RGT-419B / Regor, Roche - LARVOL DELTA

First-in-human, phase 1a/b study of GDC-4198 (RGT-419B), a next generation CDK4/2 inhibitor, in patients with hormone receptor positive HER2- locally advanced/metastatic breast cancer (LA/mBC) who progressed on prior CDK4/6 inhibitors (SABCS 2025) - "GDC-4198, with potent and selective activity against CDK4 and CDK2, was well-tolerated both as a single agent and in combination with AI. GDC-4198 demonstrated preliminary evidence of efficacy in a post-CDK4/6i setting. Further dose escalation with GDC-4198 as a single agent is ongoing and updated data will be presented at the meeting."

Clinical • First-in-human • Metastases • P1 data • 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 • CDK2 • HER-2

Gdc-4198, a next-generation CDK4/2 inhibitor, induces durable cell cycle arrest and overcomes CDK2-driven adaptation to CDK4 inhibition (SABCS 2025) - "While CDK4/6 inhibitors (CDK4/6i) have changed the therapeutic landscape of hormone receptor-positive (HR+) breast cancer, resistance to these therapies is a major challenge limiting their clinical benefit...Immunofluorescence data from HR+ breast cancer cells revealed that the shift in cell cycle distribution induced by GDC-4198 was differentiated from the effects of CDK4/6i and can most closely be reproduced by a combination of atirmociclib (a CDK4 inhibitor) and tagtociclib (a CDK2 inhibitor)...Additional studies in patient-derived cell lines obtained in the setting of metastatic HR+ breast cancer following progression on letrozole/ribociclib, as well as in patient-derived cell lines with acquired in vitro resistance to palbociclib, confirmed the enhanced antitumor activity of GDC-4198 compared to current CDK4/6i or atirmociclib...Pharmacokinetic and pharmacodynamic analyses indicated favorable drug exposure and pharmacodynamic modulation in tumor tissues consistent..."

Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • CCNE1 • CDK2

A Study to Evaluate the Effect of GDC-4198 Alone and in Combination With Giredestrant Versus Abemaciclib and Giredestrant in Participants With Locally Advanced or Metastatic Estrogen Receptor-Positive (ER+), Human Epidermal Growth Factor Receptor-Negative (HER2-) Breast Cancer (clinicaltrials.gov) - P1/2 | N=285 | Recruiting | Sponsor: Genentech, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

A Study to Evaluate the Effect of GDC-4198 Alone and in Combination With Giredestrant Versus Abemaciclib and Giredestrant in Participants With Locally Advanced or Metastatic Estrogen Receptor-Positive (ER+), Human Epidermal Growth Factor Receptor-Negative (HER2-) Breast Cancer (clinicaltrials.gov) - P1/2 | N=285 | Not yet recruiting | Sponsor: Genentech, Inc.

New P1/2 trial • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

A Phase I Study of RGT-419B in Patients With HR-Positive, HER2-Negative Advanced Breast Cancer or Other Solid Tumors (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: Regor Pharmaceuticals Inc. | Recruiting ➔ Active, not recruiting | Trial primary completion date: Dec 2024 ➔ Jul 2025

Enrollment closed • Monotherapy • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

FIH Study of RGT-419B Alone and With Endocrine Therapy in HR-Positive, HER2-Negative Advanced/Metastatic Breast Cancer (clinicaltrials.gov) - P1 | N=64 | Recruiting | Sponsor: Regor Pharmaceuticals Inc. | N=18 ➔ 64

Enrollment change • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • HER-2 • PIK3CA

Regor Enters into a Definitive Purchase Agreement for Genentech to Acquire Regor's Portfolio of next-generation CDK inhibitors for the Treatment of Breast Cancer (PRNewswire) - "Regor Pharmaceuticals (USA)...has entered into a definitive purchase agreement whereby Genentech...will acquire a portfolio of next-generation CDK inhibitors from Regor for the treatment of breast cancer. Under the terms of the agreement, Regor will receive an upfront cash payment of $850 million and is eligible to receive additional cash payments based on the achievement of certain predetermined development, regulatory and commercial milestones. Genentech will be responsible for clinical development, manufacturing and commercialization worldwide. Regor will continue to manage the two ongoing Phase 1 trials to their completion: Regor will also advance its other distinct assets, unrelated to this deal, in oncology, metabolic diseases and auto-immunity...The proposed transaction is expected to close in the fourth quarter of 2024. The closing of the proposed transaction is subject to the satisfaction of customary closing conditions."

Licensing / partnership • Breast Cancer • Oncology • Solid Tumor

FIH Study of RGT-419B Alone and With Endocrine Therapy in HR-Positive, HER2-Negative Advanced/Metastatic Breast Cancer (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: Regor Pharmaceuticals Inc. | Trial completion date: Aug 2024 ➔ Sep 2026 | Trial primary completion date: Feb 2024 ➔ Dec 2025

Metastases • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • HER-2 • PIK3CA

A Phase I Study of RGT-419B in Chinese Patients (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: Regor Pharmaceuticals Inc.

Metastases • Monotherapy • New P1 trial • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

First-in-human phase 1A study of RGT-419B, a next generation CDK4 inhibitor, in patients (pts) with hormone receptor positive (HR+) HER2- advanced/metastatic breast cancer (ABC) who progressed on prior CDK4/6 inhibitors (CDK4/6i) (SABCS 2023) - "All had prior palbociclib + ET (2 pts had abemaciclib or ribociclib after palbociclib); a majority received fulvestrant (67%) and prior chemotherapy (50%). RGT-419B, with potent selective CDK4 activity, CDK2 activity and CDK6 selectivity, demonstrated a favorable safety and PK profile in an ongoing phase I study, with no grade 3 or higher TRAEs observed thus far. RGT-419B administered as once daily monotherapy also demonstrated preliminary evidence of efficacy as well. Dose expansions of RGT-419B as a single agent and in combination with ET in pts with HR+/HER2- ABC following prior CDK4/6i progression are planned."

Clinical • Metastases • P1 data • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK2 • HER-2

Regor Announces Promising Safety And Single Agent Efficacy Data Evaluating RGT-419B In HR+/HER2- Advanced Breast Cancer Patients Who Have Progressed On CDK4/6 Inhibitors And Endocrine Therapy (PRNewswire) - P1a | N=18 | NCT05304962 | Sponsor: Regor Pharmaceuticals Inc. | "Regor...announced the results from Phase 1A single agent dose escalation study of RGT-419B...in HR+ HER2- ABC patients who have progressed on prior CDK4/6is and ET. These results (cutoff date September 26, 2023) were presented...at the San Antonio Breast Cancer Symposium....Across 12 patients with HR+HER2- ABC who have progressed on CDK4/6is and ET, RGT-419B administered as oral (PO) monotherapy in continuous 28-day cycles was safe and well-tolerated with no dose-limiting toxicities. No patients discontinued treatment with RGT-419B due to an adverse event....RGT-419B demonstrated single agent efficacy in the heavily pretreated HR+/HER2- ABC patients who have progressed on CDK4/6i and ET. Three patients achieved partial responses and are still on treatment. 6 patients received treatment > 24 weeks."

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

First-in-Human Study of RGT-419B Alone and With Endocrine Therapy in Subjects With HR-Positive, HER2-Negative Advanced/Metastatic Breast Cancer (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: Regor Pharmaceuticals Inc. | Active, not recruiting ➔ Recruiting | N=12 ➔ 18

Enrollment change • Enrollment open • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • HER-2 • PIK3CA

First-in-Human Study of RGT-419B Alone and With Endocrine Therapy in Subjects With HR-Positive, HER2-Negative Advanced/Metastatic Breast Cancer (clinicaltrials.gov) - P1 | N=12 | Active, not recruiting | Sponsor: Regor Pharmaceuticals Inc. | Recruiting ➔ Active, not recruiting | N=48 ➔ 12

Enrollment change • Enrollment closed • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • HER-2 • PIK3CA

First-in-Human Study of RGT-419B Alone and With Endocrine Therapy in Subjects With HR-Positive, HER2-Negative Advanced/Metastatic Breast Cancer (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: Regor Pharmaceuticals Inc.

New P1 trial • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • HER-2 • PIK3CA

Regor Therapeutics Announces U.S. FDA Authorization to Conduct Regor's First-in-Human Clinical Trial with the Next Generation Targeted Inhibitor RGT-419B for Oncology (PRNewswire) - "On December 23, Regor Therapeutics...announced authorization from the US Food and Drug Administration (FDA) to proceed with Regor's Phase 1 clinical development plans for RGT-419B. RGT-419B...is expected to improve the safety of and combat the resistance to currently approved CDK4/6 inhibitors that are given in combination with endocrine-based therapy for treatment of pre/perimenopausal or postmenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer."

IND • Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor

[VIRTUAL] Targeting resistance to current CDK4/6 therapies by RGT-419B, an inhibitor with optimized kinase activity spectrum (SABCS 2020) - "However, the currently approved CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib have dose-limiting toxicities that require treatment holidays or reductions to sub-optimal doses, thus limiting full target inhibition. RGT-419B also demonstrated more durable in vivo tumor growth inhibition when compared with abemaciclib in an ER+ breast cancer xenograft model. The optimized kinase activity spectrum of RGT-419B provides an opportunity to treat ER+ breast cancer patients refractory to the existing CDK4/6 inhibitors, as either a single agent or in combination with other therapies."

Breast Cancer • Hormone Receptor Breast Cancer • Oncology • CCNE1 • CDK2 • CDK4