Airuikai (glecirasib)

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.

In targeted therapies, KRASG12C targeted drugs, including Sotorasib, Adagrasib, Fulzerasib, Garsorasib, and Glecirasib, have demonstrated certain therapeutic efficacies in clinical trials and have obtained marketing approval. To tackle drug resistance and enhance patient's prognoses, combination therapeutic strategies that integrate targeted agents with chemotherapy, immune checkpoint inhibitors, Src homology region 2 domain-containing phosphatase 2 (SHP2) inhibitors, and epidermal growth factor receptor (EGFR) monoclonal antibodies have emerged. This paper systematically reviews the advancements in the diagnosis and targeted therapy of NSCLC with KRASG12C mutation, aiming to offer a reference for the selection of clinical treatment regimens and subsequent research..

Glecirasib showed promising efficacy and was well tolerated in patients with PDAC and other advanced solid tumors (beyond NSCLC and CRC), warranting further expedited clinical development in this patient population.

P2, N=86, Not yet recruiting, Abbisko Therapeutics Co, Ltd

P2, N=88, Recruiting, Allist Pharmaceuticals, Inc. | Trial completion date: Nov 2025 --> Dec 2027 | Trial primary completion date: May 2025 --> Dec 2026

JAB-3312 in combination with RTK/RAS/MAPK or PD-1 blockage therapies is a promising strategy that warrants further clinical investigation.

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).

P1/2, N=104, Recruiting, Allist Pharmaceuticals, Inc. | Trial primary completion date: Dec 2023 --> Feb 2026

Glecirasib exhibited promising clinical efficacy and manageable safety profiles in these patient populations. ClinicalTrials.gov identifier: NCT05009329 .

P1/2, N=48, Active, not recruiting, Allist Pharmaceuticals, Inc. | Trial primary completion date: Dec 2024 --> Dec 2025

P1/2, N=240, Recruiting, Allist Pharmaceuticals, Inc. | N=124 --> 240

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.