Piqray (alpelisib) / Novartis - LARVOL DELTA

Results of a phase I study of alpelisib and sacituzumab govitecan (SG) in patients with HER2-negative metastatic breast cancer (MBC). (ASCO 2025) - P1 | "Clinical Trial Registration Number: NCT05143229 The abstract will be released to the public on May 22, 2025 at 5:00 PM EDT"

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

ET-Based Combinations and Novel Agents in HR+/HER2- Advanced Breast Cancer (GBCC 2025) - "Tumors with alterations in the PIK3CA/AKT/PTEN pathway may be offered a pathway inhibitor such as capivasertib or alpelisib, and patients with high risk recurrence of HR+ disease with a PIK3CA mutation may benefit from early introduction of a first-line inavolisib triplet...The oral SERD elacestrant is approved as monotherapy in pretreated patients with tumors harboring an ESR1 mutation. Additional oral SERDs, including imlunestrant, camizestrant, and giredestrant, have demonstrated activity and are in registrational trials. An additional maneuver in the pretreated space includes continuation of a CDK4/6 inhibitor after prior CDK4/6 inhibitor, with activity seen from switching to abemaciclib or ribociclib from a prior agent, and novel CDK inhibitors are in trials as a next generation approach. The mTOR inhibitor everolimus remains an option for pretreated patients as well, particularly when actionable mutations are not present. The continued introduction of novel agents..."

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 • ER • HER-2 • 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

Targeting the PI3K pathway with alpelisib in patient-derived xenografts: a multi-cancer type approach (AACR 2025) - "Moderate responses were seen in WHIM84 and WHIM18, while HCI-011 and WHIM16 showed no response. Proteogenomic analyses are ongoing to discern response biomarkers."

Clinical • Breast Cancer • Clear Cell Renal Cell Carcinoma • Colorectal Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Skin Cancer • Solid Tumor • BRCA • PIK3CA • TSC1 • TSC2

Co-targeting AR, mTOR, and PI3K inhibitors in DSRCT as a novel therapeutic approach (AACR 2025) - "Next, we explored the sensitivity of DSRCT cell lines to Enzalutamide and Darolutamide inhibitors; Temsirolimus (an mTOR inhibitor); Alpelisib (a PI3K inhibitor); and Gedatolisib (a dual mTOR and pan-PI3K inhibitor). We conclude that DSRCT cell lines are responsive to AR blocking and highly sensitive to PI3K/mTOR inhibitors. A co-targeting strategy that jointly inhibits the AR and PI3K/mTOR pathways is being investigated in murine models and might be considered for future studies if the regimens have non-overlapping toxicity profiles."

Genito-urinary Cancer • Oncology • Prostate Cancer • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • AR

Mutations in PIK3R1 activate multiple targetable pathways in triple-negative breast cancer [WITHDRAWN] (AACR 2025) - "Our prior studies showed that breast cancer cells lacking PIK3R1 protein had increased MEK activation, enhancing their responsiveness to the MEK inhibitors trametinib and binimetinib. Mutations in PIK3R1 sensitize TNBCs to combined MEK and PI3K pathway inhibition. NF1 mutations alone do not confer sensitivity to single agents but enhance response when combined with binimetinib and alpelisib. These findings support the combination of MEK and PIK3CA inhibitors as a potential strategy for treating PIK3CAMUT TNBCs.Disclaimer: AMA is employed by AstraZeneca but contributed to this publication in his own capacity."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • NF1 • PIK3CA • PIK3R1

Identification and characterization of an allosteric and mutant-selective PI3Kα inhibitor (AACR 2025) - P1, P1/2 | "Orthosteric inhibitors of PI3Kα, such as alpelisib and inavolisib have been approved for the treatment of patients with advanced HR+/HER2− breast cancer. TY-2291 is a potent kinase inhibitor of mutant PI3Kα with high selectivity over WT PI3Kα. In in vitro antiproliferative test, TY-2291 showed better antiproliferative activity against multiple PI3Kα mutant cells than LOXO-783, STX-478, and RLY-2608. In the mouse HCC1954 CDX model, TY-2291 showed potent tumor-inhibitory activity and excellent tolerance."

Breast Cancer • Colon Cancer • Colorectal Cancer • Gastric Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Uterine Cancer • HER-2 • PIK3CA

Involvement of the PI3K/AKT signaling pathway in the cancer cell response to tumor treating fields (TTFields) (AACR 2025) - "These findings provide a molecular understanding of the cellular response to TTFields, with early PI3K/AKT activation through FAK cell-surface interactions, and late activation via N-cadherin cell-cell interactions. PI3K inhibition presents a potential therapeutic strategy to sensitize cancer cells to TTFields treatment."

Brain Cancer • CNS Tumor • Glioblastoma • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pleural Mesothelioma • Solid Tumor • CDH2

Developing oncogenic mutant-selective antisense oligonucleotide to treat PIK3CA-mutated cancers (AACR 2025) - "The FDA approved a WT p110-specific inhibitor, alpelisib, to treat PIK3CA-mutant breast cancer patients a few years ago...Based on our previous findings that p85β dissociates from PIK3CA/p110α E545K mutant protein and translocates into the nucleus to stabilize EZH2, we further demonstrated that a combination of ASO18 with an EZH2 inhibitor tazemetostat synergistically suppress xenograft growth of tumors harboring a PIK3CA E545K mutation...Experiments assessing the efficacy of the LNP-ASO in xenograft models are ongoing. To our knowledge, our study represents the first mutant-selective ASO against an oncogenic mutation, which may lead to the development of a mutant-selective ASO to treat patients whose tumors harbor a PIK3CA E545K mutation."

Breast Cancer • Oncology • Solid Tumor • PIK3CA

Co-alterations in PIK3CA and ARID1A lead to greater sensitivity to PI3K pathway inhibition (AACR 2025) - "Previously we have shown that patients with mutations in both genes are more sensitive to copanlisib (cop) treatment than those with just PIK3CA(PK) mutation...An enhanced response was observed with some other PI3K inhibitors, including sapanisertib (PK=0.13; PKAD=0.014; p < 0.005) everolimus (PK=0.66, PKAD=0.36; p < 0.005) and capivasertib (PK=0.85; PKAD=0.47; p < 0.05). Cancers with PK and AD alterations have enhanced efficacy to PI3K pathway inhibition, especially those inhibitors with downstream activity against AKT or MTOR. Further mechanistic and in vivo studies are warranted in addition to further clinical validation."

Colorectal Cancer • Endometrial Cancer • Oncology • Solid Tumor • ARID1A • IFNG • IL6 • PIK3CA

Preclinical characterization of CGT6297, a novel PI3Kα H1047R mutant-selective inhibitor (AACR 2025) - "The approved PI3Kα inhibitor, alpelisib, shows promise for this targeted class of agents with improvements in progression-free survival in ER+/Her2- breast cancer patients in combination with fulvestrant. A PI3K mutant inhibitor that spares WT PI3K is predicted to be better tolerated, require fewer dosing modifications, and therefore, have the potential to provide improved clinical benefit. Herein, we present the preclinical characterization of CGT6297, a wild type sparing PI3Kα H1047R inhibitor."

Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA

GSC002639, a brain penetrating and mutant-selective PI3Kα inhibitor, exhibits potent mono- and combination therapy against PI3CA mutant tumors (AACR 2025) - "Our study also revealed a notable observation: In an HR-positive and HER2-negative PI3Kα H1047X CDX model, the combination of GSC002639 with Fulvestrant exhibited greater efficacy than the combinations of either Alpelisib or Inavolisib with Fulvestrant. In this report, we present the identification and characterization of GSC002639, a selective inhibitor targeting the PI3Kα H1047X mutation. GSC002639 demonstrates high specificity, the ability to cross the blood-brain barrier, and robust in vivo efficacy, while avoiding the insulin elevation. The promising pharmacokinetic and toxicological profiles of GSC002639 suggest its potential as a safe and effective cancer therapy."

Combination therapy • Breast Cancer • Colorectal Cancer • Endometrial Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • HER-2 • PIK3CA • PIK3CB • PIK3CD • PIK3CG

The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer (AACR 2025) - "Combining fulvestrant (a selective estrogen receptor (ER) degrader) with the PI3K-AKT signalling inhibitors such as alpelisib (PI3Kα inhibitor) or capivasertib (AKT inhibitor) gives benefit to patients with ER+ breast cancer (ER+ BC) harboring PIK3CA mutations (alpelisib) and PIK3CA, PTEN and AKT-1 altered tumors (capivasertib). Furthermore, the study highlights the pivotal role of the AKT-FOXO3-FOXM1 axis in mediating responses to AKT inhibitors in ER+ breast cancer with PIK3CA mutations regardless of PTEN expression. In addition, loss of FOXO3a expression can mediate resistance, and FOXM1 downregulation serves as a crucial biomarker of response to the combination treatment."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • FOXM1 • FOXO3 • PIK3CA • PTEN

Targeting mechanisms of adaptive resistance to the PI3Kαmutant selective inhibitor RLY-2608 in HR+/PIK3CA mutant breast cancer (AACR 2025) - "Alpelisib and inavolisib are currently FDA approved for treatment of PIK3CA-mutant breast cancers, although neither is selective for mutant PIK3CA...To identify the ERBB RTKs causing this adaptation, we tested the TKIs erlotinib, neratinib, and tucatinib, and the HER3 antibodies patritumab and zenocutuzumab, each in combination with RLY-2608...Other upregulated Hallmark pathways in both cell lines included Myogenesis, Hypoxia, and KRAS signaling down. These findings suggest that, in addition to RTK activation, adaptive resistance to RLY-2608 may involve metabolic reprogramming, increased oxidative stress, and hypoxia signaling, highlighting the need for combination strategies to overcome resistance and enhance treatment efficacy."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • EGFR • ERBB3 • ERBB4 • KRAS • PIK3CA

A longitudinal, circulating tumor molecular response biomarker as a predictor of clinical outcomes in a real-world cohort of patients with advanced solid tumors treated with tyrosine kinase inhibitors (AACR 2025) - "The most common therapies were osimertinib in NSCLC patients (n=34) and alpelisib + fulvestrant in BC patients (n=11). Median predicted rwOS among MRs receiving TKis in 1L (n=43) was 28.4 months vs. 16.5 months for nMRs (n = 19). The HR for death between MR vs nMR was consistent across different cancer subgroups and LOT: HR=0.38 for NSCLC patients, HR=0.57 for BC patients, HR=0.46 for 1L patients and HR=0.44 for 2L+ patients.These data demonstrate that longitudinal molecular treatment response can stratify rw-outcomes to TKi therapy in a heterogeneous, real-world pan cancer cohort."

Biomarker • Clinical • Clinical data • IO biomarker • Metastases • Real-world • Real-world evidence • Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

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

Targeting NRF2-responsive kinases for the treatment of esophageal squamous cell carcinoma (AACR 2025) - "Furthermore, NRF2null-KYSE70 cells showed increased sensitivity to EGFR inhibitor (Gefitinib), PIK3CA inhibitor (Alpelisib), and AKT inhibitor (Capivasertib), compared to NRF2W24C-KYSE70 cells. Consistent with these findings, pNRF2 expression correlated with PI3K signaling proteins, including pAKT and p-mTOR, in human ESCC tissues. These studies highlight the potential of combining an NRF2 inibitor with a PI3K pathway inhibitor as a promising therapeutic strategy for ESCC."

Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • AKT2 • DUSP1 • NFE2L2 • PIK3CA • PKM • PTEN

A chemoradiation platform for evaluating multimodal therapy effects on tumor viability and invasion ex vivo (AACR 2025) - "Proof-of-concept experiments with HPV-negative HNSCC lines (HN30 and HN31, established from primary and metastatic disease from the same patient) and HPV-positive HNSCC cells (SCC154) revealed that treatment with cetuximab and ibrutinib enhances radiosensitivity in HN31 cells. The PI3K inhibitor copanlisib radio-sensitized both HN30 and HN31, while alpelisib sensitized SCC154 cells. Additionally, copanlisib, afatinib, and ibrutinib were shown to limit ECM invasion of HN31, while the AKT inhibitor ipatasertib and the mTOR-targeting rapamycin promote invasion of HN30 cells, as observed in previous studies (Brolih et al., 2018). Our pilot experiments using bioprinted patient-derived HNSCC organoids confirmed the feasibility of performing sensitivity screening by integrating bioprinting, conventional viability assays, and advanced image analysis techniques. Our goal is to establish a personalized therapeutic pipeline for patients with advanced HNSCC, maximizing responses to..."

Preclinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Long-read whole genome sequencing identifies genes for targeted therapy to treat cervical cancer (AACR 2025) - "We tested the EGFR inhibitor Lapatinib on YAP1-amplified CaSki cells and found a five-fold reduction in proliferation...We conclude that oral PI3K inhibitors such as Alpelisib are a viable therapeutic option for up to 200,000 cervical patients annually and may enhance immunotherapies. Initial results suggest that EGFR pathway inhibitors may be beneficial in the most aggressive subtype of ICC. Our cell line panel can allow the testing of additional therapeutics to the YAP1 and other pathways to expand treatment further."

IO biomarker • Whole genome sequencing • Breast Cancer • Cervical Cancer • Oncology • Solid Tumor • BIRC2 • FBXW7 • KRAS • PIK3CA • PTEN • STK11 • YAP1

Monoclonal Antibodies and Small-Molecule Inhibitors Associated Osteonecrosis of Jaw: A Retrospective Pharmacovigilance Study. (PubMed, J Oral Maxillofac Surg) - "Denosumab, romosozumab, and lenvatinib are significantly associated with ONJ, particularly in older and female patients. Further research is needed to understand the mechanisms and improve risk management strategies."

Adverse events • Journal • Retrospective data

Elacestrant Combinations in Patients With Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer: Update From ELEVATE, a Phase 1b/2, Open-Label, Umbrella Study (MBCC 2025) - P1/2, P3 | "To address various resistance mechanisms, the phase 1/2 ELEVATE trial (NCT05563220) evaluates elacestrant with everolimus, alpelisib, capivasertib, ribociclib, palbociclib, or abemaciclib. Conclusion The evaluated combinations continue to demonstrate a known safety profile consistent with each drug plus SOC ET and no increased risk of associated AEs. Elacestrant has the potential to become the ET partner for multiple targeted agents, providing an all-oral treatment option in patients with ER+/HER2– metastatic breast cancer, delaying chemotherapy or antibody-drug conjugate– based regimens."

Clinical • Metastases • P1/2 data • Breast Cancer • Constipation • Dental Disorders • Diabetes • Estrogen Receptor Positive Breast Cancer • Fatigue • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Neutropenia • Oncology • Solid Tumor • Stomatitis • ER • HER-2

Post-progression treatment options after CDK4/6 inhibitors in hormone receptor-positive, HER2-negative metastatic breast cancer. (PubMed, Cancer Treat Rev) - "Endocrine therapies, including fulvestrant and novel oral selective estrogen receptor degraders (SERDs) like elacestrant, show promise, especially in patients with ESR1 mutations. Targeted therapies such as PI3K/AKT/mTOR inhibitors, exemplified by alpelisib and capivasertib, offer potential by addressing downstream signaling pathways involved in resistance. Additionally, FGFR inhibitors like erdafitinib are under investigation for their role in overcoming specific resistance mechanisms...Ongoing clinical trials are expected to provide deeper insights, guiding the development of more effective post-progression therapeutic strategies. This evolving landscape highlights the need for continuous research and individualized patient care to improve survival and quality of life in HR + mBC patients."

IO biomarker • Journal • Review • 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

Integrated multi-omics analysis and machine learning refine molecular subtypes and clinical outcome for hepatocellular carcinoma. (PubMed, Hereditas) - "Encouragingly, we observed that the high-CMLBS patients may exhibit increased sensitivity to Alpelisib, AZD7762, BMS-536,924, Carmustine, and GDC0810, whereas they may demonstrate reduced sensitivity to Axitinib, AZD6482, AZD8055, Entospletinib, GSK269962A, GSK1904529A, and GSK2606414, suggesting that CMLBS may contribute to the selection of chemotherapeutic agents for HCC patients. Therefore, in-depth examination of data from multi-omics data can provide valuable insights and contribute to the refinement of the molecular classification of HCC. In addition, the CMLBS model demonstrates potential as a screening tool for identifying HCC patients who may derive benefit from immunotherapy, and it possesses practical utility in the clinical management of HCC."

Clinical data • Journal • Hepatocellular Cancer • Oncology • Solid Tumor

Novel Estrogen Receptor - Targeted Therapies in Hormone-Receptor Positive Breast Cancer. (PubMed, Curr Treat Options Oncol) - "For those with PIK3CA or AKT1 mutation or PTEN inactivation, combination therapy with the AKT pathway inhibitor capivasertib is recommended. Alpelisib, the first AKT1 inhibitor approved in combination therapy with fulvestrant in PIK3CA mutated tumors only, is now less in favor given its challenging side effect profile. When mutations are not present, options include combination therapy with the mTOR inhibitor everolimus or changing endocrine therapy and continuing a CDK 4/6 inhibitor...Optimal sequencing of treatment options depends on several factors: (1) the presence of specific molecular aberrations; (2) previous treatment history, duration of response and patient's performance status; (3) balance between maximizing survival benefits with quality of life/toxicities; (4) disease burden. In the upcoming years, we anticipate FDA approvals for more of the SERD molecules both in monotherapy and in combination therapy which will continue to expand the options available..."

Journal • Review • Breast Cancer • Endocrine Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA • PTEN

Alpelisib associated hyperglycemia in patients with advanced breast cancer (ESPE-ESE 2025) - No abstract available

Clinical • Metastases • Breast Cancer • Diabetes • Oncology • Solid Tumor