GSK2636771 / GSK - LARVOL DELTA

EAY131-N: Testing GSK2636771 as a Potential Targeted Treatment in Cancers With PTEN Genetic Changes (MATCH-Subprotocol N) (clinicaltrials.gov) - P2 | N=24 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Nov 2025 ➔ Dec 2026

Trial completion date • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • Solid Tumor • PTEN

EAY131-P: Testing GSK2636771 as a Potential Targeted Treatment in Cancers With PTEN Loss of Expression (MATCH-Subprotocol P) (clinicaltrials.gov) - P2 | N=35 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Nov 2025 ➔ Dec 2026

Trial completion date • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • Solid Tumor • PTEN

NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial) (clinicaltrials.gov) - P2 | N=6452 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Biomarker • Trial completion date • Trial primary completion date • Bladder Cancer • Brain Cancer • Breast Cancer • Cervical Cancer • Colon Cancer • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Genito-urinary Cancer • Glioblastoma • Glioma • Head and Neck Cancer • Hematological Malignancies • Hormone Receptor Positive Breast Cancer • Kidney Cancer • Liver Cancer • Lung Cancer • Lymphoma • Melanoma • Multiple Myeloma • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Refractory Ovarian Cancer • Renal Cell Carcinoma • Skin Cancer • Solid Tumor • Thyroid Gland Carcinoma • Uterine Cancer • CD4 • MSI

PIK3CB Inhibitor GSK2636771 in Cancers With PTEN Mutation/Deletion or Loss of PTEN Protein Expression: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocols N and P. (PubMed, JCO Precis Oncol) - "Although the primary end point of OR was not met, GSK2636771 demonstrated modest single-agent activity among patients with relapsed/refractory cancer having PTEN mutation/deletion with PTEN expression or PTEN protein loss."

Journal • Bladder Cancer • Endocrine Disorders • Endometrial Cancer • Fatigue • Genito-urinary Cancer • Hematological Disorders • Hematological Malignancies • Leiomyosarcoma • Lymphoma • Multiple Myeloma • Oncology • Prostate Cancer • Sarcoma • Solid Tumor • Uterine Leiomyosarcoma • PIK3CB • PTEN

Validation of genetically defined Oncopig hepatocellular carcinoma cell lines for in vitro evaluation of targeted therapeutic efficacy (AACR 2025) - "Therapeutic susceptibility of the established Oncopig WT, PTENKO, AXIN1KO, and ARID1KO HCC cell lines was assessed for PI3K inhibitors (GSK2636771, BAY 80-6946, and BKM120). These results validate the utility of the Oncopig HCC model for preclinical evaluation of novel targeted therapeutics in vitro. Future work demonstrating consistent results in vivo will enable the genetically defined Oncopig HCC model to be an ideal animal system to test precision medicine therapeutics prior to entry into the clinic.Therapeutic Susceptibility (Log IC50 (µM))PI3K InhibitorOncopig WT HCCOncopig AXIN1KO HCCOncopig ARID1KO HCCOncopig PTENKO HCCHuman PTEN Null CellsGSK26367711.461.170.660.07ResponsiveBAY80-694611.55.64.52.38ResponsiveBKM1202.050.95NA2.3Non-Responsive"

Preclinical • Hepatocellular Cancer • Oncology • Solid Tumor • ARID1A • KRAS • PTEN

Biomarker-Integrated Umbrella, Advanced Gastric Cancer (clinicaltrials.gov) - P2 | N=400 | Completed | Sponsor: Yonsei University | Active, not recruiting ➔ Completed | Trial completion date: Dec 2022 ➔ Mar 2024

Biomarker • Trial completion • Trial completion date • Esophageal Cancer • Gastric Cancer • Oncology • Solid Tumor • PD-L1

Biomarker-Integrated Umbrella, Advanced Gastric Cancer (clinicaltrials.gov) - P=N/A | N=400 | Completed | Sponsor: Yonsei University | Phase classification: P2 ➔ P=N/A

Biomarker • Phase classification • Esophageal Cancer • Gastric Cancer • Oncology • Solid Tumor • PD-L1

EAY131-N: Testing GSK2636771 as a Potential Targeted Treatment in Cancers With PTEN Genetic Changes (MATCH-Subprotocol N) (clinicaltrials.gov) - P2 | N=35 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Nov 2024 ➔ Nov 2025 | Trial primary completion date: Nov 2024 ➔ Nov 2025

Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • Solid Tumor • PTEN

EAY131-P: Testing GSK2636771 as a Potential Targeted Treatment in Cancers With PTEN Loss of Expression (MATCH-Subprotocol P) (clinicaltrials.gov) - P2 | N=35 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Nov 2024 ➔ Nov 2025 | Trial primary completion date: Nov 2024 ➔ Nov 2025

Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • Solid Tumor • PTEN

Combined inhibition of CDK4/6 and AKT is highly active against the luminal androgen receptor (LAR) subtype of triple negative breast cancer (TNBC) (AACR 2024) - "Enzalutamide, an AR antagonist, exerted no growth inhibitory activity (IC50, 15-25 μM)...The combination of palbociclib+capivasertib synergistically inhibited the proliferation of MDAMB453 and MFM223 cells (synergistic scores 7.34, p=5.81-11, and 4.78, p=0.012, respectively) better than palbociclib+alpelisib...PI3Kβ inhibitors (TGX221, GSK2636771) did not block AKT substrate upregulation, suggesting PI3Kβ does not mediate adaptive responses...Treatment with palbociclib and the PDGFRβ small-molecule antagonist CP673451 arrested LAR TNBC growth similar to palbociclib+capivasertib, suggesting an adaptive response involving PDGFRβ signaling. In conclusion, this study supports the clinical testing of the palbociclib and capivasertib combination for LAR TNBC patients and reveals adaptive responses after palbociclib treatment through PDGFRβ signaling."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AKT1S1 • AR • CDK4 • PDGFRB • PIK3CA • PIK3CB • STAT3

Testing GSK2636771 as a Potential Targeted Treatment in Cancers With PTEN Loss of Expression (MATCH-Subprotocol P) (clinicaltrials.gov) - P2 | N=35 | Active, not recruiting | Sponsor: National Cancer Institute (NCI)

Trial completion date • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • Solid Tumor • PTEN

Testing GSK2636771 as a Potential Targeted Treatment in Cancers With PTEN Loss of Expression (MATCH-Subprotocol P) (clinicaltrials.gov) - P2 | N=35 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial primary completion date: Nov 2023 ➔ Nov 2024

Trial primary completion date • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • Solid Tumor • PTEN

Testing GSK2636771 as a Potential Targeted Treatment in Cancers With PTEN Genetic Changes (MATCH-Subprotocol N) (clinicaltrials.gov) - P2 | N=35 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Nov 2023 ➔ Nov 2024 | Trial primary completion date: Nov 2023 ➔ Nov 2024

Trial completion date • Trial primary completion date • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • Solid Tumor • PTEN

Open-Label, Multicenter, Randomized, Biomarker-Integrated Umbrella Trial for Second-Line Treatment of Advanced Gastric Cancer: K-Umbrella Gastric Cancer Study (J Clin Oncol) - P2 | N=400 | NCT02951091 | "A total of 318 patients were randomly assigned into the control (n = 64) and biomarker (n = 254; EGFR, n = 67; PTEN, n = 37; NIVO, n = 48; NONE, n = 102) groups. Median follow-up was 35 months. Median PFS and overall survival (OS) were 3.7 (95% CI, 3.1 to 4.1) and 8.6 (95% CI, 7.6 to 9.8) months in the biomarker group and 4.0 (95% CI, 3.0 to 4.6) and 8.7 (95% CI, 7.1 to 9.9) months in the control group. Afatinib addition led to marginal survival benefits to patients with EGFR 3+ compared with SOC (PFS, 4.0 v 2.2 months; P = .09), but GSK2636771 did not prolong the survival of patients with PTEN loss. Addition of nivolumab showed a durable survival benefit (median OS, 12.0 v 7.6 months; P = .08)."

P2 data • Gastric Cancer

Open-Label, Multicenter, Randomized, Biomarker-Integrated Umbrella Trial for Second-Line Treatment of Advanced Gastric Cancer: K-Umbrella Gastric Cancer Study. (PubMed, J Clin Oncol) - "Although biomarker group did not show better survival than the control group, IHC-based screening and allocation of patients with AGC to the second-line treatment in an umbrella design were feasible for effective early screening of novel agents."

Biomarker • IO biomarker • Journal • Metastases • Epstein-Barr Virus Infections • Gastric Cancer • Gastrointestinal Cancer • Microsatellite Instability • Oncology • Solid Tumor • EGFR • HER-2 • MSI • PIK3CB • PTEN

Study of the Selective PI3K-Beta Inhibitor GSK2636771 in Combination With Pembrolizumab in Patients With Metastatic Melanoma and PTEN Loss (clinicaltrials.gov) - P1/2 | N=27 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Dec 2023 ➔ Dec 2025 | Trial primary completion date: Dec 2023 ➔ Dec 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Melanoma • Oncology • Skin Cancer • Solid Tumor • PTEN

The first report of K-Umbrella Gastric Cancer Study: An open label, multi-center, randomized, biomarker-integrated trial for second-line treatment of advanced gastric cancer (AGC). (ASCO 2022) - P=N/A | "In the biomarker group, patients were treated with specific targeted agents in combination with weekly paclitaxel; 1) EGFR 2+/3+ patients for pan-ERBB inhibitor (afatinib; EGFR cohort), 2) PTEN loss/null (H-score <100) patients for PIK3Cβ inhibitor (GSK2636771; PTEN cohort), and 3) PD-L1+, dMMR/MSI-high, or EBV-related cases for anti-PD-1 inhibitor (nivolumab; NIVO cohort). Control group and NONE cohort in biomarker group without predefined biomarkers were treated with SOC (weekly Paclitaxel±Ramucirumab)... Considering the characteristics of umbrella design with multiple biomarkers having different biological roles, biomarker group did not show the improved survival over control arm with these 3 drugs. For optimal biomarker-driven targeted agent applications, NGS-based biomarker driven K-Umbrella GC-2 study is ongoing."

Biomarker • Clinical • IO biomarker • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • EGFR • HER-2 • PD-L1 • PIK3CB • PTEN

Targeting PI3K isoforms to improve the effectiveness of T cell mediated immunotherapy (AACR 2023) - "In PTEN-present tumors, BYL719 (BYL, a PI3Kα inhibitor) synergized with αPD1 to delay tumor growth and extend survival (median survival of MC38-bearing mice in control (Ctrl), BYL, αPD1, and combination (Comb) groups: 30, 36, 33, and >45 respectively; p<0.05: Ctrl/BYL/αPD1 vs Comb). However, a limited combinatorial effect between GSK2636771(a PI3Kβ inhibitor) and αPD1 was observed in PTEN-present tumor models...Collectively, our results demonstrate that PI3Kα inhibitor can potentiate T cell-mediated antitumor immune responses regardless of PTEN status, providing a strong rationale for the clinical development of the BYL-based IO combination. In collaboration with Novartis, MD Anderson Cancer Center will launch a Phase I/II trial of the FDA-approved BYL in combination with αPD1 in advanced melanoma and breast cancer patients."

IO biomarker • Breast Cancer • Melanoma • Oncology • Solid Tumor • BRAF • CD8 • PIK3CA • PIK3CB • PIK3CD • PIK3CG • PTEN

Co-targeting CK1ε and PIK3CB/p110ß as a Therapeutic Approach for Glioblastoma. (AAN 2023) - "Future directions include a dose response experiment to determine the most effective dose of GSK2636771 and IC261 in order to yield stronger synergistic effects. To further elucidate the mechanism of GBM cell death, immunoblotting will also be performed to detect β-catenin activity after inhibition of CK1ε and PIK3CB/p110β."

Brain Cancer • CNS Tumor • Glioblastoma • Immune Modulation • Oncology • Solid Tumor • PIK3CB

Whole Genome and Transcriptome Sequencing Analyses Elucidate Relevant Molecular Phenotypes in Gastric/Gastroesophageal Junction (GEJ) Adenocarcinomas (USCAP 2023) - "Integrative analysis of WGS/RNAseq in Gastric/GEJ adenocarcinomas increases the capacity to uncover potential targets beyond targeted panels by identifying driver mutations, germline mutations, structural variants, gene fusions and likely relevant genomic signatures via a single modality. Our findings warrant further validation and clinical correlation."

IO biomarker • Tumor mutational burden • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Microsatellite Instability • Oncology • ARID1A • BRCA1 • BRCA2 • CDK12 • CDKN2A • FGFR1 • HER-2 • KRAS • MET • MSI • NRG1 • PIK3CA • PTCH1 • PTEN • RAD51B • SMARCA4 • STAT3 • TMB • TNFRSF10D • TSC2

Whole Genome and Transcriptome Sequencing Analyses Elucidate Relevant Molecular Phenotypes in Gastric/Gastroesophageal Junction (GEJ) Adenocarcinomas (USCAP 2023) - "Integrative analysis of WGS/RNAseq in Gastric/GEJ adenocarcinomas increases the capacity to uncover potential targets beyond targeted panels by identifying driver mutations, germline mutations, structural variants, gene fusions and likely relevant genomic signatures via a single modality. Our findings warrant further validation and clinical correlation."

IO biomarker • Tumor mutational burden • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Microsatellite Instability • Oncology • ARID1A • BRCA1 • BRCA2 • CDK12 • CDKN2A • FGFR1 • HER-2 • KRAS • MET • MSI • NRG1 • PIK3CA • PTCH1 • PTEN • RAD51B • SMARCA4 • STAT3 • TMB • TNFRSF10D • TSC2

Integrative Whole Genome and Transcriptome Sequencing Analysis of Advanced Prostate Cancer Unearths Genomic Signatures and Novel Events of Potential Significance (USCAP 2023) - "Results Table: Mutated Genes / Fusions Alteration Treatment N. of Cases Tumor Type CDKN2A Oncogenic mutation CDK inhibitors 2 1 Adenocarcinoma 1 NEPC HRAS Oncogenic mutation Tipifarnib 1 Adenocarcinoma PTEN Oncogenic mutation AZD8186 and GSK2636771 12 7 Adenocarcinoma 4 NEPC 1 Carcinosarcoma MET Amplification Tepotinib, Capmatinib and Crizotinib 1 Adenocarcinoma TMB Tumor Mutational Burden-High Check Point Inhibitors 2 1 Adenocarcinoma 1 NEPC MSI Microsatellite Instability-High Check Point Inhibitors 1 NEPC CDK12 Truncating and Oncogenic mutation Check Point Inhibitors Olaparib 2 1 Adenocarcinoma 1 NEPC FGFR1/ FGFR2 Amplification/ Oncogenic mutation FGFR inhibitors 2 NEPC mTOR Oncogenic mutation Temsirolimus and Everolimus 1 NEPC NF1 Oncogenic mutation Cobimetinib and Trametinib 1 NEPC ALK SLC45A3-ALK ALK inhibitors 1 Adenocarcinoma PIK3CA Oncogenic mutation Alpelisib and Fulvestrant 1 Carcinosarcoma PALB2 Oncogenic mutation PARP inhibitors 1 Adenocarcinoma BRCA2..."

Metastases • Tumor mutational burden • Genito-urinary Cancer • Microsatellite Instability • Oncology • Prostate Cancer • Sarcoma • Solid Tumor • BRCA1 • BRCA2 • CDK12 • CDKN2A • ERG • ETV4 • FGFR1 • FGFR2 • HRAS • HRD • MBD4 • MED1 • MET • MSI • MUTYH • NF1 • PALB2 • PIK3CA • POLD1 • PPM1D • PTEN • RAD51B • SLC45A3 • TMB

Insights into the compensation mechanism behind targeting PI3K and Wnt in triple-negative breast cancer (SABCS 2021) - P1 | " Twelve PI3K inhibitors including alpelisib, buparlisib, idelalisib, duvelisib, GSK2636771, GSK2292767, and CAY10505 were tested. Refining clinical trial combinations and therapies to optimize drug efficacy while decreasing toxicity is a vital part of precision medicine. Here we have sought to optimize our previous clinical experience of dual targeting of PI3K and PTK7 and found two potential FDA approved therapies that may provide better efficacy and toxicities. Taking the previous trial and this preclinical data, future trials are warranted in TNBC."

Breast Cancer • Oncology • Triple Negative Breast Cancer

Phase I, open-label, dose-finding study of GSK2636771, a phosphoinositide 3-kinase (PI3K)β inhibitor, in combination with enzalutamide in male subjects with metastatic castration-resistant prostate cancer (mCRPC) (ESMO 2017) - P1; "Our preliminary data indicate that GSK2636771 in combination with enzalutamide is largely well tolerated and confirm the clinical relevance of PI3Kb inhibition in PTEN-deficient mCRPC. GSK funds this study."

Combination therapy • Prostate Cancer

Study of the Selective PI3K-Beta Inhibitor GSK2636771 in Combination With Pembrolizumab in Patients With Metastatic Melanoma and PTEN Loss (clinicaltrials.gov) - P1/2 | N=27 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Dec 2022 ➔ Dec 2023 | Trial primary completion date: Dec 2022 ➔ Dec 2023

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Melanoma • Oncology • Skin Cancer • Solid Tumor • PTEN