Piqray (alpelisib) / Novartis - LARVOL DELTA

Efficacy, safety, and pharmacokinetics of alpelisib (ALP) in pediatric and adult patients with PIK3CA-related overgrowth spectrum (PROS): Epik-P4, a Phase II study (ASH 2025) - P2 | "Secondary objectives include evaluating the efficacy, safety, PK, and tolerability of ALP in adult and pediatric participants with PROS by assessing changes in lesions, symptoms, complications, healthcare utilization, patient-reported outcomes, duration of response, time to treatment failure, and overall clinical response at scheduled protocol defined time points. The first patient first visit is planned for October 2025."

Clinical • P2 data • PK/PD data • Pediatrics • Rare Diseases • PIK3CA

Epik-L1: A Phase 2/3 study of alpelisib in pediatric and adult patients with PIK3CA-driven lymphatic malformations (ASH 2025) - P2/3 | "Key exclusion criteria include pts with physician-confirmed diagnosis of PROS, centralconducting lymphatic anomaly, generalized lymphatic anomaly, Gorham-Stout disease, or Kaposiformlymphangiomatosis; with a history of Stevens-Johnson syndrome, erythema multiforme, toxic epidermalnecrolysis, or a diagnosis of type I diabetes mellitus or uncontrolled type II diabetes; prior treatment withALP or other PI3K inhibitors lasting ≥2 weeks.Stage 1 enrollment (Groups 1 and 2 = 21 each) has been completed. The study now aims to enrollapproximately 192 pts in Stage 2 (Groups 3 and 4 = 90 each, Group 5 = ~12)."

Clinical • P2/3 data • Dermatology • Diabetes • Infectious Disease • Kaposi Sarcoma • Metabolic Disorders • Pediatrics • Steven-Johnson Syndrome • Type 1 Diabetes Mellitus • Type 2 Diabetes Mellitus • PIK3CA

Use of angiopoietin-2 as a biomarker in vascular anomalies beyond complex lymphatic anomalies (ASH 2025) - "Among 30 patients with VA (4 GLA, 3 GSD, 9 CLVM with and without overgrowth, 8 extensive VM, 6isolated LM), 46 serum Ang-2 measurements were obtained. At first Ang-2 measurement, 8 patients (3GLA, 3 CLVM, 1 VM, 1 LM) were on disease-modifying therapies (DMT), including sirolimus or alpelisib.Most patients with VM (6/8, 75%) had D-dimer levels > 2 times the upper limit of normal (>2x ULN)without elevated Ang-2. Mildly elevated Ang-2 (4141 – 9999 pg/mL) was observed in 1 patient with GLA(on DMT) and 1 patient with GSD (not on DMT)."

Biomarker • Gastrointestinal Disorder • Infectious Disease • Septic Shock • Thrombocytopenia

ReInspire: A phase 2 study of mutant-selective PI3Kα inhibitor, RLY-2608, in adults and children with PIK3CA-related overgrowth spectrum and malformations driven by PIK3CA mutation (ASH 2025) - P2 | "VMs are noncancerous lesions that may be managed with treatments such as surgery,sclerotherapy, sirolimus, and non-mutant-selective PI3Kα inhibitors; however, use of systemic therapiesin patients is frequently limited by drug-related adverse effects...Part 1 is the open-label dose-finding portion, which initiates with randomization of Group 1 patients(n=45) to one of three dose levels with stratification according to prior alpelisib use, and will be followedby weight-based dose escalation using a Bayesian optimal interval (BOIN) design in Groups 2 and 3, ifopened...Patients ≥12 years are now enrolling in Part 1. For more information,contact clinicaltrials@relaytx.com"

Clinical • P2 data • Breast Cancer • Diabetes • Metabolic Disorders • Rare Diseases • AKT1 • PIK3CA

Selective inhibition of PI3Kp110α enhances chemotherapy efficacy by suppressing hepatic stellate cell activation in liver cancer (ESMO Asia 2025) - "The HSC activation was examined in vitro when cultured in conditioned media or mixed-cell spheroids of human HCC cells treated with cisplatin or doxorubicin. Cisplatin treatment activates HSCs via a PI3K pathway. Selective targeting of PI3K p110α provides a novel strategy to inhibit chemotherapy-induced HSC activation and improve treatment response."

Clinical • Liver Cancer • Oncology • Solid Tumor • ACTA2 • CAFs • COL1A1 • PIK3CA

The PIK3CA/AKT pathway drives therapy resistance in rhabdomyosarcoma. (PubMed, Nat Commun) - "Olaparib and temozolomide (OT) combination therapy is in clinical trial evaluation for rhabdomyosarcoma (RMS). The combination of OT + alpelisib also kills RMS cells which are resistant to standard-of-care combination chemotherapy and was effective in preclinical xenograft mouse models at curbing tumor growth. Our work defines a common resistance pathway in RMS and has credentialled PIK3CA/AKT inhibition as a preclinical strategy to kill therapy resistant RMS."

Journal • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • PIK3CA

A prospective, direct-to-patient study to evaluate clinical and molecular mechanisms of resistance to capivasertib in estrogen receptor-positive metastatic breast cancer (SABCS 2025) - "PI3Kα inhibitors including alpelisib and inavolisib improve progression free survival (PFS) in PIK3CA-mutated ER+ MBC, but are often associated with high-grade toxicities such as hyperglycemia...In the CAPItello-291 trial, capivasertib combined with fulvestrant more than doubled PFS to 7.3 months versus 3.1 months with fulvestrant alone, and exhibited a favorable toxicity profile...Since January 2025, 10 patients have been enrolled and provided pre-treatment ctDNA samples. Further study details are available at https://contributeher.wixsite.com/capivaresistance."

Clinical • Metastases • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • AKT1 • ER • PIK3CA • PTEN

Liquid Biopsy-Based Molecular Profiling Using Guardant360 CDx at Progression on CDK4/6i+ET: Findings from the AGO-B CAPTOR Study (SABCS 2025) - P4 | "The AGO-B "Comprehensive Analysis of Spatial, Temporal and Molecular Patterns of Ribociclib Efficacy and Resistance in Advanced Breast Cancer Patients" (CAPTOR) trial (NCT05452213) is a single-arm, open-label phase IV study of patients with advanced HR+/HER2- breast cancer who were treated with ribociclib and endocrine therapy...Twelve (39%) had an indication for Alpelisib due to an activating mutation in PIK3CA, nine (29%) an indication for Elacestrant based on an activating mutation in ESR1, sixteen (52%) an indication for Capivasertib due to PIK3CA, AKT1 or PTEN mutation and one patient (3%) had a ERBB2 amplification resulting in an indication for an anti-HER2 treatment...Of those, seven (41%) received treatment in accordance with ctDNA test result (29% Capivasertib, 6% Trastuzumab, 6% Elacestrant). Guardant360 CDx testing was initiated for 37 patients between December 2024 and June 2025. Of those, two were cancelled due to shipment delays and four..."

Biopsy • Liquid biopsy • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • AKT1 • BRCA1 • BRCA2 • CDK4 • ER • PIK3CA • PTEN

Investigating association of comorbidities and race with all-cause mortality outcomes of PI3K inhibitor use in metastatic breast cancer (mBC) (SABCS 2025) - "PI3K and AKT pathway inhibitors Alpelisib, Inavolisib, and Capivasertib (PI3K/AKTi) are FDA approved treatments with demonstrated significant clinical benefit, improving progression free survival for Hormone receptor positive (HR+) mBC. We did not identify disparities in mortality between our 3 racial cohorts. Future studies are needed to understand interactions between individual PI3K/AKTi agents and comorbidities to inform appropriate management strategies and ultimately improve patient outcomes."

Metastases • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Sequencing PIK3CA, AKT and mTOR Inhibitors in HR+/HER2- Metastatic Breast Cancer: A Real-World Retrospective Analysis (SABCS 2025) - "Approved agents—everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor)—have demonstrated median progression-free survival (mPFS) ranging from 5.5 to 7.3 months in patients previously treated with CDK4/6 inhibitors. Our findings support the consideration of sequencing pathway inhibitors regardless of tolerance to the first agent. These results reinforce sequential PI3K/AKT/mTOR inhibition as a viable strategy in modern metastatic breast cancer care, though prospective studies are needed to validate this approach in pretreated populations."

Metastases • Real-world • Real-world evidence • Retrospective data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • 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

Disease stabilization in atypical schwannomatosis with BAP1 and PIK3CA mutations treated with olaparib and alpelisib (SNO 2025) - "Her disease progressed rapidly following standard treatments, including temozolomide, doxorubicin, and cabozantinib...It supports the consideration of molecularly guided targeted therapies in rare, treatment-refractory peripheral nerve sheath tumors with atypical or metastatic behavior. Further studies are needed to evaluate the role of precision medicine in managing atypical schwannomatosis and related low-grade spindle cell neoplasms."

Brain Cancer • Cough • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Spindle Cell Sarcoma • BAP1 • 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

Real-world Treatment Patterns of Capivasertib in Metastatic Breast Cancer in the US (SABCS 2025) - "Prior therapies for MBC included: CDK4/6 inhibitors (87.1%), fulvestrant (66.0%), chemotherapy (31.8%), alpelisib (20.6%), and antibody-drug conjugates (14.1%) in any prior LOT. Findings from this large database analysis of US patients demonstrate the effectiveness of capivasertib + fulvestrant in real-world practice. Clinical outcomes in 2L and 3L closely match those observed in the CAPItello-291 Phase 3 randomized controlled trial, which supported FDA approval of the capivasertib + fulvestrant regimen. Numerically improved outcomes were observed in patients who used capivasertib in earlier vs later line settings."

Clinical • HEOR • Metastases • Real-world • Real-world evidence • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • AKT1 • ER • HER-2 • PIK3CA • PTEN

Therapeutic Implications of Concurrent ESR1 and PI3K Pathway Mutations in HR+/HER2- Metastatic Breast Cancer (SABCS 2025) - "Likewise, alpelisib and capivasertib improved PFS in patients with PIK3CA-mutated, HR+, HER2- advanced breast cancer who had progressed on prior endocrine therapy.Little is known about the clinical significance of concurrent ESR1 and PIK3CA mutations in breast cancer patients...However, our data uniquely demonstrates that patients with concurrent ESR1 and PIK3CA mutations, who were treated initially with PIK3CA inhibitor followed by elacestrant, had longer PFS and OS. This sequencing may offer improved outcomes, as PI3K mutations may confer a worse prognosis than ESR1 mutations. Prior studies, including EMERALD and EMBER-3, have indicated shorter PFS in patients with PI3K mutations treated with oral SERDs compared to those without PI3K pathway alterations.These findings highlight the need for future studies comparing institutional data across larger cohorts and prospective trials to better define optimal sequencing strategies for this subset of patients."

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

PIK3R1 (p85α) alterations define a targetable subset of breast cancer with broad sensitivity to PI3K and AKT inhibitors (SABCS 2025) - "Strikingly, PIK3R1 mutations conferred pan-sensitivity to active-site PI3Ki (alpelisib, inavolisib), AKTi (capivasertib), and mutant-selective PI3Ki (STX-478, RLY-2608) in vitro. This is the first comprehensive study of PIK3R1 alterations in breast cancer. Our findings establish PIK3R1 as a functional driver of oncogenic PI3K signaling and show that PIK3R1 alterations confer sensitivity to both established and investigational PI3K and AKT inhibitors. These findings nominate PIK3R1 alterations as an actionable genomic biomarker and support the inclusion of patients with PIK3R1-altered breast cancer in clinical trials testing PI3K and AKT inhibitors."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • AKT1 • ER • PIK3CA • PIK3R1 • PTEN

Real World Experience of PIK3CA, AKT inhibitors, and oral SERD in patients with hormone receptor positive metastatic breast cancer (SABCS 2025) - "Result A total of 107 patients who had PIK3CA pathway alteration and received PI3CK/AKT inhibitors were identified: fulvestrant alpelisib (N=51), fulvestrant capivasertib (N=35), inavolisib (N=2), 2 or more PIK3CA/AKT inhibitors (N=11), and PIK3CA/AKT inhibitors and Elacestrant (N=8). Our study is limited by its small sample size, and we observed most patients with ESR1 and PIK3CA pathway co-mutation were able to benefit from sequential therapy of oral SERD or PIK3CA pathway inhibitors, whichever treatment comes first, and showed a favorable response to either treatment. Future effort for a multi-institutional study is planned."

Clinical • Metastases • Real-world • Real-world evidence • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ATM • BRCA1 • CDH1 • CHEK2 • ER • PIK3CA

Identification of 2 Ubiquitin-Proteasome System-Related Subtypes in Esophageal Squamous Cell Carcinoma for Prognostic and Immunotherapeutic Response Prediction. (PubMed, J Immunother) - "Selumetinib, entinostat, and erlotinib were identified as candidate drugs for cluster 2, whereas tozasertib, alpelisib, and cediranib showed higher suitability for cluster 1. Ten potential biomarkers, 13 transcription factors, and 2 miRNAs were characterized. This study elucidates the role of UPS in ESCC progression and provides a framework for personalized treatment strategies."

IO biomarker • Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • Targeted Protein Degradation • CD8 • TP53

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

Real-world clinical outcomes and genomic insights for patients with PIK3CA-mutant metastatic breast cancer following progression on CDK4/6 inhibitor therapy (SABCS 2025) - "Exposures of interest included treatment with capivasertib (CAPI), alpelisib (ALP), and elacestrant. In this real-world analysis, pts with PIK3CAmut mBC and CDK4/6i progression were most frequently treated with CAPI as subsequent therapy when no ESR1mut was identified; co-mutant disease received elacestrant most often. CAPI responses may differ based upon genomic alterations in baseline ctDNA, including the presence of ESR1mut, though these exploratory findings require additional follow up for data maturity. Higher frequencies of FGFR1, CCND1, and KRAS alterations at CAPI progression warrant further testing as potential acquired resistance mediators."

Clinical • Clinical data • Metastases • Real-world • Real-world evidence • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CCND1 • ER • FGFR1 • KRAS • PIK3CA • TP53

PROSPERITY: A Prospective Observational Study to Describe Clinical Outcomes, Treatment Patterns, Patients Characteristics Among Patients With HR+/HER2- Advanced BC Initiating Treatment With Risarg®, Piqray®, Endocrine Therapy or Chemotherapy in Routine Clinical Practice in Russia (clinicaltrials.gov) - P=N/A | N=2424 | Completed | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Completed

Trial completion • Breast Cancer • Oncology • Solid Tumor

A case report of tumor-associated liver injury alleviated with antineoplastic drug. (PubMed, Front Oncol) - "This article reports a case of tumor-associated Liver Injury (TALI) who suffered HER2-negative metastatic breast cancer with liver metastasis, but her liver function was recovery after treatment with Alpelisib, an anti-tumor drug, as meanwhile as achieving anti-tumor. Through this case we aims to emphasize to differentiate the causes of TALI and make the treatment strategies accordingly."

Journal • Breast Cancer • Hepatology • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Liver Failure • Oncology • Solid Tumor • HER-2

Metformin enhances alpelisib sensitivity in HER2+ breast cancer by suppressing cancer stemness and oncogenic signaling. (PubMed, Front Oncol) - "These findings indicate that metformin synergistically enhances the antitumor activity of alpelisib in HER2-positive breast cancer by inhibiting oncogenic signaling and stemness pathways. Beyond its metabolic benefit in mitigating hyperglycemia, metformin may potentiate PI3K-targeted therapies, supporting further preclinical and clinical evaluation of this combination strategy."

Journal • Breast Cancer • Diabetes • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ALDH1A1 • CTNNB1 • HER-2 • KLF4 • MYC • NANOG • PIK3CA • SOX2

The PI3K pathway is a downstream effector of NRF2 activation in the esophagus. (PubMed, Transl Oncol) - "Furthermore, co-treatment with Pyrimethamine and Alpelisib significantly inhibited hyperproliferation and hyperkeratinization in the esophageal epithelium of Sox2CreER;LSL-Nrf2E79Q/+mice. Together, our data demonstrates the PI3K pathway as a downstream effector of NRF2 activation in the esophagus, and co-targeting of NRF2 and the PI3K pathway may offer a promising therapeutic strategy for NRF2Mut ESCC."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • EGFR • KEAP1 • PIK3CA • PTEN

Molecular Profiling of Malignant Effusions in Advanced Breast Cancer via cfDNA and Tumor Cells Analysis: A Complementary Approach to Guide Targeted Therapy (SABCS 2025) - "ESR1 D538G was detected in two patients following palbociclib/letrozole and capecitabine treatments, respectively...In a sample harboring a PTEN deletion, sensitivity to everolimus was demonstrated, with a 60% reduction of cell viability at <0.001 µM dose. Additionally, in a sample with FGFR1 amplification, paclitaxel showed a 70% reduction of cell viability at <0.1µM. Finally, in a ERBB2 and KRAS G13D mutated case, TCs showed resistance to alpelisib, palbociclib, ribociclib, elacestrant and letrozole.Malignant effusions represent a valuable and overlooked source of tumor material for molecular diagnostics in advanced breast cancer...Malignant effusions represent a valuable and overlooked source of tumor material for molecular diagnostics in advanced breast cancer. Although cfDNA NGS and cytology show high correlation, NGS can detect tumoral content in samples that tested negative for cytology, and TCs' isolation is able to confirm malignancy even in..."

Cell-free DNA • Metastases • Tumor cell • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • ARID1A • BRCA1 • ER • FGFR1 • HER-2 • KRAS • PIK3CA • PTEN • TP53