^
    19d
    A Study of JAB-21822 in Advanced or Metastatic NSCLC With KRAS p.G12C and STK11 Co-mutation and Wild-type KEAP1 (clinicaltrials.gov)
    P1/2, N=104, Recruiting, Allist Pharmaceuticals, Inc. | Trial primary completion date: Dec 2023 --> Feb 2026
    Trial primary completion date
    |
    KRAS (KRAS proto-oncogene GTPase) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1)
    |
    KRAS mutation • KRAS G12C • STK11 mutation • KEAP1 mutation • KRAS G12
    |
    glecirasib (JAB-21822)
    1m
    Glecirasib in KRASG12C-mutated nonsmall-cell lung cancer: a phase 2b trial. (PubMed, Nat Med)
    Glecirasib exhibited promising clinical efficacy and manageable safety profiles in these patient populations. ClinicalTrials.gov identifier: NCT05009329 .
    P2b data • Journal
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C • KRAS G12
    |
    glecirasib (JAB-21822)
    1m
    JAB-21822 in Combination with Cetuximab in Patients with Advanced CRC and Other Solid Tumors with KRAS G12C Mutation (clinicaltrials.gov)
    P1/2, N=48, Active, not recruiting, Allist Pharmaceuticals, Inc. | Trial primary completion date: Dec 2024 --> Dec 2025
    Trial primary completion date
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C • KRAS G12
    |
    Erbitux (cetuximab) • glecirasib (JAB-21822)
    2ms
    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, Allist Pharmaceuticals, Inc. | N=124 --> 240
    Enrollment change
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C • KRAS G12
    |
    glecirasib (JAB-21822) • sitneprotafib (JAB-3312)
    2ms
    Small molecules for Kirsten rat sarcoma viral oncogene homolog mutant cancers: Past, present, and future. (PubMed, Eur J Pharmacol)
    However, due to the lack of a binding pocket, KRAS has long been considered an undruggable target in recent decades until the discovery of Sotorasib (AMG510). With the approval of Glecirasib (JAB-21822), there are three approved small molecule inhibitors of KRAS, all of which are KRAS G12C inhibitors. At the same time, the limited clinical benefits and rapid emergence of drug resistance to the approved inhibitors have also promoted the emergence of more therapeutics, such as tri-complexes and proteolysis-targeting chimeras (PROTAC). In this paper, we summarize the development of KRAS inhibitors (KRASG12C, KRASG12D, and KRASmulti inhibitors, PROTAC, and tri-complex) and discuss the challenges and opportunities in the discovery of KRAS inhibitors in the hope of providing insights into the development of novel medications for KRAS.
    Preclinical • Review • Journal
    |
    EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • mTOR (Mechanistic target of rapamycin kinase)
    |
    KRAS mutation • KRAS G12D
    |
    Lumakras (sotorasib) • glecirasib (JAB-21822)
    3ms
    Design, Structure Optimization, and Preclinical Characterization of JAB-21822, a Covalent Inhibitor of KRASG12C. (PubMed, J Med Chem)
    Biopharmaceutical optimization of the resulting leads to improve the solubility of the compounds and block the possible metabolic hotspots led to the identification of JAB-21822, a covalent KRASG12C inhibitor with high potency and excellent cross-species pharmacokinetic properties. JAB-21822 has finished the pivotal Phase II clinical trials in NSCLC, and a new drug application was submitted to the National Medical Products Administration in 2024.
    Preclinical • Journal
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C
    |
    glecirasib (JAB-21822)
    3ms
    KEAP1 mutations as key crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors. (PubMed, J Transl Med)
    This research affirms KRAS-G12C inhibitors as promising treatments, especially for certain patient subgroups, and underscores KEAP1 mutations as key biomarkers for resistance. The findings highlight the urgent need for alternative therapeutic approaches in KEAP1-mutant patients and emphasize the role of molecular profiling in tailored treatment strategies.
    Clinical • Journal • PD(L)-1 Biomarker • IO biomarker
    |
    PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1)
    |
    KRAS mutation • STK11 mutation • KEAP1 mutation • KRAS G12C + PD-L1 expression
    |
    Lumakras (sotorasib) • Krazati (adagrasib) • glecirasib (JAB-21822)
    5ms
    NUMER: Neoadjuvant Umbrella Trial for Patients With Unresectable Stage III NSCLC Harboring Rare Mutations. (clinicaltrials.gov)
    P2, N=120, Recruiting, Sun Yat-sen University | Not yet recruiting --> Recruiting
    Enrollment open
    |
    Mekinist (trametinib) • Xalkori (crizotinib) • Tafinlar (dabrafenib) • Vitrakvi (larotrectinib) • Irene (pyrotinib) • Gavreto (pralsetinib) • Ensacove (ensartinib) • Orpathys (savolitinib) • glecirasib (JAB-21822) • sunvozertinib (DZD9008)
    8ms
    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, Jacobio Pharmaceuticals Co., Ltd. | Not yet recruiting --> Recruiting
    Enrollment open • Metastases
    |
    carboplatin • Tevimbra (tislelizumab-jsgr) • pemetrexed • glecirasib (JAB-21822) • sitneprotafib (JAB-3312)
    8ms
    NUMER: Neoadjuvant Umbrella Trial for Patients With Unresectable Stage III NSCLC Harboring Rare Mutations. (clinicaltrials.gov)
    P2, N=120, Not yet recruiting, Sun Yat-sen University
    New P2 trial
    |
    Mekinist (trametinib) • Xalkori (crizotinib) • Tafinlar (dabrafenib) • Vitrakvi (larotrectinib) • Irene (pyrotinib) • Gavreto (pralsetinib) • Ensacove (ensartinib) • Orpathys (savolitinib) • glecirasib (JAB-21822) • sunvozertinib (DZD9008)
    8ms
    JAB-21822 in Combination With Cetuximab in Patients With Advanced CRC and Other Solid Tumors With KRAS G12C Mutation (clinicaltrials.gov)
    P1/2, N=48, Active, not recruiting, Jacobio Pharmaceuticals Co., Ltd. | Recruiting --> Active, not recruiting | Trial primary completion date: Dec 2023 --> Dec 2024
    Enrollment closed • Trial primary completion date • Combination therapy • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    Erbitux (cetuximab) • glecirasib (JAB-21822)
    11ms
    A Study of JAB-21822 in Adult Patients With Advanced Solid Tumors Harboring KRAS p.G12C Mutation in China (clinicaltrials.gov)
    P1/2, N=311, Active, not recruiting, Jacobio Pharmaceuticals Co., Ltd. | Recruiting --> Active, not recruiting | N=144 --> 311
    Enrollment closed • Enrollment change • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    glecirasib (JAB-21822)
    11ms
    A Clinical Trial to Evaluate JAB-21822 Drug-drug Interactions in Healthy Subjects (clinicaltrials.gov)
    P1, N=66, Completed, Jacobio Pharmaceuticals Co., Ltd. | Recruiting --> Completed | Trial completion date: Jul 2024 --> Feb 2024 | Trial primary completion date: Jun 2024 --> Feb 2024
    Trial completion • Trial completion date • Trial primary completion date
    |
    glecirasib (JAB-21822) • itraconazole • midazolam hydrochloride • omeprazole • rifampicin
    12ms
    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, Not yet recruiting, Jacobio Pharmaceuticals Co., Ltd.
    New P3 trial • Metastases
    |
    carboplatin • Tevimbra (tislelizumab-jsgr) • pemetrexed • glecirasib (JAB-21822) • sitneprotafib (JAB-3312)
    1year
    A Study of JAB-21822 in Patients With KRAS p.G12C Mutated Pancreatic Cancer (clinicaltrials.gov)
    P2, N=69, Recruiting, Jacobio Pharmaceuticals Co., Ltd. | Not yet recruiting --> Recruiting
    Enrollment open • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase) • MSI (Microsatellite instability)
    |
    KRAS mutation • MSI-H/dMMR • KRAS G12C • KRAS G12
    |
    glecirasib (JAB-21822)
    1year
    Mass Balance Study of [14C]JAB-21822 (clinicaltrials.gov)
    P1, N=6, Completed, Jacobio Pharmaceuticals Co., Ltd. | Active, not recruiting --> Completed
    Trial completion
    |
    glecirasib (JAB-21822)
    over1year
    A Food Effect Study of JAB-21822 in Healthy Subjects (clinicaltrials.gov)
    P1, N=18, Completed, Jacobio Pharmaceuticals Co., Ltd. | Active, not recruiting --> Completed | Trial completion date: Oct 2023 --> Jun 2023
    Trial completion • Trial completion date
    |
    glecirasib (JAB-21822)
    over1year
    A Clinical Trial to Evaluate JAB-21822 Drug-drug Interactions in Healthy Subjects (clinicaltrials.gov)
    P1, N=66, Recruiting, Jacobio Pharmaceuticals Co., Ltd.
    New P1 trial
    |
    glecirasib (JAB-21822) • itraconazole • midazolam hydrochloride • omeprazole • rifampicin
    over1year
    Preliminary activity and safety results of KRAS G12C inhibitor glecirasib (JAB-21822) in patients with pancreatic cancer and other solid tumors. (ASCO-GI 2024)
    Glecirasib monotherapy is well tolerated and has a manageable safety profile and exhibits promising anti-tumor activity in pts with KRAS G12C mutated PDAC and other solid tumors. Further clinical development of glecirasib in above mentioned population is ongoing (NCT06008288). Clinical trial information: NCT05009329 and NCT05002270.
    Clinical
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation
    |
    glecirasib (JAB-21822)
    over1year
    JAB-21822 Activity in Adult Patients With Advanced Solid Tumors Harboring KRAS G12C Mutation (clinicaltrials.gov)
    P1/2, N=100, Recruiting, Jacobio Pharmaceuticals Co., Ltd. | Trial primary completion date: Jul 2023 --> Jan 2024
    Trial primary completion date • Combination therapy • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C • KRAS G12
    |
    Erbitux (cetuximab) • glecirasib (JAB-21822)
    over1year
    A Study of JAB-21822 in Patients With KRAS p.G12C Mutated Pancreatic Cancer (clinicaltrials.gov)
    P2, N=69, Not yet recruiting, Jacobio Pharmaceuticals Co., Ltd.
    New P2 trial • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase) • MSI (Microsatellite instability) • CA 19-9 (Cancer antigen 19-9)
    |
    KRAS mutation • MSI-H/dMMR • KRAS G12C • KRAS G12
    |
    glecirasib (JAB-21822)
    almost2years
    Glecirasib (KRAS G12C inhibitor) in combination with JAB-3312 (SHP2 inhibitor) in patients with KRAS p.G12C mutated solid tumors (ESMO 2023)
    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
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation
    |
    glecirasib (JAB-21822) • sitneprotafib (JAB-3312)
    over2years
    A Study of JAB-21822 in Advanced or Metastatic NSCLC With KRAS p.G12C and STK11 Co-mutation and Wild-type KEAP1 (clinicaltrials.gov)
    P1/2, N=104, Recruiting, Jacobio Pharmaceuticals Co., Ltd. | Not yet recruiting --> Recruiting
    Enrollment open • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1)
    |
    KRAS mutation • KRAS G12C • STK11 mutation • KEAP1 mutation • KRAS G12
    |
    glecirasib (JAB-21822)
    almost3years
    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=124, Recruiting, Jacobio Pharmaceuticals Co., Ltd. | Not yet recruiting --> Recruiting | N=72 --> 124
    Enrollment open • Enrollment change • Combination therapy
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C • KRAS G12
    |
    glecirasib (JAB-21822) • sitneprotafib (JAB-3312)
    almost3years
    A phase I/II study of first-in-human trial of JAB-21822 (KRAS G12C inhibitor) in advanced solid tumors. (ASCO 2022)
    JAB-21822 was well tolerated with impressive preliminary efficacy in patients with heavily treated solid tumors harboring KRAS G12C mutation. The study is enrolling patients in the expansion phase. Multiple JAB-21822-based combination trials are also ongoing.
    P1/2 data
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C
    |
    glecirasib (JAB-21822)
    3years
    JAB-21822 in Combination With Cetuximab in Patients With Advanced CRC and Other Solid Tumors With KRAS G12C Mutation (clinicaltrials.gov)
    P1/2, N=62, Recruiting, Jacobio Pharmaceuticals Co., Ltd. | Not yet recruiting --> Recruiting
    Enrollment open • Combination therapy
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C • KRAS G12
    |
    Erbitux (cetuximab) • glecirasib (JAB-21822)
    3years
    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=72, Not yet recruiting, Jacobio Pharmaceuticals Co., Ltd.
    New P1/2 trial • Combination therapy
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C • KRAS G12
    |
    glecirasib (JAB-21822) • sitneprotafib (JAB-3312)
    3years
    Study to investigate JAB-21822 Monotherapy and Combination Therapy in Adult Patients with Advanced Solid Tumors Harboring KRAS G12C Mutation Estudio para evaluar JAB-21822 en monoterapia y en combinación en pacientes adultos con tumores sólidos avanzados portadores de la mutación KRAS G12C (clinicaltrialsregister.eu)
    P1/2, N=136, Ongoing, Jacobio Pharmaceuticals Co., Ltd.
    New P1/2 trial • Combination therapy
    |
    KRAS (KRAS proto-oncogene GTPase) • MSI (Microsatellite instability)
    |
    KRAS mutation • MSI-H/dMMR
    |
    Erbitux (cetuximab) • glecirasib (JAB-21822)
    3years
    A Study of JAB-21822 in Advanced or Metastatic NSCLC With KRAS p.G12C and STK11 Co-mutation and Wild-type KEAP1 (clinicaltrials.gov)
    P1/2, N=104, Not yet recruiting, Jacobio Pharmaceuticals Co., Ltd.
    New P1/2 trial
    |
    KRAS (KRAS proto-oncogene GTPase) • STK11 (Serine/threonine kinase 11) • KEAP1 (Kelch Like ECH Associated Protein 1)
    |
    KRAS mutation • KRAS G12C • STK11 mutation • KEAP1 mutation • KRAS G12
    |
    glecirasib (JAB-21822)
    over3years
    JAB-21822 in Combination With Cetuximab in Patients With Advanced CRC and Other Solid Tumors With KRAS G12C Mutation (clinicaltrials.gov)
    P1/2, N=62, Not yet recruiting, Jacobio Pharmaceuticals Co., Ltd.
    New P1/2 trial • Combination therapy
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C • KRAS G12
    |
    Erbitux (cetuximab) • glecirasib (JAB-21822)
    over3years
    JAB-21822 Activity in Adult Patients With Advanced Solid Tumors Harboring KRAS G12C Mutation (clinicaltrials.gov)
    P1/2, N=100, Recruiting, Jacobio Pharmaceuticals Co., Ltd. | Not yet recruiting --> Recruiting
    Clinical • Enrollment open • Combination therapy
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C • KRAS G12
    |
    Erbitux (cetuximab) • glecirasib (JAB-21822)
    over3years
    FIH Study of JAB-21822 in Adult Patients With Advanced Solid Tumors Harboring KRAS G12C Mutation in China (clinicaltrials.gov)
    P1/2, N=144, Recruiting, Jacobio Pharmaceuticals Co., Ltd.
    Clinical • New P1/2 trial
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C • KRAS G12
    |
    glecirasib (JAB-21822)
    over3years
    JAB-21822 Activity in Adult Patients With Advanced Solid Tumors Harboring KRAS G12C Mutation (clinicaltrials.gov)
    P1/2, N=100, Not yet recruiting, Jacobio Pharmaceuticals Co., Ltd.
    Clinical • New P1/2 trial • Combination therapy
    |
    KRAS (KRAS proto-oncogene GTPase)
    |
    KRAS mutation • KRAS G12C • KRAS G12
    |
    Erbitux (cetuximab) • glecirasib (JAB-21822)