alpelisib Therapy in 2 Patients With Congenital Hyperinsulinism. (PubMed, JCEM Case Rep) - "Alpelisib shows promise as both an adjunctive and primary therapy for CHI, improving glucose levels and reducing dependence on continuous feeding and other medications. Randomized controlled trials are needed to assess its long-term safety and efficacy for CHI."

Journal • Hypoglycemia • Inherited Retinal Dystrophy • Ophthalmology • Severe Hypoglycemia • KCNJ11

ETX-636, a novel allosteric pan-mutant-selective PI3Kα dual inhibitor and degrader with best-in-class potential (AACR 2025) - "Orthosteric ATP-competitive inhibitors, alpelisib and inavolisib, which inhibit both Wild-type (WT) and mutant PI3Kα, are approved in combination regimens for treating PIK3CA-mutant, HR+/HER2-, advanced or metastatic BrCA...In addition to greater biochemical selectivity for mutant PI3Kα over WT PI3Kα, ETX-636 has stronger target binding affinity, better on-target potency in biochemical and cellular pharmacodynamic assays, and demonstrates superior anti-tumor activity in vivo when compared to other allosteric, pan-mutant-selective PI3Kα inhibitors (i.e. RLY-2608 and STX-478)...In an ER-positive, HER2-negative, PI3Kα-mutant BrCA xenograft, ETX-636 is efficacious as a single agent and shows synergistic activity with fulvestrant, inducing tumor regression while being well-tolerated...In addition, based on pharmacokinetic, pharmacodynamic, efficacy, and toxicology studies, predicted human efficacious doses of ETX-636 are not projected to cause hyperglycemia. The preclinical..."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA • ER • HER-2 • PIK3CA

Clinical investigators' (CIs) practice patterns for patients with hormone receptor-positive metastatic breast cancer (HR+ mBC) harboring PI3K/AKT/PTEN pathway abnormalities (PAPm). (ASCO 2025) - "The recent availability of capi and inavo has significantly affected current practice patterns, with the majority of CIs rapidly incorporating these therapies into their treatment algorithms for specific patient types. Future work is needed to explore how other factors (eg, age, comorbidities, HER2-low status) and rapidly emerging clinical trial findings (eg, EMBER-3) affect decision-making. A = anastrozole; IPF = inavolisib + palbociclib + fulvestrant; F = fulvestrant; AI = aromatase inhibitor; C = capivasertib; Alp = alpelisib; E = elacestrant"

Clinical • Metastases • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA • PTEN

Treatment patterns in HR+/HER2- metastatic breast cancer (MBC) with co-occurring PIK3CA and ESR1 mutations. (ASCO 2025) - "Clinical and treatment data, including PI3Ki (alpelisib, inavolisib or investigational agents) and/or SERDs (fulvestrant or oral agents) were abstracted. Prior CDK4/6i ≥ 12 m in patients with co-occurring mutations treated with a SERD was associated with significantly improved PFS, potentially reflecting a conditioning effect of prior therapy. The total PFS (PFS1 + PFS2) in patients treated with sequential targeted therapies was similar; however, small sample sizes and potential confounders in this retrospective cohort limit definitive interpretations. Larger prospective studies are needed to determine optimal sequencing strategies."

Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • ER • HER-2 • PIK3CA

A single center experience of PIK3CA and AKT inhibitors in patients with hormone receptor positive metastatic breast cancer. (ASCO 2025) - "Funded by No funding sources reported Background: Currently there are 3 FDA- approved PI3K/AKT inhibitors: alpelisib, capivasertib and inavolisib...In addition, 12 pts received alpelisib or capivasertib after everolimus and mPFS of were 5.8m... The single center experience of PIK3CA/AKT inhibitors reflected clinical trial result with similar PFS. A lower rate of dose interruptions and lower rate of all grades diarrhea were observed in the real-world data. Prophylactic use of antidiarrhea agents may contribute to the finding although precautions need to be taken due to the retrospective chart review nature of this study."

Clinical • Metastases • Breast Cancer • Dermatology • Diabetes • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • PIK3CA

Enhanced efficacy of inavolisib combined with anti-PD-1 or anti-HER2 antibody in treating brain metastases from breast cancer. (ASCO 2025) - "Alpelisib is the only approved PI3K inhibitor for treating PIK3CA mutation-positive breast cancer...In addition to the Inavolisib monotherapy and vehicle control groups, Inavolisib was combined with a PD-1 antibody or albumin-bound paclitaxel in the triple-negative model...However, overall, the combination with trastuzumab achieved unexpectedly good results, which were comparable to SHR-A1811 and superior to Tucatinib... Our findings suggest that the combination of the PI3K inhibitor Inavolisib with anti-PD-1 or anti-HER2 antibody therapy may offer an effective strategy for treating brain metastases in breast cancer. This discovery provides new insights and possibilities for improving treatment options in breast cancer brain metastasis. Further research is needed to validate the efficacy and safety of this combination therapy."

Clinical • IO biomarker • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • PIK3CA • PTEN

Phase Ib study of inavolisib (INAVO) + weekly paclitaxel (wP) in patients (pts) with locally advanced/metastatic (LA/m) incurable solid tumors: Safety, pharmacokinetics (PK), and preliminary antitumor activity. (ASCO 2025) - "However, it has an unfavorable benefit–risk profile when given with pan-PI3K inhibitors or alpelisib. INAVO, a potent and selective PI3Kα inhibitor that also promotes mutated p110α degradation, was FDA approved in combination with palbociclib + fulvestrant for hormone receptor-positive, HER2-negative (HR+, HER2–), endocrine-resistant advanced breast cancer (BC) following recurrence on/after completing adjuvant endocrine therapy... In CO42800, INAVO + wP was well tolerated in pts with LA/m solid tumors, including those with a PIK3CA mutation, with no new safety signals or drug–drug interactions observed. Encouraging preliminary antitumor activity shown in pts with HR+, HER2– BC or TNBC supports further investigation."

Clinical • Metastases • P1 data • PK/PD data • Anemia • Breast Cancer • Diabetes • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Neutropenia • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PIK3CA

First report of successful pregnancies after treatment with alpelisib for PIK3CA-related overgrowth spectrum. (PubMed, Eur J Hum Genet) - "Although disease progression was observed in all three patients during pregnancy, vascular malformations remained sensitive to alpelisib without evidence of secondary resistance upon resuming treatment. In conclusion, we provide the first evidence that alpelisib does not appear to affect fertility in female patients with PROS."

Journal • PIK3CA

Molecular profiling in targeted therapy of gliomas in a community setting. (ASCO 2025) - "Accordingly, 11 patients received targeted therapy: 3 patients olaparib (RAD51C, BRCA2, H3.3 G34), 2 pembrolizumab (TMB high), 1 ivosidenib (IDH1), 1 selumetinib (NF1), 1 alpelisib (PIK3CA), 1 erdafitinib (FGFR3), 1 trametinib (NF1) and 1 dabrafenib/trametinib (BRAF) and then everolimus (TSC2). Molecular profiling nowadays is not only mandatory in glioma classification but can also provide additional therapies in patients with limited options."

IO biomarker • Tumor mutational burden • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • High Grade Glioma • Oligodendroglioma • Oncology • Solid Tumor • ATRX • BRAF • BRCA2 • EGFR • FGFR3 • IDH1 • MSI • NF1 • PD-L1 • PIK3CA • PTEN • RAD51C • TERT • TMB • TP53 • TSC2

management of an adrenal cortical carcinoma induced non-islet cell tumor hypoglycemia: a case report (ENDO 2025) - "She was started on adjuvant mitotane, and chemotherapy (cisplatin, etoposide, and doxorubicin) which induced cardiomyopathy...Osilodrostat was initiated for Cushing syndrome...Patient had recurrent severe hypoglycemic episodes, which were refractory to increasing carbohydrate intake, high-dose prednisone, and octreotide...She also received pasireotide 60mg and diazoxide 5mg/kg every 8 hours...Upon applying for alpelisib approval, her clinical status rapidly declined, and she died after 3 months of NITCH diagnosis...IGF2-mediated hypoglycemia was refractory to numerous therapeutic interventions, including paseriotide, pembrolizumab, olaparib, ivosidenib, and cabozantinib. This case emphasizes rare manifestations of metastatic ACC and limitations of existing medical therapies for NITCH."

Case report • Clinical • Adrenal Cortex Carcinoma • Cardiomyopathy • Cardiovascular • Cushing’s Disease • Diabetes • Endocrine Disorders • Hypoglycemia • Metabolic Disorders • Oncology • Pancreatic Cancer • Severe Hypoglycemia • Solid Tumor • IGF1 • IGF2

Targeting Semaphorin 7a signaling in preclinical models of estrogen receptor-positive breast cancer. (PubMed, bioRxiv) - "Our studies propose inhibition of a novel target in estrogen receptor-positive (ER+) breast cancer (BC) with an anti-Semaphorin 7a (SEMA7A) monoclonal antibody (SmAbH1). We show efficacy of SmAbH1 as a single agent and in combination with endocrine therapy in preclinical models. We also show that targeting of SEMA7A signaling, including the use of well-known and novel PI3K inhibitors, could be an effective treatment strategy for patients with SEMA7A+ BC, particularly in combination with standard of care. Our mechanistic studies detail the cellular signaling pathway activated by SEMA7A and support the further investigation of these novel drug combinations for clinical use. Further, SEMA7A is a biomarker for poor prognosis and decreased patient survival, posing the need for a clinical diagnostic test for SEMA7A levels in BC patients, which we are currently developing."

Journal • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • SEMA7A

Utilizing Continuous Glucose Monitoring to Characterize and Manage Hyperglycemia in Patients Initiating Alpelisib (clinicaltrials.gov) - P=N/A | N=15 | Active, not recruiting | Sponsor: HealthPartners Institute | Trial completion date: Jun 2025 ➔ Oct 2025 | Trial primary completion date: Jun 2025 ➔ Jan 2025

Trial completion date • Trial primary completion date • Breast Cancer • Diabetes • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

Association of mitotic circulating tumor cells with clinical outcomes in metastatic breast cancer. (ASCO 2025) - "Interestingly at 2 years, a sole non-progressive pt with a mitotic CTC was receiving alpelisib (a specialized PI3KCA inhibitor). Overall, the detection of CTCs indicated poor outcomes in pts, with mitotic CTCs correlating with significantly more aggressive disease and further reduced survival rates regardless of systemic therapy type. This study highlights the need for larger, more comprehensive studies to expand upon and validate these findings."

Circulating tumor cells • Clinical • Clinical data • Metastases • Tumor cell • Breast Cancer • Oncology • Solid Tumor • CTCs • PTPRC

Comparison of PI3K Inhibitor Versus AKT Inhibitor on Hyperglycemia with Continuous Glucose Monitoring in Metastatic Breast Cancer (ENDO 2025) - "Clinical Case: A 59-year-old woman with a history of T2DM, diastolic heart failure, and metastatic breast cancer (ER+, PR+, HER2+), was started on alpelisib 250 mg daily in combination with fulvestrant after a liquid biopsy analyzing tumor biomarkers confirmed a PIK3CA (H1047R) mutation. Her diabetes was previously well-managed with metformin extended release, yielding a glucose management indicator (GMI) of 5.6%...Alpelisib was stopped and empagliflozin 10 mg daily was started, and glycemia normalized four days later (average glucose of 120 mg/dL)... This case underscores the pronounced hyperglycemic effects of alpelisib, emphasizing the need for diligent monitoring and management of glycemia. Options to manage hyperglycemia from PI3K inhibitors are limited as medications binding to the insulin receptor can activate the PI3K tissue proliferation cascade. The transition to capivasertib improved her glycemic control and highlights the importance of individualized cancer..."

Metastases • Breast Cancer • Cardiovascular • Congestive Heart Failure • Diabetes • Heart Failure • HER2 Breast Cancer • HER2 Positive Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • Type 2 Diabetes Mellitus • HER-2 • IR • PGR • PIK3CA

The impact of ethnicity on benefit from novel drugs approved for breast cancer treatment: a systematic review and meta-analysis of randomized phase 3 trials of the last decade. (SABCS 2024) - "23 phase III RCTs were identified in the aBC setting, with 1547 (11.1%) patients of Asian ethnicity. Experimental drugs tested included CDK4/6i (palbociclib, ribociclib, abemaciclib), SERD (elacestrant), PI3Ki (alpelisib), PARPi (olaparib, talazoparib), broad variety of anti-HER2 drugs (tucatinib, trastuzumab deruxtecan, pertuzumab, T-DM1, neratinib, margetuximab), anti-PD-1 and anti-PD-L1 drugs (pembrolizumab, atezolizumab) and anti-TROP2 drug (sacituzumab govitecan). 16 RCTs provided HR (95%CI) for PFS in the subgroup of Asians and 17 RCTs for Non-Asians."

IO biomarker • P3 data • Retrospective data • Review • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

Elacestrant combinations in patients (pts) with ER+/HER2- locally advanced or metastatic breast cancer (mBC): Safety update from ELEVATE, a phase (Ph) 1b/2, open-label, umbrella study. (ASCO 2025) - P1/2 | "ELEVATE (NCT05563220) evaluates Ela in combination with everolimus (Eve), alpelisib (Alp), capivasertib (Capi), ribociclib (Ribo), palbociclib (Palbo), or abemaciclib (Abema) to address different resistance mechanisms. Elacestrant combinations continue to demonstrate safety consistent with the known profiles of each drug + SOC ET without increased risk of associated AEs. Elacestrant has the potential to become an ET backbone for multiple targeted agents, providing an all-oral treatment option in pts with ER+/HER2- mBC, delaying chemo or ADC-based regimens. Treatment-emergent AEs (≥30%).*Combined terms; †Maculopapular rash."

Clinical • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • ER • HER-2

Managing Capivasertib Induced Hyperglycemia in a Patient with Pre-Existing Type 2 Diabetes (ENDO 2025) - "The AKT inhibitor, capivasertib, has been approved by the US Food and Drug Administration (FDA) in combination with fulvestrant in the treatment of HR+, HER2- breast cancer...Clinical Case: A 71-year-old woman with class I obesity, type 2 diabetes, and metastatic ER+/PR+/HER2- breast cancer with osseous metastases and PIK3CA mutation, was started on alpelisib... Therapeutic agents that target the PI3K/AKT/mTOR signaling pathway are increasingly common in breast cancer treatment. Hyperglycemia is prevalent with aleplisib, the first FDA approved PI3K inhibitor, occurring in 64% of patients in the SOLAR-1 trial. While management of PI3K inhibitor associated hyperglycemia remains under investigation, low carbohydrate diets and oral antiglycemic agents have been reported."

Clinical • Breast Cancer • Diabetes • Genetic Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Metabolic Disorders • Obesity • Oncology • Solid Tumor • Type 2 Diabetes Mellitus • HER-2 • PGR • PIK3CA

Elacestrant (Ela) combinations with ribociclib (Ribo) and everolimus (Eve) in patients (pts) with ER+/HER2- locally advanced or metastatic breast cancer (mBC): Update from ELEVATE, a phase (Ph) 1b/2, open-label, umbrella study. (ASCO 2025) - P1/2 | " ELEVATE evaluates Ela in combination with everolimus (Eve), alpelisib (Alp), capivasertib (Capi), ribociclib (Ribo), palbociclib (Palbo), or abemaciclib (Abema) to address different resistance mechanisms. Elacestrant plus Ribo or Eve demonstrates promising Ph 1b efficacy in pts with ER+/HER2- mBC with progressive disease after ET+CDK4/6i in all patients. Ela 345 mg + Ribo 400 mg QD was determined as the RP2D. Previously, Ela 345 mg + Eve 7.5 mg was identified as the RP2D."

Clinical • Metastases • P1/2 data • Breast Cancer • Dental Disorders • Fatigue • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Neutropenia • Oncology • Solid Tumor • Stomatitis • CDK4 • ER • HER-2

Single center study of efficacy and safety of capivasertib in hormone receptor–positive (HR+), HER2-negative metastatic breast cancer (MBC). (ASCO 2025) - "Our findings suggest that capivasertib could be an option for pts previously treated with alpelisib, with a manageable toxicity. The shorter PFS observed in our study compared to the CAPItello-291 trial is likely due to relatively short follow-up period, with 13 pts still on treatment at last follow-up, and the inclusion of a heavily pretreated population, many of whom had received multiple lines of chemotherapy, including T-DXd."

Clinical • Metastases • Anorexia • Breast Cancer • Diabetes • Fatigue • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA • PTEN

Targeted agents for the treatment of hormone receptor–-positive, human epidermal growth factor receptor 2–negative metastatic breast cancer (HR+/HER2- MBC) with co-alterations in ESR1 and AKT pathway: A retrospective analysis. (ASCO 2025) - "Tumors with an ESR1m are targeted with elacestrant (E), and those with alterations in PIK3CA, AKT, or PTEN are candidates for capivasertib (C) or, if PIK3CAm, alpelisib (A). In this real-world cohort, pts with HR+/HER2- MBC with co-alterations in ESR1 and AKT pathway, mTOT was longest with A, with the caveat that A treated pts received the fewest prior lines of therapy. mOS was significantly longer in those who received E vs those who did not. Analysis of pts receiving E+A/C was limited by small sample size and optimal sequencing should be studied in randomized prospective clinical trials."

Metastases • Retrospective data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA • PTEN

EPIK-B5: Study to Assess the Efficacy and Safety of Alpelisib Plus Fulvestrant in Participants With HR-postitive (HR+), HER2-negative, Advanced Breast Cancer After Treatment With a CDK4/6 Inhibitor and an Aromatase Inhibitor. (clinicaltrials.gov) - P3 | N=211 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA

Challenges in Hyperglycemia Management in a Patient Treated With a Phosphatidylinositol 3-Kinase Inhibitor (ENDO 2025) - "Hyperglycemia is an on-target side effect of PI3K inhibitors that presents unique challenges in glycemic management for patients receiving these therapies.Clinical Case: A 72-year-old woman with a history of type 2 diabetes on empagliflozin monotherapy, hypertension, hyperlipidemia, and uterine clear cell carcinoma presented with shortness of breath, hyperglycemia, and word finding difficulty. She had been started on the PI3K inhibitor alpelisib 300 mg daily eight days prior to admission and developed worsened hyperglycemia...Pioglitazone, one of the preferred options as it does not interfere with the PI3K pathway, was not recommended due to recent history of Takotsubo cardiomyopathy and reduced ejection fraction... Hyperglycemia is an on-target side effect of PI3K inhibitors. Metformin, SGLT2 inhibitors and thiazolidinediones are preferred medications to treat PI3K-induced hyperglycemia because their mechanism of action does not affect the PI3K signaling pathway...."

Clinical • Cardiomyopathy • Cardiovascular • Clear Cell Carcinoma • Diabetes • Dyslipidemia • Hematological Malignancies • Hypertension • Metabolic Disorders • Oncology • Type 2 Diabetes Mellitus

Results of a phase I study of alpelisib and sacituzumab govitecan (SG) in patients with HER2-negative metastatic breast cancer (MBC). (ASCO 2025) - P1 | "Combination of SG + alpelisib was feasible, with manageable side effects. The toxicity profile of the combination was consistent with the known safety profiles of the two agents. This combination demonstrated encouraging efficacy in HER2-negative MBC, with prolonged duration of responses, and warrants further evaluation in larger studies."

Clinical • Metastases • P1 data • Breast Cancer • Diabetes • Hepatology • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Neutropenia • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

EPIK-P4: A Phase II Single-arm Study to Assess the Efficacy, Safety and Pharmacokinetics of Alpelisib (BYL719) in Pediatric and Adult Patients With PIK3CA-related Overgrowth Spectrum (PROS) (clinicaltrials.gov) - P2 | N=104 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals

New P2 trial • Pediatrics

EPIK-B3: Study Assessing the Efficacy and Safety of Alpelisib + Nab-paclitaxel in Subjects With Advanced TNBC Who Carry Either a PIK3CA Mutation or Have PTEN Loss (clinicaltrials.gov) - P3 | N=137 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: May 2025 ➔ Sep 2025

Trial completion date • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • PIK3CA • PTEN