BMS-986466 / BridgeBio, LianBio, BMS - LARVOL DELTA

THE RAF/MEK INHIBITOR VS-6766 SHOWS EFFICACY IN RAS-MUTANT PEDIATRIC PRECLINICAL XENOGRAFT MODELS- A REPORT FROM THE PEDIATRIC PRECLINICAL IN VIVO TESTING CONSORTIUM (CTOS 2025) - "To evaluate drug combinations, RMS PDXs were treated with VS-6766 in doublet with 14 other drugs targeting additional areas of the MAPK/ERK pathway along with untreated control, VS-6766 alone, and vincristine + irinotecan (standard of care) for a total of 17 treatment groups...In combination testing, survival advantage was most notable when VS-6766 was combined with VS-4718 (FAK), everolimus (mTOR), copanlisib (PI3Kδ/α), capivasertib (AKT), BBP-398 (SHP2) and LY3023414 (PI3K) compared to VS-6766 alone. VS-6766 exhibited antitumor activity across several pediatric cancers... VS-6766 exhibited antitumor activity across several pediatric cancers. As single agent, there was activity in the majority of solid tumor models tested with prolongation of time on study and stabilization of disease. Solid tumor models harboring RAS mutations appear more likely to respond, although limited non-mutant models were tested."

Preclinical • Hematological Malignancies • Leukemia • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • HRAS • KRAS • NF1 • NRAS • PIK3CD

Argonaut: SHP2 Inhibitor BBP-398 in Combination With Sotorasib in Patients With Advanced Solid Tumors and a KRAS-G12C Mutation (clinicaltrials.gov) - P1 | N=28 | Terminated | Sponsor: Navire Pharma Inc., a BridgeBio company | N=85 ➔ 28 | Trial completion date: Jun 2025 ➔ Aug 2024 | Recruiting ➔ Terminated; Business Reasons

Combination therapy • Enrollment change • Metastases • Trial completion date • Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

First-in-Human Study of the SHP2 Inhibitor BBP-398 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=72 | Terminated | Sponsor: Navire Pharma Inc., a BridgeBio company | N=130 ➔ 72 | Trial completion date: Feb 2025 ➔ Jul 2024 | Active, not recruiting ➔ Terminated; Business decision

Enrollment change • Metastases • Trial completion date • Trial termination • Oncology • Solid Tumor • BRAF • EGFR • KRAS

SHP2 Inhibitor BBP-398 in Combination With Nivolumab in Patients With Advanced Non-Small Cell Lung Cancer With a KRAS Mutation (clinicaltrials.gov) - P1 | N=21 | Terminated | Sponsor: Navire Pharma Inc., a BridgeBio company | N=45 ➔ 21 | Trial completion date: Jan 2025 ➔ Jul 2024 | Recruiting ➔ Terminated; Business reasons

Combination therapy • Enrollment change • Metastases • Trial completion date • Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

BBP-398 in Combination With Osimertinib in Locally Advanced or Metastatic NSCLC Patients With EGFR Mutations (clinicaltrials.gov) - P1 | N=4 | Terminated | Sponsor: LianBio LLC | Phase classification: P1a/1b ➔ P1 | N=52 ➔ 4 | Trial completion date: Jul 2026 ➔ Mar 2024 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2025 ➔ Mar 2024; Business reason

Combination therapy • Enrollment change • Metastases • Phase classification • Trial completion date • Trial primary completion date • Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Phase I Study of the BBP-398 in Patients With Advance Solid Tumors (clinicaltrials.gov) - P1 | N=7 | Terminated | Sponsor: LianBio LLC | N=28 ➔ 7 | Trial completion date: Sep 2024 ➔ Mar 2024 | Recruiting ➔ Terminated; Business reason

Enrollment change • Metastases • Trial completion date • Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

A Study of BMS-986466 With Adagrasib With or Without Cetuximab in Participants With Kirsten Rat Sarcoma Virus Glycine 12 to Cysteine (KRAS G12C)-Mutant Solid Tumors (clinicaltrials.gov) - P1/2 | N=5 | Terminated | Sponsor: Bristol-Myers Squibb | N=410 ➔ 5 | Active, not recruiting ➔ Terminated; Business objectives have changed

Combination therapy • Enrollment change • Metastases • Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • KRAS

A Study of BMS-986466 With Adagrasib With or Without Cetuximab in Participants With Kirsten Rat Sarcoma Virus Glycine 12 to Cysteine (KRAS G12C)-Mutant Solid Tumors (clinicaltrials.gov) - P1/2 | N=410 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Active, not recruiting | Trial completion date: Jul 2029 ➔ May 2024 | Trial primary completion date: Aug 2027 ➔ May 2024

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

First-in-Human Study of the SHP2 Inhibitor BBP-398 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=130 | Active, not recruiting | Sponsor: Navire Pharma Inc., a BridgeBio company | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Oncology • Solid Tumor • BRAF • EGFR • KRAS

Preclinical translational platform of neuroinflammatory disease biology relevant to neurodegenerative disease. (PubMed, J Neuroinflammation) - "Three structurally distinct inhibitors of PTPN11 (RMC-4550, TN0155, IACS-13909) reversed the neuroinflammatory disease signature. Collectively, these results highlight the utility of this novel neuroinflammatory platform for facilitating identification and validation of targets for neuroinflammatory neurodegenerative disease drug discovery."

Journal • Preclinical • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Huntington's Disease • Inflammation • Movement Disorders • DHFR • NLRP3 • PTPN11

Discovery of 1H-pyrazolo[3,4-b]pyrazine derivatives as selective allosteric inhibitor of protein tyrosine phosphatase SHP2 for the treatment of KRAS-mutant non-small cell lung cancer. (PubMed, J Biomol Struct Dyn) - "In this study, we used the previously reported SHP2 allosteric inhibitor IACS-13909 as a lead drug for structural derivation and modification, and synthesized three SHP2 inhibitors...Furthermore, the combination therapy of compound 4b and KRAS inhibitor sotorasib would play a strong synergistic effect against NCI-H358 cells...Molecular docking study predicted that compound 4b bound to the allosteric site of SHP2 and formed H-bond interactions with key residues Thr108, Glu110, Arg111, and Phe113. In summary, this study aims to provide new ideas for the development of SHP2 allosteric inhibitors for the treatment of KRAS mutant non-small cell lung cancer.Communicated by Ramaswamy H. Sarma."

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

A Study of BMS-986466 With Adagrasib With or Without Cetuximab in Participants With Kirsten Rat Sarcoma Virus Glycine 12 to Cysteine (KRAS G12C)-Mutant Solid Tumors (clinicaltrials.gov) - P1/2 | N=410 | Recruiting | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • KRAS

BBP-398 in Combination With Osimertinib in Locally Advanced or Metastatic NSCLC Patients With EGFR Mutations (clinicaltrials.gov) - P1a/1b | N=52 | Recruiting | Sponsor: LianBio LLC

Combination therapy • Metastases • New P1 trial • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor

A Study of BMS-986466 With Adagrasib With or Without Cetuximab in Participants With Kirsten Rat Sarcoma Virus Glycine 12 to Cysteine (KRAS G12C)-Mutant Solid Tumors (clinicaltrials.gov) - P1/2 | N=410 | Not yet recruiting | Sponsor: Bristol-Myers Squibb

Combination therapy • Metastases • New P1/2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • KRAS

LianBio Reports Second Quarter 2023 Financial Results and Provides Corporate Update (GlobeNewswire) - "BBP-398: LianBio expects to initiate a Phase 1 clinical trial of BBP-398 in combination with a PD-1 inhibitor in advanced solid tumors in the first half of 2024."

New P1 trial • Oncology • Solid Tumor

First-in-Human Study of the SHP2 Inhibitor BBP-398 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=130 | Recruiting | Sponsor: Navire Pharma Inc., a BridgeBio company | Trial completion date: Oct 2023 ➔ Feb 2025 | Trial primary completion date: Apr 2023 ➔ May 2024

Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor • BRAF • EGFR • KRAS

LianBio Announces First Patient Treated in Phase 1 Trial of SHP2 Inhibitor BBP-398 in Combination with Osimertinib in Patients with Non-Small Cell Lung Cancer with EGFR Mutations (GlobeNewswire) - "LianBio...announced the first patient has been dosed in its Phase 1 clinical trial of BBP-398, an investigational SHP2 inhibitor, in combination with AstraZeneca’s osimertinib, an epidermal growth factor receptor (EGFR) inhibitor, for the treatment of patients with non-small cell lung cancer (NSCLC) with EGFR mutations....The multi-center, open-label Phase 1 trial is designed to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of BBP-398 in combination with osimertinib in patients with locally advanced or metastatic NSCLC with EGFR mutations."

Trial status • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

LianBio Announces Clinical Supply Agreement with AstraZeneca in China to Evaluate BBP-398 in Combination with Osimertinib in Patients with Non-Small Cell Lung Cancer with EGFR Mutations (GlobeNewswire) - "LianBio...announced a clinical supply agreement with AstraZeneca in China to evaluate the safety and efficacy of BBP-398, an investigational SHP2 inhibitor, in combination with AstraZeneca’s osimertinib, an epidermal growth factor receptor (EGFR) inhibitor, in a Phase 1 clinical study for the treatment of patients with non-small cell lung cancer (NSCLC) with EGFR mutations....The planned multi-center, open-label Phase 1 trial is designed to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of BBP-398 in combination with osimertinib in patients with locally advanced or metastatic NSCLC with EGFR mutations. The trial includes a dose escalation phase, followed by expansion cohorts. LianBio expects to initiate this trial in the second half of 2023."

Licensing / partnership • New P1 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

TARGETING THE SRC HOMOLOGY 2 DOMAIN-CONTAINING PHOSPHATASE SHP2 ENHANCES THE THERAPEUTIC EFFICACY OF JAK INHIBITION IN MYELOPROLIFERATIVE NEOPLASMS (EHA 2023) - "Pharmacologic targeting by SHP2 inhibitors TNO155 or IACS-13909 as well as dual SHP2/JAK2 targeting was evaluated in MPN cell lines and primary MPN patient cells. Our findings suggest a relevant role of SHP2 in MPN given enhanced MAPK pathway suppression and correctiveeffects when SHP2 is targeted in MPN cells, mouse models and primary patient isolates. Further studies will delineate the involvement of SHP2 phosphatase vs. non-phosphatase functions and detail the potential of JAK2/SHP2 inhibition as therapeutic approach in MPN."

Clinical • Hematological Disorders • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Transplantation • CALR • DUSP6 • GAB1 • STAT3

LianBio Reports First Quarter 2023 Financial Results and Provides Corporate Update (GlobeNewswire) - "Key Anticipated Milestones:...BBP-398 - LianBio expects to initiate a Phase 1 clinical trial of BBP-398 in combination with an EGFR-inhibitor in non-small cell lung cancer in the second half of 2023."

New P1 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

BridgeBio Pharma Announces First Lung Cancer Patient Dosed in Phase 1 Trial for SHP2 Inhibitor BBP-398 in Combination with Bristol Myers Squibb’s OPDIVO (nivolumab) (GlobeNewswire) - "BridgeBio Pharma, Inc...announced that the first patient with non-small cell lung cancer (NSCLC) has been dosed in its Phase 1/2 clinical trial of BBP-398, an investigational SHP2 inhibitor, with Bristol Myers Squibb’s OPDIVO^® (nivolumab) in advanced solid tumors with KRAS mutations....Initial Phase 1 data from the ongoing BBP-398 trial is expected in 2023."

P1 data • Trial status • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

SHP2 Inhibitor BBP-398 in Combination With Nivolumab in Patients With Advanced Non-Small Cell Lung Cancer With a KRAS Mutation (clinicaltrials.gov) - P1 | N=45 | Recruiting | Sponsor: Navire Pharma Inc., a BridgeBio company | Initiation date: May 2022 ➔ Oct 2022

Combination therapy • Metastases • Trial initiation date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Phase I Study of the BBP-398 in Chinse Patients With Advance Solid Tumors (clinicaltrials.gov) - P1 | N=28 | Recruiting | Sponsor: LianBio LLC

New P1 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR

LianBio Doses First Patient in Phase 1 Trial of BBP-398 in Chinese Patients with Advanced Solid Tumors (GlobeNewswire) - "LianBio...announced the first patient has been dosed in its Phase 1 clinical trial of BBP-398, a SHP2 inhibitor, in Chinese patients with advanced solid tumors....In this two-part, open label, dose escalation and dose expansion Phase 1 study, safety and preliminary anti-tumor activity will be examined....LianBio expects to initiate a Phase 1 clinical trial of BBP-398 in combination with an EGFR inhibitor in Chinese patients with EGFR-mutant NSCLC in the first half of 2023."

New P1 trial • Trial status • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • EGFR

BridgeBio Pharma Announces First Lung Cancer Patient Dosed in Phase 1/2 Trial and US FDA Fast Track Designation for SHP2 inhibitor BBP-398 in Combination with Amgen’s LUMAKRAS (sotorasib) (GlobeNewswire) - "BridgeBio Pharma, Inc... announced that the first patient with non-small cell lung cancer (NSCLC) has been dosed in its Phase 1/2 clinical trial of BBP-398, an investigational SHP2 inhibitor, with Amgen Inc.’s (Amgen) LUMAKRAS^® (sotorasib), the first and only currently approved targeted treatment for patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, in advanced solid tumors with the KRAS G12C mutation....Initial data is expected by the end of 2024....Additionally, the US Food and Drug Administration (FDA) granted Fast Track designation for the investigation of BBP-398 in combination with LUMAKRAS for adult patients with previously treated, KRAS G12C-mutated, metastatic NSCLC....BBP-398, as a monotherapy or in combination with other targeted therapies, could potentially be a promising therapy for patients with the KRAS G12C mutation. Initial Phase 1 data from the ongoing BBP-398 trial is expected in 2023."

Fast track designation • P1 data • P1/2 data • Trial status • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS