sitneprotafib (JAB-3312) / Jacobio Pharma, Allist - LARVOL DELTA

Glecirasib plus sitneprotafib in patients with KRASG12C-mutated non-small-cell lung cancer in China: an open-label, multicentre, single-arm, phase 1/2a trial. (PubMed, Lancet Respir Med) - P1/2 | "Glecirasib combined with sitneprotafib showed promising efficacy and manageable safety in patients with advanced KRASG12C -mutated NSCLC, particularly among those who had not received previous treatment. These findings support the evaluation of this combination in a phase 3 trial comparing this chemotherapy-free regimen to current standard of care in this patient group."

Journal • P1/2 data • Dyslipidemia • Hematological Disorders • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Pneumonia • Solid Tumor • KRAS

Genomic Biomarkers for Whole-Process Stratification in KRASG12C-Mutant NSCLC: A Phase 1/2 Trial Analysis of Glecirasib Plus Sitneprotafib (IASLC-WCLC 2026) - P1/2 | "Additionally, treatment-related hepatic adverse events correlated with improved survival, and the HLA-A*11:01 allele was identified as a host genetic protective factor against such hepatotoxicity, mediated by enhanced M2 macrophage polarization and TGFB1-TGFBR2 pathway activity that attenuates hepatic inflammation. Conclusions : Our findings first of all establish a novel molecular framework for precision management of KRASG12C-mutant NSCLC treated with glecirasib plus sitneprotafib, wherein baseline genomic signature stratification and dynamic single-gene KRASG12C ctDNA monitoring enable risk-adapted clinical decision-making, early efficacy assessment and identification of resistance.$$graphic_{02101649-137C-486C-8C2E-ABAF5D5FD3DA}$$"

Biomarker • P1/2 data • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • KRAS • PTPN11 • SMAD4 • SMARCA4 • SMARCB1 • TGFB1 • TGFBR2

Glecirasib (KRAS G12C inhibitor) in combination with JAB-3312 (SHP2 inhibitor) in patients with KRAS p.G12C mutated solid tumors (ESMO 2023) - P1/2 | "Conclusions Glecirasib plus JAB-3312 was well tolerated with promising efficacy in KRAS p.G12C NSCLC. Currently, dose expansion is underway to further evaluate efficacy and safety."

Clinical • Combination therapy • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Genomic Biomarkers for Whole-Process Stratification in KRASG12C-Mutant NSCLC: A Phase 1/2 Trial Analysis of Glecirasib Plus Sitneprotafib (IASLC-WCLC 2026) - P1/2 | "Additionally, treatment-related hepatic adverse events correlated with improved survival, and the HLA-A*11:01 allele was identified as a host genetic protective factor against such hepatotoxicity, mediated by enhanced M2 macrophage polarization and TGFB1-TGFBR2 pathway activity that attenuates hepatic inflammation. Conclusions : Our findings first of all establish a novel molecular framework for precision management of KRASG12C-mutant NSCLC treated with glecirasib plus sitneprotafib, wherein baseline genomic signature stratification and dynamic single-gene KRASG12C ctDNA monitoring enable risk-adapted clinical decision-making, early efficacy assessment and identification of resistance."

Biomarker • P1/2 data • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • KRAS • PTPN11 • SMAD4 • SMARCA4 • SMARCB1 • TGFB1 • TGFBR2

Updated safety and efficacy data of combined KRAS G12C inhibitor (glecirasib, JAB-21822) and SHP2 inhibitor (JAB-3312) in patients with KRAS p.G12C mutated solid tumors. (ASCO 2024) - P1/2 | "Glecirasib plus JAB-3312 has a manageable safety profile and a promising ORR and PFS as a front-line treatment for patients with KRAS p.G12C NSCLC. This combination will be further evaluated in a randomized phase III trial in NSCLC."

Clinical • Anemia • Colorectal Cancer • Dyslipidemia • Gastrointestinal Cancer • Hematological Disorders • Hypertriglyceridemia • Leukopenia • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

JAB-21822-1006: Phase 1/2a Study of JAB-21822 Plus JAB-3312 in Patients With Advanced Solid Tumors Harboring KRAS p.G12C Mutation (clinicaltrials.gov) - P1/2 | N=240 | Recruiting | Sponsor: Allist Pharmaceuticals, Inc. | Trial completion date: Mar 2026 ➔ Mar 2027 | Trial primary completion date: Mar 2026 ➔ Mar 2027

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

JAB-21822 3002: JAB-21822 Combined With JAB-3312 Compared SOC in the First Line for Treatment of Advanced Non-small Cell Lung Cancer With KRAS p.G12C Mutation (clinicaltrials.gov) - P3 | N=392 | Recruiting | Sponsor: Allist Pharmaceuticals, Inc. | Trial completion date: Feb 2027 ➔ Aug 2030 | Trial primary completion date: Sep 2026 ➔ Sep 2029

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

Revolutionizing cancer treatment with the first SHP2 PROTAC (AACR 2025) - "SHP2 inhibitors, like JAB3312, is limited to inhibiting phosphatase activity and evaluated in combination regimens rather than as standalone therapies...Mechanistic studies confirmed TRD209 acts via ubiquitin-proteasome pathway, as validated by TAK-243 and MG132 blockade assays...TDS0593 offer a novel strategy for the treatment of myeloid leukemia by correcting aberrant myeloid-biased differentiation of HSC/HSPC. This innovative approach aims to rectify the underlying dysregulation in hematopoietic differentiation processes, achieving efficacy in myeloid leukemia.TDS0593 reduces leukemic burden and promotes the restoration of HSC% of Myeloid cells in BM% of Myeloid cells in PBHSC/45.2+ in BMnaive48.72(39.47~52.37)40.16(37.27~43.06)0.00312(0.00257~0.004635)kras-mut mouse models + vehicle66.50(64.40~69.40)59.40(41.00~72.10)0.01079(0.007630~0.01500)kras-mut mouse models + TDS059354.07(47.60~63.20)38.32(29.10~51.30)0.005865(0.002350~0.009110)"

IO biomarker • Late-breaking abstract • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • KRAS • PD-1 • PTPRC

A First-in-Human, Phase 1 Study of JAB-3312 in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=40 | Completed | Sponsor: Jacobio Pharmaceuticals Co., Ltd. | Recruiting ➔ Completed | N=24 ➔ 40

Enrollment change • First-in-human • Trial completion • Breast Cancer • Colorectal Cancer • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Head and Neck Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Jacobio combo delivers 71% ORR, sets stage for first SHP-2–based NSCLC therapy (Indian Pharma Post) - "The regimen pairs glecirasib, a KRAS G12C inhibitor, with sitneprotafib, an SHP-2 inhibitor, aiming to offer a fully oral, chemotherapy-free option for patients with KRAS G12C-mutated NSCLC."

P1/2 data • Non Small Cell Lung Cancer

A Study of JAB-3312 in Adult Patients With Advanced Solid Tumors in China (clinicaltrials.gov) - P1 | N=17 | Completed | Sponsor: Allist Pharmaceuticals, Inc. | Recruiting ➔ Completed

Trial completion • Breast Cancer • Colorectal Cancer • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Glecirasib, a potent and selective covalent KRAS G12C inhibitor exhibiting synergism with cetuximab or SHP2 inhibitor JAB-3312. (PubMed, Cancer Res Commun) - P1/2, P3 | "Glecirasib could effectively inhibit HRAS G12C, NRAS G12C, and several G12C-inclusive KRAS double mutants that showed resistance to adagrasib. A new drug application for glecirasib has been submitted in China, seeking approval for the treatment of non-small cell lung cancer, supported by a pivotal phase 2 single-arm study (NCT05009329). Additionally, glecirasib is being explored in clinical trials in combination with cetuximab (phase 2, NCT05194995) and JAB-3312 (phase 3, NCT06416410)."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • HRAS • KRAS • NRAS

SHP2 INHIBITOR SITNEPROTAFIB COMBINATION THERAPY DATA PUBLISHED IN ACADEMIC JOURNAL (HKEXnews) - "The article details in vitro/in vivo preclinical data and representative cases of patients on the SHP2 inhibitor in combination therapies targeting the RTK/RAS/MAPK pathway and PD-1 blockade therapies. The study demonstrates that sitneprotafib significantly enhances the anti-tumor activity of the KRAS G12C inhibitor glecirasib in both treatment-naïve and resistant models. Combination of sitneprotafib with MEK inhibitors significantly delayed RTK signaling reactivation and enhanced tumor growth inhibition in KRAS-mutated cancer models. Sitneprotafib-osimertinib combination exhibited great efficacy in osimertinib-resistant non-small cell lung cancer (NSCLC) models."

Preclinical • Non Small Cell Lung Cancer

JAB-3312, a Potent Allosteric SHP2 Inhibitor that Enhances the Efficacy of RTK/RAS/MAPK and PD-1 Blockade Therapies. (PubMed, Clin Cancer Res) - P1/2 | "JAB-3312 in combination with RTK/RAS/MAPK or PD-1 blockage therapies is a promising strategy that warrants further clinical investigation."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • KRAS

JAB-3312 Based Combination Therapy in Adult Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=58 | Completed | Sponsor: Allist Pharmaceuticals, Inc. | Recruiting ➔ Completed | N=200 ➔ 58

Enrollment change • Trial completion • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A Study of JAB-3312 in Adult Patients with Advanced Solid Tumors in China (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Allist Pharmaceuticals, Inc. | Trial completion date: Dec 2023 ➔ Apr 2026 | Trial primary completion date: Dec 2023 ➔ Apr 2025

Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Head and Neck Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

JAB-21822-1006: Phase 1/2a Study of JAB-21822 Plus JAB-3312 in Patients with Advanced Solid Tumors Harboring KRAS P.G12C Mutation (clinicaltrials.gov) - P1/2 | N=240 | Recruiting | Sponsor: Allist Pharmaceuticals, Inc. | N=124 ➔ 240

Enrollment change • Colorectal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Jacobio Presents Pre-clinical Data of SHP2 plus KRAS G12C (Jacobio Press Release) - "Jacobio Pharma...presented the pre-clinical data of SHP2 inhibitor JAB-3312 in combo with KRAS G12C inhibitor glecirasib as form of poster at the Fifth RAS Initiative Symposium 2024. The data showed that glecirasib and JAB-3312 demonstrate potent anti-tumor effect both in vitro and in vivo, and JAB-3312 enhances the anti-tumor effect of glecirasib. Representative patients cases were also included in the poster."

Preclinical • Oncology

Jakos (01167.HK): Received RMB 173 million including down payment from exclusive external licensing agreement with Ellis [Google translation] (Yahoo Finance) - "Jakosi...announced that on August 30, its indirect non-wholly owned subsidiary Jakosi’s new drug research and development project was announced by Ellison on the KRAS G12C inhibitor Glecirasib (JAB-21822) and the SHP2 allosteric inhibitor JAB-3312. For the external licensing agreement entered into, a payment of RMB 173 million (the same below) has been received, including a down payment of RMB 150 million and partial compensation for research and development expenses and other payments."

Financing • Oncology

Efficacy of glecirasib in combination with JAB-3312 as a front-line treatment for patients with KRAS p.G12C mutated NSCLC with PD-L1 expression levels or co-mutations (ESMO 2024) - P1/2 | "Glecirasib plus JAB-3312 demonstrated a favorable ORR as a front-line treatment in KRAS p.G12C mutated NSCLC, regardless of PD-L1 expression. Co-mutations in SMARC family members may predict poor prognosis in this study population. More data will be presented at the incoming meeting."

Biomarker • Clinical • Combination therapy • IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1 • TP53

JAB-21822 3002: JAB-21822 Combined With JAB-3312 Compared SOC in the First Line for Treatment of Advanced Non-small Cell Lung Cancer With KRAS p.G12C Mutation (clinicaltrials.gov) - P3 | N=392 | Recruiting | Sponsor: Jacobio Pharmaceuticals Co., Ltd. | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Jacobio Out-licensed KRAS G12C Inhibitor Glecirasib and SHP2 Inhibitor JAB-3312 to Allist in China (PRNewswire) - "Jacobio Pharma...announced that it has granted the China rights (including mainland China, Hong Kong, Macau, and Taiwan) of KRAS G12C inhibitor glecirasib and SHP2 inhibitor JAB-3312 to Shanghai Allist Pharmaceuticals Co., Ltd (688578.SH). According to the terms of the agreement, Jacobio shall receive around RMB200 million in the near term, which includes an upfront payment of RMB150 million, and around RMB50 million of compensation for research and development expenses and other payments....Jacobio is also entitled to receive tiered double-digit royalty payments on net sales of glecirasib and JAB-3312 from Allist, among which the royalty payments on net sales of JAB-3312 is up to 20%."

Commercial • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor

After being "returned" by AbbVie, Jacobs terminated the development of a SHP2-targeted drug [Google translation] (Sina Corp) - "...CASI Pharmaceuticals mentioned that the clinical development of the SHP2 allosteric inhibitor JAB-3068 has been terminated....In February of this year, JAB-3312 and the KRAS G12C inhibitor JAB-21822 were approved for Phase III clinical trials in China, becoming the world's first SHP2 inhibitor to enter Phase III registration clinical studies. Relevant clinical data are expected to be announced in the second half of this year."

Discontinued • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Discovery of JAB-3312, a Potent SHP2 Allosteric Inhibitor for Cancer Treatment. (PubMed, J Med Chem) - "JAB-3312 was well-tolerated in animal models, and a close correlation was observed between the plasma concentration of JAB-3312 and the p-ERK inhibition in tumors. Currently, JAB-3312 is undergoing clinical trials as a potential anticancer agent."

Journal • Oncology • PD-1

Jacobio Pharma Presents SHP2 Plus KRAS G12C Data at ASCO (PRNewswire) - P1/2a | N=124 | NCT05288205 | Sponsor: Jacobio Pharmaceuticals Co., Ltd. | "About 102 frontline NSCLC patients have been enrolled in 7 dose groups. The confirmed objective response rate (cORR) was 64.7% (66/102), the disease control rate (DCR) was 93.1% (95/102), and the median progression-free survival (mPFS) was 12.2 months, respectively. This trial explored a total of 7 different dose cohorts, and the optimal dose group was glecirasib at 800mg daily combined with JAB-3312 at 2mg daily one week on and one week off. The cORR of the optimal dose group was 77.4% (18/31), and 54.8% (17/31) of patients achieved a deep response with tumors shrinking by more than 50%....The new drug application (NDA) of glecirasib monotherapy for the second-line NSCLC with KRAS G12C mutation was granted Priority Review designation by China CDE on May 21, 2024."

P2a data • Priority review • Non Small Cell Lung Cancer