Relay Therapeutics Shares Updated Interim Data for Novel PI3Kα Inhibitor in Breast Cancer Treatment

Relay Therapeutics, a clinical-stage precision medicine company, has announced updated interim clinical data for its investigational allosteric PI3Kα inhibitor, RLY-2608, at the San Antonio Breast Cancer Symposium.

The data reveal significant improvements in progression-free survival (PFS) and objective response rates (ORR), building on previous results reported in September, when we highlighted the drug's promising early efficacy and safety profile. This new information hints at RLY-2608’s potential to redefine the standard of care for patients with PI3Kα-mutated HR+/HER2- metastatic breast cancer.

RLY-2608 is the first allosteric, pan-mutant, and isoform-selective PI3Kα inhibitor developed through Relay Therapeutics’ cutting-edge computational and experimental technologies, designed to address previously challenging protein targets in oncology.

Key Updates from the December Data

The latest results highlight several critical advancements since the previous report:

1. Updated Efficacy Data:

   • In the earlier report, the median progression-free survival (PFS) was approximately 9.2 months across all patients, with partial responses in 10 patients.
   • By December, PFS improved to 11.4 months for second-line patients with kinase mutations at the recommended Phase 2 dose (RP2D), demonstrating continued maturation of efficacy data.
   • The objective response rate (ORR) in kinase-mutated patients increased to 67%, up from the broader 75% tumor reduction in measurable disease reported earlier.

2. Refined Patient Subgroup Analysis:

   • New data delves deeper into subgroup performance, distinguishing kinase mutations from non-kinase mutations and excluding patients with PTEN or AKT co-mutations from the efficacy analysis.
   • This refined analysis supports the planned pivotal trial population.

3. Tolerability Profile:

   • The update confirms a low rate of treatment-related adverse events (TRAEs), with only two patients discontinuing due to low-grade TRAEs and 94% median dose intensity maintained.
   • Hyperglycemia events remain minimal, addressing a significant concern with PI3Kα inhibitors.

4. Ongoing Triplet Studies:

   • The earlier report mentioned planned triplet combinations. The update brings details on the RLY-2608 + ribociclib + fulvestrant and the RLY-2608 + atirmociclib + fulvestrant regimens, with dose escalation ongoing.

5. Study Expansion Plans:

   • The update confirms a 2025 initiation of a pivotal study in second-line patients and introduces plans to evaluate RLY-2608 in vascular malformations starting in early 2025.

6. Context and Validation:

   • The update emphasizes the differentiation of RLY-2608 from existing PI3Kα inhibitors, reinforcing its potential superiority in both efficacy and safety.

Don Bergstrom, President of R&D at Relay Therapeutics:

“Today’s data represents a significant step forward in our mission to bring a more effective and safer treatment option to patients with metastatic breast cancer. We are encouraged by the progression-free survival and objective response rates in the planned pivotal trial population and are excited to advance RLY-2608 into late-stage development.”

RLY-2608 targets PI3Kα, the most frequently mutated kinase in cancers, and leverages a unique allosteric mechanism to achieve mutant-selective inhibition. This approach reduces wild-type toxicity and has demonstrated a differentiated safety profile compared to conventional PI3Kα inhibitors.

Current Pipeline Overview

Relay Therapeutics’ current pipeline consists of several precision oncology and genetic disease candidates, each leveraging its innovative Dynamo platform to address previously intractable targets:

• RLY-4008 (FGFR2 Inhibitor):
  An oral, small-molecule, selective inhibitor of FGFR2, designed to minimize off-target toxicities associated with pan-FGFR inhibitors. It is in the early clinical stage, with ongoing first-in-human trials showing tumor regression in multiple cancers.

• RLY-2608 (PI3Kα Inhibitor):
  A first-in-class, allosteric, pan-mutant, and isoform-selective inhibitor of PI3Kα. This candidate is being developed for HR+/HER2- advanced breast cancer and vascular malformations, currently in clinical trials.

• Fabry Disease Candidate:
  A non-inhibitory chaperone to stabilize the αGal enzyme, aiming to enhance Gb3 clearance across organs. This candidate is targeted as a potential chronic treatment for Fabry disease and is in the preclinical stage.

• NRAS-Selective Inhibitor:
  Designed to selectively inhibit NRAS, sparing KRAS and HRAS, with applications in cancers such as melanoma and colorectal cancer. Currently in the preclinical stage.

• RLY-1013 (ERα Degrader):
  A bifunctional degrader targeting estrogen receptor alpha (ERα), intended for hormone receptor-positive breast cancer. This program is in preclinical development.

• RLY-2139 (CDK2 Inhibitor, Paused):
  A potent and selective CDK2 inhibitor designed to address resistance to CDK4/6 inhibitors in HR+/HER2- breast cancer. This program is currently paused.

• Discovery Programs (5+):
  Focused on targeted oncology (3 programs) and genetic diseases (2 programs), these initiatives leverage the Dynamo platform to explore additional therapeutic areas.

Current pipeline; Source: Relay Therapeutics

Looking Ahead

Relay Therapeutics plans to release comprehensive Phase 1/2 data in 2025 and expand its research pipeline to include vascular malformations. With a cash balance of $840 million, the company is well-positioned to advance its clinical programs and bring innovative therapies to patients in need.

See also: A Landscape of AI-discovered Molecules and Target Novelty Analysis

Earlier this year, Relay regained rights to its SHP2 inhibitor RLY-1971 after Genentech ended their collaboration, part of an industry-wide trend of major pharmaceutical companies scaling back investments in SHP2 inhibitor programs.

Topics: Clinical Trials