migoprotafib (RLY-1971) / Relay Therap - LARVOL DELTA

Discovery of drug combinations with momelotinib to improve myelofibrosis outcomes (ASH 2025) - "The VAF screen identified numerous inhibitors of signaling pathways operating parallel to the JAK-STAT signaling pathway including SHP2 (migoprotafib), PI3K (copanlisib), MEK (cobimetinib), agents targeting BET (BMS-986158), and STAT transcriptional targets, including BCLxL (navitoclax). The hepcidin screen identified inhibitors that combined to further suppress expression of the HiBiT transgene including CDK4 (atirmociclib) and MDM2 (navtemadlin). Notably, selinexor, an XPO1 inhibitor, combined positively with momelotinib to both kill malignant cells and suppress hepcidin expression. These results highlight several promising drug combinations that could enhance outcomes for MF patients by effectively controlling anemia and halting disease progression. These discoveries provide the scientific justification to identify optimal combination regimens aimed at addressing the multifaceted challenges of myelofibrosis."

IO biomarker • Myelofibrosis • ACVR1 • BCL2L1 • BMP6 • CDK4 • JAK1

Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-1971 in Combination With Either Osimertinib in Participants With Unresectable, Locally Advanced, or Metastatic Non-Small Cell Lung Cancer, or With Cetuximab in Participants With Metastatic Colorectal Cancer (clinicaltrials.gov) - P1 | N=10 | Completed | Sponsor: Genentech, Inc. | Active, not recruiting ➔ Completed | N=172 ➔ 10 | Trial completion date: Dec 2026 ➔ Sep 2025 | Trial primary completion date: Dec 2026 ➔ Sep 2025

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Colon Adenocarcinoma • Colon Cancer • Colorectal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • KRAS • NRAS

GO42144: A Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-6036 Alone or in Combination in Participants With Advanced or Metastatic Solid Tumors With a KRAS G12C Mutation (clinicaltrials.gov) - P1 | N=498 | Active, not recruiting | Sponsor: Genentech, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Feb 2026 ➔ Sep 2026 | Trial primary completion date: Feb 2026 ➔ Sep 2026

Enrollment closed • Trial completion date • Trial primary completion date • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Designing scalable syntheses of pharmaceutical intermediates by utilizing low-temperature continuous flow chemistry (ACS-Fall 2025) - "Recent case studies include the development of a key transformation in the synthesis of SHP2 inhibitor GDC-1971 (migoprotafib), in which implementation of a continuous process enabled the use of a highly unstable organolithium intermediate...The precise and scalable control over reaction time and temperature afforded by a fast-mixing plug flow reactor was leveraged for careful investigation of reaction kinetics. The resulting continuous process allowed for consistent generation and rapid consumption of the fleeting organolithium intermediate, leading to the desired α-hydroxyketone product in excellent yield with minimal material lost due to decomposition."

RIT1M90I is a driver of lung adenocarcinoma tumorigenesis and resistance to targeted therapy. (PubMed, Cancer Res) - "Finally, RIT1M90I drove resistance to the KRASG12C inhibitor, divarasib, and the combination with migoprotafib reverted this phenotype. Together, our data shows that RIT1M90I is a bona fide oncogenic driver of lung cancer and mediator of targeted therapy resistance as a co-occurring mutation and suggests that RIT1-altered cancer patients may benefit from combination treatments with a SHP2 inhibitor."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • RIT1

A Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-1971 in Combination With Atezolizumab in Participants With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=57 | Completed | Sponsor: Genentech, Inc. | Active, not recruiting ➔ Completed | N=232 ➔ 57 | Trial completion date: Mar 2026 ➔ Jun 2025 | Trial primary completion date: Mar 2026 ➔ Jun 2025

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ALK • BRAF • EGFR

RIT1M90I is a driver of lung adenocarcinoma tumorigenesis and resistance to targeted therapy (AACR 2025) - "Finally, we showed that RIT1M90I can also drive resistance to the KRASG12C inhibitor, divarasib, and that the combination with migoprotafib can revert this phenotype. Our data shows that RIT1M90I is a bona fide oncogenic driver of NSCLC and mediator of targeted therapy resistance as a co-occurring mutation. Taken together, our study suggests that RIT1-altered cancer patients may benefit from combination treatment with SHP2 inhibitor in the primary and resistance setting."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • RIT1

Divarasib plus migoprotafib combination treatment in patients with KRAS G12C-positive non-small cell lung cancer (NSCLC) (AACR 2025) - P1 | "Divarasib in combination with migoprotafib demonstrated an acceptable safety profile and preliminary clinical activity in patients with KRAS G12C-positive NSCLC."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

GO42144: A Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-6036 Alone or in Combination in Participants With Advanced or Metastatic Solid Tumors With a KRAS G12C Mutation (clinicaltrials.gov) - P1 | N=498 | Recruiting | Sponsor: Genentech, Inc. | Trial primary completion date: Mar 2025 ➔ Feb 2026

Trial primary completion date • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

A Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-1971 in Combination With Atezolizumab in Participants With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=232 | Active, not recruiting | Sponsor: Genentech, Inc. | Trial completion date: May 2025 ➔ Mar 2026 | Trial primary completion date: May 2025 ➔ Mar 2026 | Recruiting ➔ Active, not recruiting

Enrollment closed • Trial completion date • Trial primary completion date • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ALK • BRAF • EGFR

GO42144: A Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-6036 Alone or in Combination in Participants With Advanced or Metastatic Solid Tumors With a KRAS G12C Mutation (clinicaltrials.gov) - P1 | N=498 | Recruiting | Sponsor: Genentech, Inc. | Trial completion date: Nov 2024 ➔ Mar 2026 | Trial primary completion date: Nov 2024 ➔ Mar 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

First results of migoprotafib, a potent and highly selective Src homology-2 domain-containing phosphatase 2 (SHP2) inhibitor in patients with advanced solid tumors. (PubMed, Mol Cancer Ther) - "Migoprotafib had predictable, dose-dependent PK with an effective half-life that supports QD dosing and demonstrated promising safety, tolerability, and clinical activity at the RP2D. Further clinical testing of migoprotafib in combination with other targeted agents is warranted."

Journal • Metastases • Constipation • Fatigue • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Oncology • Pulmonary Disease • Solid Tumor

A Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-1971 in Combination With Atezolizumab in Participants With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=232 | Recruiting | Sponsor: Genentech, Inc. | Active, not recruiting ➔ Recruiting

Enrollment open • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ALK • BRAF • EGFR

Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-1971 in Combination With Either Osimertinib in Participants With Unresectable, Locally Advanced, or Metastatic Non-Small Cell Lung Cancer, or With Cetuximab in Participants With Metastatic Colorectal Cancer (clinicaltrials.gov) - P1 | N=172 | Active, not recruiting | Sponsor: Genentech, Inc. | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Metastases • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • KRAS • NRAS

A Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-1971 in Combination With Atezolizumab in Participants With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=232 | Active, not recruiting | Sponsor: Genentech, Inc. | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Metastases • Head and Neck Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • ALK • BRAF • EGFR

Relay Therapeutics Reports Second Quarter 2024 Financial Results and Corporate Highlights (GlobeNewswire) - "Migoprotafib (GDC-1971)​: As previously disclosed, Genentech has terminated the collaboration agreement for the development and commercialization of migoprotafib. The company will not continue development of migoprotafib."

Discontinued • Licensing / partnership • Solid Tumor

Umpolung Flow Chemistry for the Synthesis of a 3-Oxo-3H-spiro[benzofuran-2,4'-piperidine] Building Block. (PubMed, J Org Chem) - "Treatment of the resulting tetrahedral intermediate with oxalic acid resulted in collapse to the corresponding 4-(2-fluorobenzoyl)-4-hydroxypiperidine, which was isolated as a solid via crystallization. The synthesis concluded with an optimized intramolecular SNAr reaction and final crystallization to generate tert-butyl 3-oxo-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate as a stable, high-quality intermediate suitable for further functionalization toward GDC-1971."

Journal

A Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-6036 Alone or in Combination in Participants With Advanced or Metastatic Solid Tumors With a KRAS G12C Mutation (clinicaltrials.gov) - P1 | N=498 | Recruiting | Sponsor: Genentech, Inc. | Phase classification: P1a/1b ➔ P1

Combination therapy • Metastases • Phase classification • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors. (PubMed, J Med Chem) - "We were drawn to the pharmacological potential of SHP2 inhibition, especially following the initial observation that drug-like compounds could bind an allosteric site and enforce a closed, inactive state of the enzyme. Here, we describe the identification and characterization of GDC-1971 (formerly RLY-1971), a SHP2 inhibitor currently in clinical trials in combination with KRAS G12C inhibitor divarasib (GDC-6036) for the treatment of solid tumors driven by a KRAS G12C mutation."

Journal • Oncology • Solid Tumor • KRAS

Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-1971 in Combination With Either Osimertinib in Participants With Unresectable, Locally Advanced, or Metastatic Non-Small Cell Lung Cancer, or With Cetuximab in Participants With Metastatic Colorectal Cancer (clinicaltrials.gov) - P1 | N=172 | Recruiting | Sponsor: Genentech, Inc. | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Metastases • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • KRAS • NRAS

Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-1971 in Combination With Either Osimertinib in Participants With Unresectable, Locally Advanced, or Metastatic Non-Small Cell Lung Cancer, or With Cetuximab in Participants With Metastatic Colorectal Cancer (clinicaltrials.gov) - P1 | N=172 | Not yet recruiting | Sponsor: Genentech, Inc.

New P1 trial • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • KRAS • NRAS

Discovery and characterization of the potent, allosteric SHP2 inhibitor GDC-1971 for the treatment of RTK/RAS driven tumors (AACR 2022) - P1a/1b | "In rodent and dog toxicology studies, GDC-1971 is well tolerated at exposures above those required to induce regression in xenograft models. The biochemical and cellular potency and favorable pharmaceutical properties of GDC-1971 support the further clinical development in RTK/MAPK pathway altered tumors using continuous daily dosing alone and in combination with other targeted agents, including the KRAS-G12C inhibitor GDC-6036 (clinical trial NCT04449874)."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • EGFR • KRAS • NF1 • PTPN11

The Molecular Landscape of Artificial Intelligence and Machine Learning (AI/ML) Accelerated Small Molecule Drug Discovery:RLY-1971 is a Prominent case (BGICC 2023) - No abstract available

Clinical • Machine learning • Breast Cancer

RLY-1971 in Subjects With Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=46 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed | N=70 ➔ 46

Enrollment change • Metastases • Trial completion • Oncology • Solid Tumor

A Study to Evaluate the Safety, Pharmacokinetics, and Activity of GDC-6036 Alone or in Combination in Participants With Advanced or Metastatic Solid Tumors With a KRAS G12C Mutation (clinicaltrials.gov) - P1a/1b | N=498 | Recruiting | Sponsor: Genentech, Inc. | Trial completion date: Aug 2023 ➔ Nov 2024 | Trial primary completion date: Aug 2023 ➔ Nov 2024

Combination therapy • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS