P2, N=13, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=27 --> 13

E/M-CTC ≤ 1 showed a trend toward improved OS (p = 0.086). In addition, patients with > 1 CTC who received local radiotherapy for progressive lesions after glecirasib targeted therapy had significantly prolonged PFS and OS compared to those who did not (p < 0.05).

Herein we outline the biology and epidemiology of KRAS alterations at the lineage and allele levels, reviewing the clinical evidence for KRASG12C inhibition from the discovery of the recessive switch pocket to sotorasib, adagrasib and other novel molecules, and extending to the non-KRASG12C era, including RAS (ON)- and KRASG12D-selective strategies and early efficacy signals. We propose a 'three-clock, two-window' framework, which includes half-life exposure, occupation retention and extracellular signal-regulated kinase (ERK) rebound calibration of dosing rhythm; a vascular normalization window and an immune/myeloid plasticity window to achieve longitudinal Src homology 2-containing protein tyrosine phosphatase 2/son of sevenless homologue 1 and transverse epidermal growth factor receptor, phosphoinositide 3-kinase-protein kinase-mammalian target of rapamycin synergy. At the same time, we construct and propose a closed loop of exposure, occupation, pathway inhibition, circulating tumour DNA (ctDNA) and imaging by utilizing ctDNA dynamics, phosphorylated ERK rebound and perfusion imaging, as well as myeloid lineage quantification, to improve durable inhibition and overall survival through time-aligned combined effects.

P1/2, N=713, Completed, Amgen | Active, not recruiting --> Completed

Moreover, we show that GNE-8025 increases the activity of a broad range of MAPK pathway inhibitors in vitro as well as the KRASG12C inhibitor Divarasib both in vitro and in vivo. In addition, GNE-2181 inhibits growth of an intracranial tumor model in vivo. Altogether we present a next-generation class of TEAD inhibitors representing a significant advancement towards potent, specific, and effective Hippo-targeting cancer therapies.

P2, N=43, Recruiting, Second Affiliated Hospital, School of Medicine, Zhejiang University

Allele-specific KRAS inhibitors such as the KRASG12C inhibitors sotorasib and adagrasib have demonstrated clinical activity as monotherapy but adaptive signaling in response to KRAS pathway inhibition can promote resistance and limit the efficacy of these drugs. Using xenograft models, we observed that pharmacologic blockade of FAK enhanced the anti-tumor activity of KRAS inhibitors. These data highlight the therapeutic potential of FAK/SRC inhibitors to mitigate adaptive signaling induced by KRAS inhibition and enhance the clinical activity of KRAS inhibitors.

P2, N=90, Active, not recruiting, Mirati Therapeutics Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Jun 2026 --> Sep 2026

Competition with MRTX849 blocked KRAS degradation, supporting on-target covalent engagement at Cys12. These findings establish carborane as a compact, functional HyT that drives proteasome-dependent degradation of endogenous KRASG12C and suppresses downstream signaling, broadening degrader design to include an E3-independent modality for the degradation of oncogenic proteins.

P1, N=45, Recruiting, Theras Inc. | Not yet recruiting --> Recruiting

P3, N=338, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Sep 2027 --> May 2026

Postmortem examination revealed pleomorphic carcinoma. ERBB3 amplification may contribute to off-target resistance to sotorasib, and transformation to pleomorphic carcinoma may represent an additional resistance mechanism.