batoprotafib (TNO155) / Novartis - LARVOL DELTA

KontRASt-01 update: Safety and efficacy of JDQ443 in KRAS G12C-mutated solid tumors including non-small cell lung cancer (NSCLC). (ASCO 2023) - P1/2 | "JDQ443 demonstrates an acceptable safety and tolerability profile at 200 mg BID, with clinical activity in pts with NSCLC. Enrollment is ongoing to the JDQ443 monotherapy DEx and the JDQ443 + TNO155 and JDQ443 + tislelizumab combination arms. Clinical trial information: NCT04699188."

Clinical • IO biomarker • Colorectal Cancer • Fatigue • Gastrointestinal Cancer • Hematological Disorders • Lung Cancer • Musculoskeletal Pain • Neutropenia • Non Small Cell Lung Cancer • Oncology • Pain • Solid Tumor • KRAS

KontRASt-01: Preliminary Safety and Efficacy of JDQ443 + TNO155 in Patients with Advanced, KRAS G12C-Mutated Solid Tumors (IASLC-WCLC 2023) - P1/2 | "JDQ443+TNO155 was tolerated with notable toxicities of edema, cytopenias, and fatigue. MTD was not reached; the RD for further evaluation was selected based on collective safety, pharmacokinetics, and efficacy. Preliminary anti-tumor activity was observed, including in KRASG12C inhibitor previously-treated NSCLC."

Clinical • Metastases • Anemia • Fatigue • Hematological Disorders • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Thrombocytopenia • KRAS

Compensatory Receptor Tyrosine Kinase Signaling Reactivates the RAF–MEK–ERK pathway causing resistance to MEK-inhibition in Glioblastoma. (EACR 2026) - "Treatment efficacy was assessed in 2D using Alamar Blue and crystal violet assays, and in 3D spheroid models, with Bliss scores calculated to determine drug synergy.Result and MEK inhibition with trametinib or selumetinib induced adaptive kinase network remodeling across all GB models, characterized by MEK–AKT crosstalk and enhanced JNK/c-JUN activity...Interestingly, ERK blockade with ulixertinib produced a comparable compensatory response. Combining MEK with JNK inhibition (SP600125) to block parallel activated JNK signaling synergistically reduced cell viability, but did not prevent MEK inhibitor induced MEKSer221 hyperphosphorylation. This study outlines a mechanistic strategy for selecting SMIs to overcome MEK-inhibitor resistance in pdGB models."

Brain Cancer • Glioblastoma • Solid Tumor

KontRASt-R: Rollover Study for Participants Who Have Been Treated With and Are Continuing to Benefit From Opnurasib as a Single Agent or in Combination With Other Study Treatments (clinicaltrials.gov) - P1/2 | N=40 | Recruiting | Sponsor: Novartis Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

CJDQ443B12105B: Rollover study for participants who are currently being treated with and are continuing to benefit from opnurasib as a single agent or in combination with other study treatments. (clinicaltrialsregister.eu) - P1/2 | N=16 | Not yet recruiting | Sponsor: Novartis Pharma AG

New P1/2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

TEAD inhibitors synergize with MEK, SHP2 and mTOR inhibitors in NF1 and NF2 cell lines. (PubMed, MicroPubl Biol) - "VT103 consistently synergized with inhibitors of MEK (trametinib and selumetinib), SHP2 (TNO155) and mTOR (everolimus). The highest synergy ZIP score, calculated using SynergyFinder, was ~65 in the NF2 -SWN cell line SC4, with lower magnitudes in an NF1 cell line."

Journal • Preclinical • Brain Cancer • Genetic Disorders • Neurofibromatosis • Oncology • Solid Tumor • NF1

Harnessing SHP2-targeted signaling to reinforce anti-tumor immune responses (AACR 2026) - "These findings demonstrate that SHP2 inhibition enhances anti-tumor immune responses and supports its potential as a dual-function therapeutic strategy in cancer immunotherapy. This study provides a robust preclinical foundation for the translational development of SHP2-targeted approaches in precision oncology."

IO biomarker • Oncology • CD69 • CD8 • GZMB • HAVCR2 • IFNG • LAG3 • PD-L1

A first-in-human study of oral TNO155 (batoprotafib) alone and in combination with EGF816 (nazartinib) in adult patients with advanced solid tumors (AACR 2025) - P1 | "Arm B EXP required progression on osimertinib as the most recent prior therapy. As of 1-Aug-2024, 227 pts were treated (Arm A: ESC; n=141; EXP; n=42; Arm B; ESC; n=29; EXP; n=15), and 224 (98.6%) pts had discontinued study treatment, mainly due to progressive disease. TNO155 shows acceptable safety as a SA and with nazartinib and demonstrates evidence of MAPK pathway suppression in tumors."

Clinical • Combination therapy • First-in-human • Metastases • P1 data • Cutaneous Melanoma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • DUSP6 • KRAS • NRAS

Characterizing mechanisms of BRAF/MEK inhibitor resistance in BRAF V600 mutant colorectal cancer vs. melanoma (AACR 2024) - "We developed cells with acquired resistance to BRAF+MEK inhibitors (Encorafenib+Binimetinib; E+B) by culturing cells in increasing concentrations of drug over several months. Together, these data identify key, actionable drivers of MAPK inhibitor resistance in CRC and highlight Shp2 as a potential therapeutic target for BRAF V600 CRC."

Colorectal Cancer • Gastrointestinal Cancer • Melanoma • Oncology • Solid Tumor • ERBB3 • FGF3 • HBEGF • HER-2 • PDGFA • PDGFRB

MRAS the forgotten member of the GTPase superfamily plays a role in KRASG12Ci resistance (AACR 2024) - "Pathway suppression was deepened by combining adagrasib with either a SOS1i (e.g. BI-3406) or SHP2i (e.g. TNO155) resulting in enhanced anti-tumor effects observed in the KRASG12Ci-resistant models. Our findings underscore the role of MRAS in acquired resistance in KRASG12Ci and the potential to overcome this with vertical pathway combinations, such as SOS1i or SHP2i."

Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

KontRASt-01: Study of JDQ443 in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation (clinicaltrials.gov) - P1/2 | N=344 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Aug 2026 ➔ Jan 2027 | Trial primary completion date: Aug 2026 ➔ Jan 2027

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

KontRASt-R: Rollover Study for Participants Who Have Been Treated With and Are Continuing to Benefit From Opnurasib as a Single Agent or in Combination With Other Study Treatments (clinicaltrials.gov) - P1/2 | N=40 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals

New P1/2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=255 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Apr 2024 ➔ Aug 2024 | Trial primary completion date: Feb 2024 ➔ Aug 2024

First-in-human • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Stromal Tumor • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • DUSP6 • KRAS

Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=255 | Recruiting | Sponsor: Novartis Pharmaceuticals | N=135 ➔ 255

Enrollment change • First-in-human • Cutaneous Melanoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Stromal Tumor • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Thoracic Cancer • DUSP6 • KRAS

Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=135 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Aug 2021 ➔ Aug 2022 | Trial primary completion date: Aug 2021 ➔ Aug 2022

First-in-human • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Stromal Tumor • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Thoracic Cancer • DUSP6 • KRAS

Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=255 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Oct 2024 ➔ Apr 2025 | Trial primary completion date: Oct 2024 ➔ Apr 2025

First-in-human • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Stromal Tumor • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • DUSP6 • KRAS

Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=105 | Recruiting | Sponsor: Novartis Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • First-in-human • Cutaneous Melanoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Stromal Tumor • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • DUSP6 • KRAS

Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=227 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: May 2025 ➔ Nov 2025 | Trial primary completion date: May 2025 ➔ Nov 2025

First-in-human • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Stromal Tumor • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • DUSP6 • KRAS

Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=135 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Aug 2020 ➔ Aug 2021 | Trial primary completion date: Aug 2020 ➔ Aug 2021

First-in-human • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Stromal Tumor • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Thoracic Cancer • DUSP6 • KRAS

Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=135 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Mar 2019 ➔ Aug 2020 | Trial primary completion date: Mar 2019 ➔ Aug 2020

First-in-human • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Stromal Tumor • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Thoracic Cancer • DUSP6 • KRAS

Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=227 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial primary completion date: Nov 2025 ➔ Jul 2025 | Trial completion date: Nov 2025 ➔ Jul 2025

First-in-human • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Stromal Tumor • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • DUSP6 • KRAS

Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=227 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; Business reasons and not due to any safety concerns

First-in-human • Trial termination • Cutaneous Melanoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Stromal Tumor • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • DUSP6 • KRAS

Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=255 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Aug 2022 ➔ Aug 2023 | Trial primary completion date: Aug 2022 ➔ Aug 2023

First-in-human • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Stromal Tumor • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • DUSP6 • KRAS

Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=227 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • First-in-human • Cutaneous Melanoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Stromal Tumor • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • DUSP6 • KRAS

Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=135 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Mar 2020 ➔ Mar 2019 | Trial primary completion date: Mar 2020 ➔ Mar 2019

First-in-human • Trial completion date • Trial primary completion date • Cutaneous Melanoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Stromal Tumor • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • DUSP6 • KRAS