Piqray (alpelisib) / Novartis - LARVOL DELTA

EPIK-B5: Study to Assess the Efficacy and Safety of Alpelisib Plus Fulvestrant in Participants With HR-positive (HR+), HER2-negative, Advanced Breast Cancer After Treatment With a CDK4/6 Inhibitor and an Aromatase Inhibitor. (clinicaltrials.gov) - P3 | N=212 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Oct 2026 ➔ Mar 2027 | Trial primary completion date: Sep 2026 ➔ Jan 2027

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

Gedatolisib, a multi-target PI3K/AKT/mTOR (PAM) inhibitor, plus fulvestrant with or without palbociclib for second-line (2L) treatment of patients with HR+/HER2-/PIK3CA-wild type (WT) advanced breast cancer (ABC): updated results from the randomized, phase 3 VIKTORIA-1 trial (SABCS 2025) - "In preclinical studies, gedatolisib demonstrated superior potency and cytotoxicity compared to alpelisib, capivasertib, and everolimus, regardless of PI3K-pathway mutation status, and combinations of gedatolisib + fulvestrant, with and without palbociclib, were active in treatment-naive and resistant cell lines. These updated results support gedatolisib combination therapy as a potential new standard of care for the 2L treatment of patients with HR+/HER2-/PIK3CA WT ABC."

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

ReDiscover-2, a phase 3 study of RLY-2608 + fulvestrant versus capivasertib + fulvestrant as treatment for locally advanced or metastatic PIK3CA-mutant HR+/ HER2- breast cancer following recurrence or progression on or after treatment with a CDK4/6 inhibitor (trial in progress) (SABCS 2025) - P3 | "While the PI3K inhibitors alpelisib and inavolisib and the AKT inhibitor capivasertib have been approved by the FDA to treat this substantial patient population, these therapies cause significant toxicity, notably hyperglycemia, rash, and diarrhea, due to their non-selective targeting of the pathway. Type 1 diabetes, or Type 2 diabetes requiring antihyperglycemic medication are excluded• No prior PI3K, AKT, or mTOR inhibitors or any agent whose mechanism of action is to inhibit the PI3K/AKT/mTOR pathwayReDiscover-2 (NCT06982521) is open for enrollment. For further information, contact: clinicaltrials@relaytx.com."

Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA • PTEN

PI3K inhibition with alpelisib: a new hope for congenital hyperinsulinism. (PubMed, Ann Med Surg (Lond)) - No abstract available

Journal

Prenatal Detection of Somatic PIK3CA Mosaicism Using Next-Generation Sequencing (ACMG 2026) - "Patient 2 was counselled about a targeted pharmacologic therapy, Alpelisib, which has been FDA-approved for the reduction of overgrowth, vascular lesions, and other functional complications...Prenatal diagnosis of PROS may also enable precision treatment via targeted PIK3CA inhibition. Together, these cases support the use of prenatal sequencing to facilitate timely genetic diagnosis and appropriate treatment."

Biomarker • Next-generation sequencing • Acute Respiratory Distress Syndrome • CNS Disorders • Epilepsy • Gastroenterology • Infectious Disease • Nephrology • Respiratory Diseases • Septic Shock • Solid Tumor • Ventriculomegaly • Wilms Tumor • AFP • PIK3CA

Tissue is the Issue: Comparison of Diagnostic Yield Between Blood and Tissue-Based Genetic Testing in Individuals with Vascular Anomalies (ACMG 2026) - "Molecular testing can be helpful in making a specific diagnosis and can directly guide options for targeted therapy, such as the use of alpelisib for individuals with PIK3CA -related overgrowth spectrum... Tissue is the preferred specimen type for genetic testing in individuals with vascular anomalies due to the predominantly somatic mosaic nature of causative variants. Blood or saliva may be appropriate when there is high clinical suspicion for a germline condition such as hereditary hemorrhagic telangiectasia, capillary malformation–arteriovenous malformation, or glomuvenous malformation. Testing performed on blood or saliva can lead to non-diagnostic results and delay the identification of clinically relevant variants."

Clinical • Cardiovascular • CNS Disorders • Hematological Disorders • PIK3CA • RASA1

852355: Bridging Diagnosis and Therapy: The Expanding Role of Somatic Testing in Vascular Anomalies (ACMG 2026) - "This session will examine the evolving diagnostic strategies and highlight therapeutic opportunities, including off-label use of agents like sirolimus, alpelisib, and MEK inhibitors. Presentations will cover the molecular underpinnings of vascular anomalies, advances in somatic testing, and the clinical translation of genetic data into targeted treatments—offering a comprehensive view of the current and future landscape in this rapidly advancing field.Learning Objectives:• Describe the clinical and molecular heterogeneity of vascular anomalies and the pathways involved in their pathogenesis.• Evaluate current genetic and somatic testing methodologies, including cfDNA-based approaches, and apply them to appropriate clinical scenarios while considering ethical and practical challenges.• Interpret somatic genotype data to guide therapeutic decisions, including the potential off-label use of targeted agents."

Evaluating PTEN mutations as a predictor of response to combinatorial therapy in ovarian cancer (LCC 2026) - "Cell growth assays indicated that combinatorial therapies with the PARP inhibitor Olaparib, plus PI3K pathway inhibitors including PI3K inhibitor BYL-719 or AKT inhibitor MK-2206, were more efficacious than monotherapies in suppressing cell growth. To extend the relevance of our studies, we will next use patient-derived OC organoids, as a more physiological model. We will provide further evidence regarding the efficacy of PARP plus PI3K inhibition for OC treatment and aim to identify additional predictors of sensitivity."

Genito-urinary Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • BRCA1 • BRCA2 • PIK3CA • PTEN

Phase 1b Clinical Trial with Alpelisib plus Olaparib for Patients with Advanced Triple-Negative Breast Cancer. (PubMed, Clin Cancer Res) - P1 | "Alpelisib in combination with olaparib is tolerable in patients with pre-treated TNBC, with evidence of activity in non-BRCA carriers. CfDNA provided important prognostic information. Results highlight potential synergistic use of a PI3Ki to sensitize HR-proficient (BRCA wild-type) TNBC to PARPi and suggest the potential to expand the use of PARPi beyond BRCA-mutant tumors."

Journal • P1 data • Breast Cancer • Diabetes • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • BRCA • PIK3CA

SGLT2 INHIBITOR DAPAGLIFLOZIN ATTENUATES CARDIOMYOCYTE INJURY INDUCED BY PI3Kα-SELECTIVE INHIBITOR ALPELISIB AND FULVESTRANT UNDER HYPERGLYCEMIA (ACC 2026) - "Abstract is embargoed at this time."

Diabetes • PIK3CA

Optimizing second-line endocrine-based treatment in HR positive HER2 negative metastatic breast cancer: a comprehensive expert statement from the Gulf Cooperation Council Region. (PubMed, Front Oncol) - "This consensus uniquely contextualizes global evidence for GCC-specific healthcare constraints, addressing gaps in diagnostic access, affordability, and real-world feasibility, while providing treatment recommendations that help clinicians refine therapeutic strategies and incorporate patient preferences for improved outcomes. The panel recommends early genomic testing (PIK3CA, AKT, BRCA, ESR1) to guide therapy, prioritizing targeted agents such as oral SERDs and PI3K/AKT inhibitors in second-line sequencing, cautious use of alpelisib in diabetic patients, and incorporating patient preferences through shared decision-making and multidisciplinary care."

Journal • Review • Breast Cancer • Diabetes • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • BRCA • ER • HER-2 • PIK3CA

Alpelisib plus fulvestrant for PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer after a CDK4/6 inhibitor (EPIK-B5): Phase III, randomized, double-blind, placebo-controlled, multicenter study (SABCS 2025) - "EPIK-B5 met its primary objective with ALP+FUL showing a statistically significant and clinically meaningful improvement in PFS in patients with HR+, HER2− ABC harboring a PIK3CA-m after CDK4/6i. There was a positive trend for a prolonged OS in favor of ALP+FUL over PBO with about 5.7 mo improvement in the median OS. There were no new safety signals.Table: Demographic and baseline characteristics"

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

Elacestrant in combination with everolimus or abemaciclib in patients with ER+/HER2- locally advanced or metastatic breast cancer (mBC): phase 2 results from ELEVATE, an open-label, umbrella study (SABCS 2025) - " ELEVATE is evaluating elacestrant combined with everolimus, alpelisib, capivasertib, abemaciclib, ribociclib,or palbociclib to address different resistance mechanisms...PFS benefit was consistent across subgroups, including those with visceral metastases, prior fulvestrant or primary ET resistance... Elacestrant in combination shows a consistent PFS benefit irrespective of ESR1m status in pts with ER+/HER2-mBC after progressive disease on ET ± prior CDK4/6i. Elacestrant has the potential to become an ET backbone for combination strategies with targeted agents, supporting an all-oral approach that may delay the need for chemo or ADC-based regimens in this patient population. Table 1:Phase 2 mPFS, mo[95% CI] in all patients and subgroupsNR, not reached"

Clinical • Combination therapy • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • ER • HER-2 • PIK3CA

Personalized Biomarker-Based Umbrella Trial for Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: KCSG HN 15-16 TRIUMPH Trial. (PubMed, J Clin Oncol) - "To our knowledge, this study is the first biomarker-driven umbrella trial for platinum-refractory HNSCC using matched molecular targeted agents. We found that NGS-based genomic phenotyping was methodologically feasible and applicable."

Biomarker • IO biomarker • Journal • Metastases • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • EGFR • FGFR • PIK3CA

EPIK-B2: Study of Alpelisib (BYL719) in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy in Patients With HER2-positive Advanced Breast Cancer With a PIK3CA Mutation (clinicaltrials.gov) - P3 | N=19 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jun 2026 ➔ Feb 2027 | Trial primary completion date: Jun 2026 ➔ Feb 2027

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

Phase Ib Study of AlpeliSib With PEmbroLizumab in Patients With mEtastatic Breast caNcer or melanomA (SELENA) (clinicaltrials.gov) - P1/2 | N=50 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

Metastases • New P1/2 trial • Acute Myelogenous Leukemia • Breast Cancer • Hematological Malignancies • Leukemia • Melanoma • Myelodysplastic Syndrome • Oncology • Solid Tumor

IMPRESS-Norway: A nationwide precision-oncology study for off-label targeted therapies - Results from the first 1,740 patients (ESMO 2025) - P2 | "The most common treatments were trametinib ± dabrafenib (n=72), trastuzumab + pertuzumab (n=51), atezolizumab ± bevacizumab (n=48), alpelisib ± fulvestrant (n=30) and cobimetinib + vemurafenib (n=23). Among patients with CR, PR or SD (80/250), the median duration of treatment was 41 weeks. Conclusions IMPRESS-Norway demonstrates how a publicly funded and equally accessible precision medicine framework can be implemented and provides DCR in 32% of patients."

Clinical • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • Colorectal Cancer • Glioblastoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor

Imlunestrant with or without everolimus or alpelisib, in ER+, HER2- advanced breast cancer (aBC): Results from the phase Ia/b EMBER study (ESMO 2023) - P1a/1b | "In the first-in-human phase 1a/b EMBER study, imlunestrant demonstrated favorable safety, pharmacokinetics (PK), and clinical benefit rate when administered as monotherapy (Jhaveri ASCO 2022) or with abemaciclib (Jhaveri SABCS 2022)...Median number of prior aBC therapies in combination cohorts was: 1 (range 1-2); including prior ET (100%), CDK4/6i (100%), fulvestrant (35%) and chemo (17%)...Conclusions Imlunestrant alone or in combination with everolimus or alpelisib demonstrated robust efficacy in pts with pre-treated ER+, HER-2 aBC. Toxicities were consistent with the known safety profile of both alpelisib and everolimus."

Metastases • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • CDK4 • ER • HER-2 • PIK3CA

BRACELET-1 (PrE0113): Inducing an inflammatory phenotype in metastatic HR+/HER2- breast cancer with the oncolytic reovirus pelareorep in combination with paclitaxel and avelumab. (ASCO 2023) - P2 | "Six pts (12%) previously received everolimus, and 3 alpelisib. The addition of pelareorep to PTX is an active regimen with a high 6-month PFS rate worthy of further study. One third of patients discontinued either pelareorep or avelumab due to toxicity, highlighting the need for attentive supportive care. Survival data is maturing."

Combination therapy • IO biomarker • Metastases • Oncolytic virus • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Immune Modulation • Oncology • Solid Tumor • HER-2 • PD-1 • PD-L1

Imlunestrant, an Oral Selective Estrogen Receptor Degrader, as Monotherapy and in Combination With Targeted Therapy in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Phase Ia/Ib EMBER Study. (PubMed, J Clin Oncol) - "Imlunestrant, as monotherapy or in combination with targeted therapy, had a manageable safety profile with evidence of preliminary antitumor activity in ER+/HER2- ABC."

Combination therapy • Journal • Metastases • Monotherapy • P1 data • Breast Cancer • Endometrial Cancer • 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

Mapping the Kinase Inhibitor Landscape in Canine Mammary Carcinoma: Current Status and Future Opportunities. (PubMed, Animals (Basel)) - "In vitro studies demonstrate that palbociclib, alpelisib, everolimus, and lapatinib inhibit growth and signalling in CMC cell lines. Translational research, including xenograft and organoid models, followed by clinical trials in dogs, is required. Gaining this knowledge could lead to targeted treatment for dogs while advancing comparative understanding of mammary cancer biology across species."

Journal • Review • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

A multicenter, dose-finding, phase 1b study of imatinib in combination with alpelisib as third-line treatment in patients with advanced gastrointestinal stromal tumor. (PubMed, BMC Cancer) - P1 | "The MTD of alpelisib was estimated as 350 mg QD when used in combination with imatinib 400 mg QD after oral administration in patients with advanced GIST. The safety and tolerability profile of this combination was acceptable; however, the combination did not demonstrate sufficient clinical activity to justify additional clinical testing."

Combination therapy • Journal • P1 data • Diabetes • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma

Alpelisib (BYL719) with continued endocrine therapy following progression on endocrine therapy in hormone receptor–positive, HER2-negative, PIK3CA-mutant metastatic breast cancer: A Big Ten Cancer Research Consortium Study (BTCRC-BRE19-409) (SABCS 2024) - "The benefit of adding alpelisib to fulvestrant following progression on non-fulvestrant endocrine therapy (ET) was demonstrated in the SOLAR-1 study, but the majority of these patients were CDK4/6 inhibitor (CDKi) naïve...90.5% of patients had prior palbociclib, and 9.5% had prior ribociclib...Additionally, only 14.2% patients discontinued due to toxicities, lower than the rates reported in SOLAR-1 and BYLieve, possibly due to the encouraged use of prophylaxis with anti-histamine and metformin... In HR+HER2- PIK3CA-mutant metastatic breast cancer progressing on ET/CDKi combination therapy, continued ET with switch from CDK4/6 inhibitor to alpelisib at time of disease progression is feasible and safe and clinical responses are seen. Planned correlative studies will assess circulating biomarkers of PI3K signaling that may identify which patients would benefit from this approach."

Metastases • 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 • HER-2 • PIK3CA

A Three-subtype Molecular model of Cervical Cancer: Multiple PI3K Pathway inhibitors suppress growth and cooperate with HPV-directed immunotherapy. (PubMed, medRxiv) - "The pan-AKT inhibitor, Capivasertib (AZD5363), suppressed some but not all tested PIK3CA -mutated cell lines and one PIK3CA -wt cell line (SiHa). Further research on targeted therapies will improve the prognosis of patients with cervical cancer. Identified 3 molecular subtypes of CC based on PIK3CA and YAP1 amplification status Cervical cell lines with PIK3CA mutation are suppressed by targeted inhibitors PI3K inhibitors Alpelisib/Inavolisib selectively block PIK3CA-mutant cells PIK3CA mutation is associated with higher expression of the checkpoint CD274/PD-L1 PI3K inhibitors cooperate with donor-derived T cells to kill cervical cells."

IO biomarker • Journal • Cervical Cancer • Human Papillomavirus Infection • Infectious Disease • Oncology • Solid Tumor • EGFR • PIK3CA • YAP1

Tipifarnib (TIP) and alpelisib (ALP) in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): Phase I results from KURRENT-HN (ESMO 2025) - P1/2 | "8 pts not evaluable: inability to swallow (n=2); toxicity (n=2); death, clinical progression, withdrew consent, tumor hemorrhage (n=1 each) † Of 6 pts with CR/PR, 5 pts had 1 prior tx and 1 pt had 3 prior tx ‡ Off tx prior to confirmatory scan due to: disease progression (n=2), withdrawn consent and cardiac event (n=1 each) Conclusions TIP + ALP was well tolerated with a manageable toxicity profile – noteworthy considering the known challenges of PI3Kαi combos with other targeted tx. Durable antitumor activity was observed in heavily pretx molecularly selected R/M HNSCC pts, supporting that combos (eg, FTI + PI3Kαi) targeting synergistic pathways may improve modest single tx activity."

Metastases • P1 data • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PIK3CA