batoprotafib (TNO155) / Novartis - LARVOL DELTA

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 • Metastases • P1 data • Cutaneous Melanoma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • DUSP6 • KRAS • NRAS

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: Apr 2026 ➔ Aug 2026 | Trial primary completion date: Apr 2026 ➔ Aug 2026

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

KRYSTAL-2: Adagrasib in Combination With TNO155 in Patients With Cancer (KRYSTAL 2) (clinicaltrials.gov) - P1 | N=86 | Completed | Sponsor: Mirati Therapeutics Inc. | Active, not recruiting ➔ Completed

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

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1 | N=1200 | Recruiting | Sponsor: Amgen | Trial completion date: Mar 2028 ➔ Dec 2027

Monotherapy • Trial completion date • Brain Cancer • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • 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

Trial completion date • Trial primary completion date • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • 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 2025 ➔ Apr 2026 | Trial primary completion date: Aug 2025 ➔ Apr 2026

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

TNO155 is a selective SHP2 inhibitor to target PTPN11-dependent oral squamous cell carcinoma. (PubMed, Heliyon) - "However, whilst targeting EGFR with cetuximab has been approved for the treatment of OSCC, other single-agent inhibitors of the RTKs have shown modest effects in improving survival. In summary, PTPN11 is a promising therapeutic target in OSCC that can be selectively targeted by SHP2 inhibitor such as TNO155. Our findings on the use of mTOR inhibitor, everolimus to overcome resistance to TNO155 are essential to inform on next phases of clinical trials which is warranted for the treatment of OSCC."

Journal • Oncology • Oral Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • EGFR • JAK1 • PTPN11 • STAT3

Somatic PTPN11 Variants Associated with Mesial Temporal Lobe Epilepsy Confer Selective Advantage to the Mutant Progenitors Through a Gain of Phosphatase Activity (AES 2024) - "Furthermore, we showed that SHP2 allosteric inhibitors like SHP099 and TNO155 restore normal activity to MTLE-associated SHP2 variants with gain of phosphatase function. In conclusion, most MTLE-associated PTPN11 variants appear to cause a dominant gain of SHP2 function, which may be normalized with clinically available SHP2 drugs. Furthermore, we provide a potential mechanism for how progenitors harboring PTPN11 variants make an asymmetrically greater contribution to hippocampal developmental which is likely key in MTLE pathophysiology."

CNS Disorders • Epilepsy • PTPN11

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: Mar 2026 ➔ Aug 2025 | Trial primary completion date: Mar 2026 ➔ Aug 2025

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

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1 | N=1200 | Recruiting | Sponsor: Amgen | Trial completion date: Jun 2029 ➔ Mar 2028 | Trial primary completion date: Jan 2027 ➔ Apr 2026

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

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1 | N=1200 | Recruiting | Sponsor: Amgen | Trial completion date: Mar 2028 ➔ Jun 2029 | Trial primary completion date: Sep 2025 ➔ Jan 2027

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

Discovery of novel phenyl urea SHP2 inhibitors with anti-colon cancer and potential immunomodulatory effects. (PubMed, Eur J Med Chem) - "Currently, no SHP2 inhibitors have been approved for clinical use, and colorectal cancer (CRC) cells exhibited frequent resistance to reported SHP2 inhibitors, such as SHP099 and TNO155. A8 significantly suppressed in vivo tumor growth in a CT26 mouse model and activated immunomodulatory effects in tumor microenvironment. Our work demonstrated that A8 has the potential to be a lead compound for the further development of SHP2 inhibitor and the treatment of CRC."

Immunomodulating • Journal • Colon Cancer • Colorectal Cancer • Immunology • Oncology • Solid Tumor • PD-L1

A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer (clinicaltrials.gov) - P1 | N=122 | Terminated | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jan 2025 ➔ Sep 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jan 2025 ➔ Sep 2024; The decision of early termination was made due to business reasons, and was not based on any safety concerns for any of the treatment combinations.

Trial completion date • Trial primary completion date • Trial termination • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • BRAF

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 | Recruiting ➔ Active, not recruiting | Trial completion date: Jan 2027 ➔ Mar 2026 | Trial primary completion date: Jan 2027 ➔ Mar 2026

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

A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer (clinicaltrials.gov) - P1 | N=122 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Oct 2024 ➔ Jan 2025 | Trial primary completion date: Oct 2024 ➔ Jan 2025

Metastases • Trial completion date • Trial primary completion date • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF

MEST promotes immune escape in gastric cancer by downregulating MHCI expression via SHP2. (PubMed, Int J Biochem Cell Biol) - "In this study, we demonstrated that MEST inhibited IFN-γ secretion from CD8+ T cells by up-regulating SHP2, thereby downregulating MHCI expression in GC cells to promote immune escape and providing a new T cell-based therapeutic potential for GC."

IO biomarker • Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD8 • GZMB • IFNG

KRYSTAL-2: Adagrasib in Combination With TNO155 in Patients With Cancer (KRYSTAL 2) (clinicaltrials.gov) - P1 | N=86 | Active, not recruiting | Sponsor: Mirati Therapeutics Inc. | Phase classification: P1/2 ➔ P1

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

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1 | N=1200 | Recruiting | Sponsor: Amgen | Trial primary completion date: Dec 2026 ➔ Sep 2025

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

KRYSTAL-2: Adagrasib in Combination With TNO155 in Patients With Cancer (KRYSTAL 2) (clinicaltrials.gov) - P1/2 | N=86 | Active, not recruiting | Sponsor: Mirati Therapeutics Inc. | Trial completion date: Mar 2024 ➔ Dec 2024

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

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1 | N=1200 | Recruiting | Sponsor: Amgen | Phase classification: P1/2 ➔ P1

Combination therapy • Metastases • Monotherapy • Phase classification • Brain Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • 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 • Metastases • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • KRAS

Computational study on the binding mechanism of allosteric drug TNO155 inhibiting SHP2E76A. (PubMed, Mol Divers) - "The results show that SHP2E76A forms tighter interaction with TNO155 compared to SHP099. The E76A mutation brings stronger residue positive correlation and a larger conformation fluctuation between N-CH2 and PTP domains, resulting in tighter binding between TNO155 and SHP2E76A. This study offers valuable insights for the further design and development of novel SHP2E76A allosteric inhibitors."

Journal • CNS Disorders • Developmental Disorders • Oncology • Psychiatry

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1/2 | N=1126 | Recruiting | Sponsor: Amgen | Trial primary completion date: Sep 2026 ➔ Dec 2026

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

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