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

PD-1 Expression in Lymphoma Cells Mediates Cellular Proliferation By Engaging Phosphatase SHP-1/SHP-2 (ASH 2023) - "Our group showed a selective response (~40%) with the PD-1 blocking antibody pembrolizumab in patients with RT, particularly after prior exposure to ibrutinib (Ding et al, Blood, 2017)...SHP-1 (TPI-1) and SHP-1+SHP-2 (TPI-1+TNO155) inhibitor treatment promoted OCI-LY19 cell death and led to recovery of phosphorylation on ATM, Chk-2 and p53 in these cells... Our data showed robust PD-1 expression in patients with Richter transformation from CLL to DLBCL. PD-1 overexpression in DLBCL lymphoma cell lines enhanced cell proliferation in vitro and in vivo. Further investigation identified that PD-1 modified the phosphorylation/function of SHP phosphatases and thereby regulated p53 pathways (Figure 1)."

IO biomarker • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • CHEK2 • LY9 • NAT10 • PD-1 • PD-L1 • PD-L2

A phase 1b, multicenter, open-label dose-escalation and expansion platform study of select drug combinations in adult patients with advanced or metastatic BRAF V600 colorectal cancer (AACR-NCI-EORTC 2025) - P1 | "This first-in-human, phase 1b study (NCT04294160) evaluated the safety, pharmacokinetics (PK), and preliminary antitumor activity of several rationally designed combinations in patients with BRAF V600-mutant CRC. This open-label, adaptive platform trial included a doublet backbone arm (BA: dabrafenib [DRB436; BRAF V600 inhibitor] + LTT462 [ERK1/2 inhibitor]) and 6 triplet arms (TAs): A1 (DRB436 + LTT462 + trametinib [TMT212; MEK1/2 inhibitor]), A2 (DRB436 + LTT462 + LXH254 [B/C-RAF inhibitor]), A3 (DRB436 + LTT462 + TNO155 [SHP2 inhibitor]), A4 (DRB436 + LTT462 + spartalizumab [anti–PD-1]), A5 (DRB436 + TMT212 + TNO155), and A6 (DRB436 + LTT462 + tislelizumab [anti–PD-1]). This multi-arm platform study demonstrated manageable safety across several MAPK pathway inhibitor combinations in BRAF V600-mutant CRC. Although RDs were not defined, preliminary efficacy and disease control results showed modest antitumor effect in all treatment arms."

Clinical • IO biomarker • Late-breaking abstract • Metastases • P1 data • Colorectal Cancer • Oncology • Solid Tumor • BRAF • DUSP6

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1 | N=610 | Active, not recruiting | Sponsor: Amgen | Recruiting ➔ Active, not recruiting | N=1200 ➔ 610 | Trial primary completion date: Jun 2026 ➔ Dec 2026

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

Development of Patient-Derived Xenograft (PDX) Model with Acquired Resistance to KRASG12C Inhibitors (AACR-NCI-EORTC 2025) - "Then LU22002 was established from tumors of the same patient that progressed under combined treatment of MRTX849 and a SHP2 inhibitor, TNO155...Noticeably, all 6 mice treated with combined treatment of crizotinib and AMG510 showed complete tumor regression after 17 days of treatment. ConclusionWe have successfully developed KRASG12C inhibitor resistant NSCLC PDX models derived from one patient with acquired resistance to AMG510 and MRTX849 treatments, and in vivo induced KRASG12C inhibitor resistant PDX model. EGFR or MET gene amplification was observed in these resistant models, which can be used to evaluate innovative combination strategies."

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

Allosteric SHP2 inhibitors suppress lung cancer cell migration by inhibiting non-canonical activation of EphA2 via the ERK-RSK signaling pathway. (PubMed, Sci Rep) - "We herein demonstrated that the allosteric SHP2 inhibitors, SHP099 and TNO155, suppressed both the TNF-α- and growth factor-induced non-canonical phosphorylation of EphA2 at Ser-897 via the ERK-RSK pathway. In contrast, these inhibitors did not affect the signaling pathways leading to EphA2 induced by TPA in HeLa cells or by TNF-α in A549 cells, indicating the involvement of a complex signaling network in these processes. Collectively, the present results highlight the potential of allosteric SHP2 inhibitors as agents targeting the non-canonical activation of EphA2 in LUAD cells."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • EML4 • KRAS • TNFA

Identifying Acquired Resistance Mechanisms to Sotorasib in G12C Lung Adenocarcinoma (LuAD) Cell Lines (CL) (IASLC-WCLC 2025) - "Sotorasib and adagrasib trials showed promising response rates but short duration of response (11 and 8 months, respectively)...We also exposed the resistant cells to a SHP2 inhibitor (TNO155) and to a MEK inhibitor (trametinib), with and without sotorasib, and determined efficacy using cell viability and colony formation assays...AKT pathway activation could be an off-target resistance mechanism. SHP2i could be synergic in combination with sotorasib in partially resistant cell lines."

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

RAS pathway inhibitors combined with targeted agents are active in patient-derived spheroids with oncogenic KRAS variants from multiple cancer types. (PubMed, Cancer Res Commun) - "Vertical inhibition of the RAS/MEK/ERK pathway by targeting SHP2 or SOS1 and the downstream kinases MEK (trametinib) or ERK (temuterkib) was highly effective. Inhibition of upstream tyrosine receptor kinases with nintedanib in combination with batoprotafib or BI-3406 was also effective, and in combination with sotorasib, demonstrated synergy in spheroids harboring KRAS G12C. Dual inhibition of the RAS/MEK/ERK and PI3K/AKT/mTOR pathways by batoprotafib or sotorasib with either the mTORC1/2 inhibitor sapanisertib or the AKT inhibitor ipatasertib demonstrated combination activity, primarily in spheroids harboring KRAS G12C. The BCL-2 inhibitor venetoclax in combination with sotorasib, batoprotafib or BI-3406 resulted in additive and synergistic cytotoxicity. Lastly, concurrent inhibition of the KRAS pathway with sotorasib and batoprotafib demonstrated combination activity in spheroids containing KRAS G12C."

Journal • Oncology • 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

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=227 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial primary completion date: Nov 2025 ➔ Jul 2025 | Trial completion date: Nov 2025 ➔ Jul 2025

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

Adquired resistance mechanisms to KRAS G12C inhibitors in lung cancer (EACR 2025) - "The first effective covalent G12C inhibitors (i) sotorasib and adagrasib bound to mutant cysteine, trapping KRAS in its inactive GDP-bound state...We tested new drug combinations to revert off-target resistant mechanisms with a SHP2 inhibitor (TNO155) and a MEK inhibitor (trametinib), with and without sotorasib, and analyzed the efficacy by cell viability and colony formation assays... On target KRAS mutations as mutant allele amplification and secondary KRAS nonG12C mutations are the most prevalent acquired resistance mechanisms. Upstream and downstream inhibitors as SHP2i and MEKi could be synergic in combination with sotorasib in partially resistant CLs."

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

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