RLY-2608 / Relay Therap - LARVOL DELTA

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

Relay Therapeutics Announces Efficacy Subset Analysis of Zovegalisib (RLY-2608) + Fulvestrant in Breast Cancer Patients Pre-Treated with SERD or with ESR1 Mutations at SABCS 2025 (GlobeNewswire) - "As of the data cut-off date of October 15, 2025, 118 patients had enrolled into the zovegalisib + fulvestrant arm of the ReDiscover study....The total efficacy population consisted of 52 zovegalisib + fulvestrant patients....The median progression free survival (PFS) was 10.3 months for all patients. Among the total of 31 patients with measurable disease, objective response rate (ORR) was 39%. For second line (2L) patients, median PFS was 11.4 months and ORR was 47%....For patients who received prior SERD, median PFS was 11.4 months and ORR was 44% (7/16), and for patients who had a detectable ESR1 mutation at baseline, median PFS was 8.8 months and ORR was 60% (6/10)."

P1 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

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

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

Efficacy of mutant-selective PI3Kα inhibitor RLY-2608 in combination with fulvestrant in patient (pt) subset populations, including pts with PIK3CA-mutant HR+/HER2- advanced breast cancer (BC) pre-treated with fulvestrant or other SERD (SABCS 2025) - P1 | "There were no grade 4/5 TRAEs.Conclusion RLY-2608 + F demonstrates promising efficacy in pts with PIK3CA-mutated HR+/HER2- advanced BC who have progressed on CDK4/6i. These data also highlight the activity of RLY-2608 in pts with prior exposure and resistance to SERD where benefit from fulvestrant is not expected, and support the ongoing pivotal investigation of RLY-2608 + F."

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 • CDK4 • ER • HER-2 • PIK3CA • PTEN

The farnesyl transferase inhibitor KO-2806 constrains mTORC1 activity to enhance the antitumor efficacy of mutant-selective PI3Kα inhibitors (AACR-NCI-EORTC 2025) - "We have previously demonstrated farnesyl transferase inhibitors (FTIs) enhance the antitumor activity of multiple targeted therapies, including the α-selective PI3K inhibitor alpelisib, by blocking RHEB-mediated mTORC1 activation...In this study, we assessed the potential therapeutic utility of combining KO-2806 with mutant-selective PI3Kα inhibitors STX-478 or RLY-2608 in a panel of in vitro cell line and in vivo xenograft models spanning the breadth of solid tumor indications with the highest frequency of PIK3CA mutation...In the ER+ model MCF7, combination of KO-2806 and RLY-2608 was comparable to combination of fulvestrant and RLY-2608, resulting in tumor regressions, while the triplet further deepened tumor regression. These data suggest that, due to its ability to constrain mTORC1 signaling, KO-2806 holds promise as a combination agent for mutant-selective PI3Kα inhibitors across a broad range of PIK3CA-mutant solid tumor indications."

Clinical • Bladder Cancer • Colorectal Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AKT1S1 • PIK3CA • RHEB

Dual PI3K and RAS pathway inhibition overcomes therapeutic resistance in KRAS/PIK3CA co-mutant colorectal cancer patient-derived organoids (AACR-NCI-EORTC 2025) - "PDOs were stratified as wild-type, KRAS-mutant, or KRAS/PIK3CA double-mutant and treated with PI3Kα-selective inhibitors RLY-2608, STX-478, or alpelisib, either alone or in combination with the RAS inhibitor RM-042, a first-in-class oral agent targeting GTP-bound RAS. Together, our studies establish that KRAS/PIK3CA co-mutant CRC exhibits unique vulnerabilities to combined PI3K and RAS inhibition. This work provides a rationale for developing dual-pathway therapeutic strategies tailored to this aggressive molecular subtype in CRC."

Clinical • Late-breaking abstract • Colorectal Cancer • Oncology • Solid Tumor • KRAS • PIK3CA

mTOR variants activation discovers PI3K-like cryptic pocket, expanding allosteric, mutant-selective inhibitor designs. (PubMed, bioRxiv) - "The cryptic pocket created by disrupted α-packing coincides with the allosteric pocket in PI3Kα can be harmoniously fitted by the PI3Kα allosteric inhibitor RLY-2608, suggesting that analogous drugs designed based on RLY-2608 can restore the packed α-structure, resulting in mTOR inactive conformation. Our results exemplify that knowledge of detailed kinase activation mechanisms can inform innovative allosteric inhibitor development."

Journal • Oncology • PI3K • PIK3CA

ReDiscover: First-in-Human Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, as a Single Agent in Patients With Advanced Solid Tumors and in Combination With Endocrine Therapy +/- a CDK4/6 or CDK4 Inhibitor in Patients With Advanced Solid Tumors or Advanced Breast Cancer (clinicaltrials.gov) - P1 | N=930 | Recruiting | Sponsor: Relay Therapeutics, Inc. | Trial completion date: Aug 2026 ➔ Apr 2027 | Trial primary completion date: Dec 2025 ➔ Apr 2027

First-in-human • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • BRCA1 • BRCA2 • HER-2 • PIK3CA

Structural Insights into the Development of Inhibitors Against Cancer-Specific Mutations of PI3Kα. (PubMed, Annu Rev Pharmacol Toxicol) - "While early pan- and isoform-selective PI3K inhibitors (alpelisib) show clinical utility, their intrinsic toxicity and resistance to treatment persist. Recent breakthroughs include the emergence of allosteric inhibitors (RLY-2608 and STX-478) that exploit mutation-induced cryptic pockets to achieve mutant selectivity as well as covalent inhibitors and degraders (inavolisib) that enhance specificity, aiming at decoupling antitumor activity from metabolic dysfunction. This review synthesizes current progress in PI3Kα inhibitor development, emphasizing structural characteristics, clinical challenges, and emerging strategies. Addressing challenges to increase mutant selectivity, exploring conformational modulation, uncovering new mechanisms of action, and implementing personalized therapies are key future directions for PI3Kα-targeted drug discovery."

Journal • Review • Metabolic Disorders • Oncology • PIK3CA

In Silico Discovery of a Novel Potential Allosteric PI3Kα Inhibitor Incorporating 3-(2-Chloro-5-fluorophenyl)isoindolin-1-one to Target Head and Neck Squamous Cell Carcinoma. (PubMed, Biology (Basel)) - "Compared to ATP-competitive PI3Kα inhibitors such as Alpelisib, the allosteric inhibitor RLY-2608 exhibits enhanced selectivity for mutant PI3Kα while minimizing the inhibition of wild-type PI3Kα, thereby reducing side effects such as hyperglycemia. Through integrated approaches, including molecular docking studies, target validation, druggability evaluation, molecular dynamics simulations, and metabolic pathway and metabolite analyses, we successfully identified a promising novel allosteric PI3Kα inhibitor, H-18 (3-(2-chloro-5-fluorophenyl)isoindolin-1-one). H-18 has not been previously reported as a PI3Kα inhibitor, and provides an excellent foundation for subsequent lead optimization, offering a significant starting point for the development of more potent PI3Kα allosteric inhibitors."

IO biomarker • Journal • Diabetes • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • 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. | Not yet recruiting ➔ Recruiting

Enrollment open • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast 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

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

Relay Therapeutics Announces Updated Data for RLY-2608 + Fulvestrant Further Demonstrating Clinically Meaningful Progression Free Survival at ASCO 2025 (GlobeNewswire) - P1 | N=890 | ReDiscover (NCT05216432) | Sponsor: Relay Therapeutics, Inc. | "The median PFS was 10.3 months for all patients and 11.0 months for 2L patients. For 2L patients, median PFS was 18.4 months for patients with kinase mutations and 8.5 months for patients with non-kinase mutations. Clinical benefit rate (CBR) was 67% across all patients (35 of 52 CBR-evaluable patients; CBR defined as the proportion of patients with complete response, partial response or stable disease for at least 24 weeks). Among the 31 patients with measurable disease, 12 achieved a partial response (PR) (39% confirmed objective response rate, ORR). 81% of patients experienced tumor reductions (25/31). Among the 15 patients with measurable disease who had a kinase mutation, two thirds achieved a PR (67% confirmed ORR; n=10)."

P1 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

Multi-node inhibition targeting mTORC1, mTORC2 and PI3Kα potently inhibits the PI3K/AKT/mTOR pathway in endometrial and breast cancer models. (PubMed, Br J Cancer) - "Multi-node PI3K/AKT/mTOR pathway inhibition with serabelisib, sapanisertib and ISD is highly effective in preclinical models of endometrial and breast cancer, supporting continued clinical development in these and other solid tumours."

Journal • Preclinical • Breast Cancer • Endometrial Cancer • Oncology • Solid Tumor • EIF4EBP1 • 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 | Not yet recruiting | Sponsor: Relay Therapeutics, Inc.

New P3 trial • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Relay Therapeutics Reports First Quarter 2025 Financial Results and Corporate Updates (GlobeNewswire) - "RLY-2608 Highlights: Breast Cancer (i) Initiation of Phase 3 ReDiscover-2 trial of RLY-2608 + fulvestrant in PI3Kα-mutated, CDK4/6 pre-treated, HR+/HER2- advanced breast cancer remains on track for mid-2025; (ii) Abstract accepted to ASCO for update of Phase 1b ReDiscover trial of RLY-2608 + fulvestrant: Focus of the abstract is updated 600mg BID (fasted) doublet data with median follow-up now greater than 12 months...; (iii) Continued advancement of the ongoing triplet cohorts with RLY-2608 + fulvestrant + atirmociclib or ribociclib."

New P3 trial • P1 data • Trial status • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

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

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

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

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=280 | Recruiting | Sponsor: Relay Therapeutics, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders

Relay Therapeutics Reports Fourth Quarter and Full Year 2024 Financial Results and Corporate Updates (GlobeNewswire) - "Anticipated 2025 Milestones: Initiation of Phase 3 ReDiscover-2 trial of RLY-2608 + fulvestrant anticipated in the middle of 2025 in PI3Kα-mutated, CDK4/6 pre-treated, HR+/HER2- metastatic breast cancer; Additional Phase 1b doublet data in 2025."

New P3 trial • P1 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

ReDiscover: First-in-Human Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, As a Single Agent in Advanced Solid Tumor Patients and in Combination with Fulvestrant in Patients with Advanced Breast Cancer (clinicaltrials.gov) - P1 | N=890 | Recruiting | Sponsor: Relay Therapeutics, Inc. | N=400 ➔ 890

Enrollment change • Breast Cancer • Endometrial Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • BRCA1 • BRCA2 • HER-2 • PIK3CA

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=280 | Not yet recruiting | Sponsor: Relay Therapeutics, Inc.

New P2 trial