zovegalisib (RLY-2608) / Relay Therap - LARVOL DELTA

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: [email protected]."

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

Molecular architecture responsible for specific inhibition of oncogenic PI3Kα mutants by RLY-2608 and STX-478. (PubMed, Acta Pharm Sin B) - "While both inhibitors occupy this pocket, they have distinct interaction networks and propagate divergent allosteric activities: RLY-2608 induces large-scale remodeling of catalytic and membrane-interacting elements, whereas STX-478 reinforces autoinhibitory interfaces between p110α and p85α subunits. Comparative analysis provides structural insights into their differentiated potency and selectivity."

Journal • Oncology • PIK3CA

Dose optimization of zovegalisib, a novel PI3Kα inhibitor, in patients (pts) with PIK3CA-mutant (m) HR+/HER2− advanced breast cancer (BC): Results from the first-in-human (FIH) study to support the recommended phase III dose (ESMO-TAT 2026) - "The ReDiscover FIH trial studied zovega with standard-dose fulvestrant (F) in CDK4/6 inhibitor (i)-experienced pts with PIK3CAm HR+/HER2- ABC and defined 600 mg BID fasted as the recommended phase 2 dose (RP2D). Zovega 400 mg BID fed achieves comparable PK exposures, ctDNA clearance, safety, and efficacy compared to 600 mg BID fasted, with easier dosing for pts, supporting selection of 400 mg BID fed + F as the RP3D for the Phase 3 ReDiscover-2 trial in pts with PIK3CAm HR+/HER2- ABC previously treated with CDK4/6i."

Clinical • First-in-human • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

Efficacy of RLY-2608, a mutant-selective PI3Kα inhibitor in patients with PIK3CA-mutant HR+HER2- advanced breast cancer: ReDiscover trial. (SABCS 2024) - P1 | "We report efficacy and safety of RLY-2608 + standard-dose fulvestrant (F) in pts with PIK3CA-mutant, HR+HER2- BC treated in the FIH study, ReDiscover (NCT05216432). Conclusion RLY-2608 demonstrates durable initial efficacy and favorable safety/tolerability across PIK3CA genotypes in heavily pretreated pts previously exposed to CDK4/6i with advanced PIK3CA-mutant HR+HER2- BC without concurrent PTEN/AKT alterations. These data validate RLY-2608 as the first allosteric pan-mutant selective PI3Kαi and warrant pivotal clinical development."

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

A patent review of mutant-selective PI3Kα inhibitors for the treatment of different cancers (2021 - 2025). (PubMed, Expert Opin Ther Pat) - "Specifically, we examine the binding modes across two distinct allosteric domains: an H1047R-specific pocket (exemplified by Eli Lilly's inhibitors) and a pan-mutant cryptic site (engaged by RLY-2608 and STX-478). Furthermore, development of allosteric inhibitor based PROTACs is discussed as a promising frontier for enhancing therapeutic precision. Ultimately, deeper understanding of evolving resistance mechanisms provides the design principles required to develop next-generation PI3Kα therapeutics capable of overcoming clinical resistance."

Journal • Review • Oncology • Solid Tumor • PIK3CA

ReDiscover-2, a phase 3 study of zovegalisib (zovega, RLY-2608) + fulvestrant (fulv) versus capivasertib (capi) + fulv 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. (ASCO 2026) - P3 | "The PI3K inhibitors alpelisib and inavolisib and the AKT inhibitor capi are approved therapeutic options; however, they are limited by significant toxicity, notably hyperglycemia, rash, and diarrhea, due to non-selective targeting of the pathway. ReDiscover-2 (NCT06982521) is open for enrollment. For information: [email protected]."

First-in-human • Metastases • P3 data • Breast Cancer • Diabetes • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Metabolic Disorders • Oncology • Solid Tumor • Type 1 Diabetes Mellitus • Type 2 Diabetes Mellitus • HER-2 • PIK3CA • PTEN

Updated efficacy of mutant-selective PI3Kα inhibitor RLY-2608 in combination with fulvestrant in patients with PIK3CA-mutant HR+HER2- advanced breast cancer: ReDiscover trial. (ASCO 2025) - P1 | "RLY-2608 demonstrates favorable safety/tolerability along with highly encouraging PFS observed across PIK3CA genotypes in pts with advanced PIK3CA-mutant HR+HER2- BC previously exposed to CDK4/6i. These data validate RLY-2608 as the first allosteric pan-mutant selective PI3Kαi and support advancing RLY-2608 + F to pivotal testing, which is planned for later this year."

Clinical • Combination therapy • Metastases • Breast Cancer • Dental Disorders • Diabetes • Fatigue • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Stomatitis • CDK4 • HER-2 • PIK3CA • PTEN

Phase 3 1L trial in patients with endocrine-sensitive breast cancer expected to initiate in early 2027, subject to regulatory feedback (GlobeNewswire)

Commercial • New P3 trial • Breast Cancer • Estrogen Receptor Positive Breast Cancer

Identification and characterization of pan-mutant selective PI3Kα inhibitors with the capability of PI3Kα H1047R protein degradation (AACR 2026) - P3 | "Orthosteric inhibitors of PI3Kα, such as alpelisib and inavolisib, have been approved for the treatment of patients with advanced HR+/HER2− breast cancer... Several allosteric and potent pan-mutant PI3Kα inhibitors developed by TYK Medicines exhibited high selectivity over wild-type (WT) PI3Kα. Our observations revealed that the compounds inhibited AKT phosphorylation in the T47D (PI3Kα H1047R) cell line with an IC50 in the single-digit nanomolar range, demonstrating nearly 200 times more selectivity compared to SK-BR-3 (PI3Kα WT) cells at same time. In in vitro antiproliferative assays, the compounds displayed superior antiproliferative activity against various PI3Kα mutant cells, including T47D, HCC1954 (PI3Kα H1047R), and MCF7 (PI3Kα E545K), compared to STX-478 and RLY-2608."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

Discovery of QLS1522, a mutant-selective allosteric PI3Kα inhibitor for the treatment of PIK3CA-mutant solid tumors (AACR 2026) - "While approved PI3Kα inhibitors like Alpelisib validate that PI3Kα blockade can suppress tumors and improve outcomes in PIK3CA-mutant ER+HER2- breast cancer, their major on-target toxicity against wild-type PI3Kα interferes with regulation of glucose metabolism which reduces their therapeutic index and limits clinical efficacy...Notably, it maintained selectivity comparable to STX-478 and better than RLY-2608 in wild-type SKBR3 cells... QLS1522 is a mutant-selective allosteric PI3Ka inhibitor and represents a promising therapeutic candidate for treating PIK3CA-mutant solid tumors. IND-enabling studies are currently in progress."

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

RLY-2608-201: 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 (clinicaltrials.gov) - P2 | N=277 | Recruiting | Sponsor: Relay Therapeutics, Inc. | N=45 ➔ 277

Enrollment change • CNS Disorders • PIK3CA

Genome-wide CRISPR screen identifies GPX4 as a potential vulnerability in cells treated with PI3Kα-mutant selective inhibitor RLY-2608 (AACR 2026) - "Genome-wide CRISPR KO screen identified GPX4 inhibition as a vulnerability in HR+/PIK3CA-mutant breast cancer cells treated with the PI3Kα-mutant selective inhibitor RLY-2608. These data support a mechanistic link between PI3Kα inhibition, lipid peroxidation, and ferroptosis, providing a rationale for clinical trials with the combination of PI3K pathway and GPX4 inhibitors."

Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • GPX4 • PIK3CA • PTEN • TSC1 • TSC2

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 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

ReDiscover-2: Phase 3 Study of RLY-2608 + Fulvestrant vs Capivasertib + Fulvestrant as Treatment for Locally Advanced or Metastatic PIK3CA-mutant HR+/HER2- Breast Cancer (clinicaltrials.gov) - P3 | N=540 | Recruiting | Sponsor: Relay Therapeutics, Inc.

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

Strategies to overcome resistance to PI3Kalpha-selective inhibitors mediated by acquired alterations in the PI3K/AKT pathway (AACR 2024) - "The PI3Kα-selective orthosteric inhibitor alpelisib is the only drug targeting PIK3CA currently approved in this patient population, in combination with fulvestrant...Among them, we have identified for the first-time secondary mutations in PIK3CA (W780R and Q859K) that decrease the affinity of the PI3Kα-selective inhibitors alpelisib and inavolisib, leading to acquired resistance...Importantly, vertical pathway inhibition or allosteric inhibition with pan-mutant-selective PI3Kα inhibitors such as RLY-2608 or STX-478 could overcome resistance induced by all emerging secondary PIK3CA mutations.Dose-limiting toxicity in the form of hyperglycemia, rash or gastrointestinal issues are common in patients treated with orthosteric PI3Kα inhibitors...Our work suggests that combining orthosteric and allosteric PI3Kα inhibitors as well as downstream pathway deactivation with AKT inhibitors could result in an increased therapeutic index and delay the emergence of resistance in..."

Late-breaking abstract • 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

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

LAE118, a pan mutant-selective PI3Ka inhibitor with superb activity against both the kinase domain and helical domain mutants (AACR 2025) - "In response to this, pan-mutant selective PI3Ka inhibitors including RLY-2608 and STX-478 are being developed in clinical trials for cancer patients with PIK3CA mutations. Human PK projection indicates LAE118 has the potential to achieve continuous inhibition of pAKT in clinic without causing hyperglycemia. LAE118 is currently in IND enabling stage, positioning it as a promising candidate for the treatment of cancers with PIK3CA mutations."

Late-breaking abstract • Oncology • PIK3CA

The Phase 3 ReDiscover-2 trial (NCT06982521) is evaluating zovegalisib 400mg BID administered in combination with fulvestrant versus capivasertib + fulvestrant in patients with PI3Kα-mutated, HR+/HER2- advanced breast cancer who have progressed on prior CDK4/6 inhibitor therapy. (The Manila Times) - "The study initiated in mid-2025 and is enrolling globally."

Trial status • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

Relay Therapeutics Announces Data from Zovegalisib + Fulvestrant at the Phase 3 Dose of 400mg BID Fed at ESMO Targeted Anticancer Therapies Congress 2026 (The Manila Times) - "Pharmacokinetic analyses demonstrate that the 400mg BID fed regimen achieves exposures comparable to the previously evaluated 600mg BID fasted dose..Median progression-free survival (PFS) was 11.1 months (95% CI: 7.3-13.0); Median PFS was 11.2 months in patients with kinase mutations (n=33) and 11.0 months in patients with non-kinase mutations (n=24); Among 35 patients with measurable disease, confirmed objective response rate (ORR) was 43% (15/35) and in second line only patients the ORR was 52% (11/21)."

P1/2 data • PK/PD data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

Updated Efficacy of Mutant-Selective PI3K伪 Inhibitor Zovegalisib (RLY-2608) in Combination with Fulvestrant in Patients with PIK3CA-Mutant HR+HER2- Advanced Breast Cancer: ReDiscover Trial (MBCC 2026) - No abstract available

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

ReDiscover-2, a Phase 3 Study of Zovegalisib (RLY2608) + 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) (MBCC 2026) - No abstract available

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

RLY-2608-102: A Study to compare RLY-2608 + Fulvestrant with Capivasertib + Fulvestrant in people with PIK3CA-mutated, hormone-receptor positive, HER2-negative advanced or metastatic breast cancer (clinicaltrialsregister.eu) - P2/3 | N=272 | Recruiting | Sponsor: Relay Therapeutics Inc.

New P2/3 trial • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

Relay Therapeutics Announces Zovegalisib Granted Breakthrough Therapy Designation by U.S. FDA for PIK3CA-mutant, HR+/HER2- Advanced Breast Cancer (GlobeNewswire) - "Designation supported by robust clinical data from ReDiscover trial with 600mg BID fasted and 400mg BID fed doses of zovegalisib in combination with fulvestrant; Initial Phase 1/2 data of zovegalisib + fulvestrant at the 400mg BID fed (Phase 3 dose) in CDK4/6-experienced patients to be presented at ESMO Targeted Anticancer Therapies Congress on March 16"

Breakthrough therapy • P1/2 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

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