Targeted therapeutic strategies for KRAS-G12D-mutant non-small cell lung cancer: a narrative review

Introduction

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality worldwide and accounts for approximately 85% of all lung cancer cases (1). Among these, lung adenocarcinoma (LUAD) is the most common histological subtype. Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations represent one of the most frequent oncogenic drivers in LUAD, among which the KRAS-G12C subtype accounts for approximately 39% of KRAS-mutant LUAD cases, while the KRAS-G12D subtype accounts for 14–18% of KRAS-mutant LUAD cases (2).

At present, targeted drugs for KRAS-G12C mutations have achieved certain therapeutic effects in clinical practice, and represent new treatment options for patients with this alteration. For example, sotorasib has been approved by the Food and Drug Administration (FDA) and has shown objective responses in previously treated patients (3), while adagrasib has also demonstrated promising clinical results (4). In addition, emerging combination strategies are currently being explored in clinical trials, including garsorasib-based regimens for KRAS-G12C-mutant locally advanced or metastatic NSCLC (NCT07294261), which further expand the therapeutic landscape of this subgroup. However, despite these advances, gaps remain in the treatment of KRAS-G12D mutations. Due to differences in the molecular structure and biology between G12D and G12C, existing KRAS-G12C targeted drugs are difficult to effectively apply to the treatment of G12D mutations. Currently, there is a lack of drugs for patients with KRAS-G12D-mutant NSCLC, highlighting an urgent clinical need for the development of new targeted drugs.

Based on this context, this review provides a systematic overview of the latest therapeutic advances in KRAS-G12D-mutant NSCLC from a translational medicine perspective. It highlights direct-targeting strategies, indirect inhibitory approaches, and combination treatment modalities, while also exploring the impact of co-mutation landscapes, the tumor immune microenvironment, and potential resistance mechanisms to inform future clinical research and advance precision medicine for patients with NSCLC. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0639/rc).

Methods

The final search was conducted on April 5, 2026, across electronic databases, including PubMed, Web of Science, and Google Scholar. The search included publications from January 2015 to March 2026 and was restricted to articles published in English. Additional studies were identified by manually reviewing the reference lists of relevant original studies and review articles.

The following keywords and MeSH terms were used: KRAS-G12D, KRAS-G12C, non-small cell lung cancer, NSCLC, LUAD, targeted therapy, RAS inhibitors, KRAS inhibitors, SHP2 inhibitors, SOS1 inhibitors, MEK inhibitors, ERK inhibitors, clinical trials, and resistance mechanisms, along with their variants. Boolean operators (AND/OR) were applied to optimize the search strategy. Studies were considered eligible if they investigated KRAS-G12D-mutant NSCLC, reported preclinical or clinical data on targeted therapies, described molecular mechanisms, or discussed resistance mechanisms. Studies were excluded if they were unrelated to KRAS-G12D, lacked sufficient scientific rigor, or contained duplicate data. Conference abstracts [e.g., American Association for Cancer Research (AACR), American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO)], when providing the most up-to-date evidence for early-stage therapeutic approaches, were included as preliminary, non-peer-reviewed evidence and were clearly distinguished from full peer-reviewed publications in the narrative synthesis.

The literature screening was conducted independently by two authors. Any discrepancies were resolved through discussion or, when necessary, consultation with a third author until consensus was reached. All retrieved records were screened based on titles and abstracts, and articles considered potentially relevant were selected for full-text review. The search strategy is summarized in Table 1.

Molecular basis and biological characteristics

KRAS belongs to the RAS protein family. As a “binary molecular switch” that depends on guanine nucleotide exchange factors (GEF) and GTPase-activating protein (GAP) regulation, it cycles between GTP (activated) and guanosine diphosphate (GDP) (inactivated) states (5). A G12 site mutation can inhibit GAP-mediated GTP hydrolysis, resulting in the sustained activation of downstream signaling pathways (6).

Molecular structural and chemical-property differences

In terms of molecular structure, the KRAS-G12C mutation produces cysteine with a thiol-containing side chain, enabling covalently binding of inhibitors such as sotorasib and adagrasib. As a result of the binding process, KRAS-G12C remains in the form that associates with GDP, which represents the inactive state (7). Conversely, the KRAS-G12D mutation forms an aspartic acid residue without a thiol group, and thus cannot achieve similar covalent binding (8).

In terms of local conformation, the KRAS-G12C mutation can induce the formation of a cryptic allosteric pocket under Switch II [known as the Switch II pocket (SII-P)], which is the key binding site for G12C inhibitors (9). Conversely, the KRAS-G12D mutation lacks a thiol-containing side chain that can induce the SII-P (10). This limits the applicability of the same therapeutic approach to KRAS-G12D (11). In addition, the negatively charged aspartic acid at codon 12 (Asp12) side chain alters the conformation and dynamics of the P-loop vicinity (12) and the Switch II region, reducing the flexibility and inducibility of the region (13-15). These effects increase the difficulty of designing treatments targeting G12D. In addition, these molecular differences also directly determine the nucleotide cycling behavior and drug-binding kinetics of G12D mutants.

Biochemical kinetics and enzymatic properties

The endogenous activity for breaking down GTP in the G12C form, without regulation by GAP, appears closer to wild-type KRAS (16). G12C mutant protein can still move between GTP and GDP forms (17). This provides a binding-competent GDP-state configuration for SII-P inhibitors (18). The G12D form has a lower rate for breaking down GTP. The protein has a greater tendency to remain in the GTP-bound active form (19). The restricted movement between forms makes it difficult for inhibitors targeting the GDP form to bind. G12C inhibitors can function by maintaining the GDP-bound form, but G12D requires targeting the active structure or using different approaches for binding.

Downstream signaling preferences

Although both KRAS-G12C and KRAS-G12D activate multiple downstream effector pathways, studies suggest that they may exhibit distinct signaling preferences. KRAS-G12C has been reported to show relatively greater engagement of RAL A/B signaling, whereas KRAS-G12D may preferentially activate the PI3K-AKT-mTOR pathway (20,21). This difference may be related to the differences between Asp12 and Cysteine at codon 12 (Cys12) in charge, hydrophilicity/hydrophobicity, and nucleic acid preferences. While both mutants are capable of activating the mitogen-activated protein kinase (MAPK) RAF-MEK-ERK cascade, the level of phospho-extracellular signal-regulated kinase 1/2 (pERK1/2) in G12D mutants and their response to MEK/ERK inhibition are lower than those in G12C mutants (21). In addition, the G12D mutation significantly reduces the binding affinity between C-Raf and KRAS, while no significant change is observed in KRAS-G12C (22). This indicates that G12D mutant cells may rely more on other effector pathways to maintain signaling, providing a mechanistic basis for the limited efficacy of MEK inhibitors in G12D-mutant NSCLC, and supporting the rationale for combination strategies targeting PI3K or Src-homology-2-containing protein tyrosine phosphatase 2 (SHP2) signaling.

Co-mutation landscape and the tumor immune microenvironment

In NSCLC, KRAS mutations frequently co-occur with other mutations (e.g., TP53, STK11, and KEAP1) (23), and jointly affect the tumor microenvironment (TME), a concept often referred to as the co-mutation spectrum. Based on co-mutation characteristics, Skoulidis et al. (24) proposed three co-mutation subgroups in LUAD. The KP subgroup is characterized by concurrent TP53 mutations and typically exhibits an “immune-hot” phenotype; that is, high cluster of differentiation 8-positive (CD8⁺) T cell infiltration, high programmed death ligand-1 (PD-L1) expression, and activation of multiple pro-inflammatory pathways. Immunotherapy shows better efficacy in this subgroup of NSCLC patients (25), and the benefits are greater than those observed in patients with KRAS-mutant NSCLC overall (26). The KL subgroup is characterized by STK11/LKB1 inactivation. The TME of this subgroup tends to be an “immune-cold” state, manifested by low T-cell infiltration, low PD-L1 expression, impaired antigen presentation, and poor response to immune checkpoint inhibitors (ICIs) (27). Such co-mutations are associated with an unfavorable clinical prognosis (28). The KC subgroup is characterized by the inactivation of cyclin dependent kinase inhibitor 2A/2B (CDKN2A/B) and the low expression of the transcription factor NK2 homeobox 1 (NKX2-1), also known as thyroid transcription factor-1 (TTF1). It is associated with mucinous histological characteristics and the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway.

Further, studies (29,30) have demonstrated that the G12D mutation itself can induce CD4⁺ T cell differentiation into regulatory T cells by upregulating interleukin-10 (IL-10)/transforming growth factor-beta (TGF-β), and can recruit myeloid-derived suppressor cells to form an immunosuppressive microenvironment through the interferon regulatory factor 2 (IRF2)-C-X-C motif chemokine ligand 3 (CXCL3)/C-X-C motif chemokine receptor 2 (CXCR2) axis. At the same time, G12D-related enhancement of glycolysis and lactic acid accumulation can inhibit CD8⁺ T cells and strengthen Treg activity, thus triggering primary or secondary drug resistance to programmed cell death protein 1 (PD-1)/PD-L1 monotherapy.

In general, in addition to the requirements for high affinity, non-covalent binding, and pathway-specific signaling preferences, drugs targeting KRAS-G12D also need to consider the heterogeneity of the tumor immune microenvironment. This suggests that combination strategies of KRAS inhibitors with immune checkpoint blockade or Stimulator of Interferon Genes agonists may have greater clinical value.

An overview of the major signaling pathways and therapeutic targets in KRAS-G12D-mutant NSCLC is presented in Figure 1.

Figure 1 Key cellular pathways and common therapeutic targets of KRAS-G12D. Therapeutic strategies targeting KRAS-G12D in NSCLC. Direct KRAS-G12D inhibitors, upstream regulators, and downstream pathway inhibitors are illustrated. The picture is created in BioRender. Cheng, C. [2026]; https://BioRender.com/8ojstw9. GDP, guanosine diphosphate; GTP, guanosine triphosphate; NSCLC, non-small cell lung cancer.

Targeted therapeutic strategies

Direct-targeting strategies

Direct-targeting strategies inhibit downstream signal transduction by directly binding to mutants, thereby achieving anti-tumor effects. Representative agents include MRTX-1133 and RMC-9805 (zoldonrasib). This approach emphasizes single-molecule targeting and offers the advantages of high potency, strong selectivity, and a relatively low risk of off-target effects (31). However, therapeutic efficacy may be compromised by the emergence of on-target secondary mutations, bypass signaling activation, co-mutation contexts, or remodeling of the tumor immune microenvironment (32). Meanwhile, direct-targeting drugs, such as MRTX-1133, have limited coverage of other KRAS mutation subtypes such as G12C and G12V (31).

MRTX-1133

MRTX-1133 is among the first non-covalent small-molecule inhibitors specifically designed to target KRAS-G12D. It stabilizes the Switch II region in an inactive conformation by forming a network of salt bridges and hydrogen bonds with key residues, including Asp12, Glycine at codon 60 (Gly60), and Glutamic acid at codon 62 (Glu62), thereby blocking KRAS-GTP engagement and downstream signaling (31,33). Although MRTX-1133 preferentially binds the GDP-bound state, it is nevertheless capable of potently suppressing signaling driven by activated KRAS-G12D (34). The binding mechanism of MRTX-1133 is summarized in Figure 2.

Figure 2 MRTX-1133 binding mechanism. Literature (35) and the eutectic structure show that MRTX-1133, through its protonated DABO fragment, forms a stable salt bridge with KRAS-G12D Asp12, and forms an additional hydrogen bond with the Gly60 carbonate; the pyrrolizidine-like bicyclic amine at the R2 position further forms a non-classical CH···O hydrogen bond with Glu62 and participates in local electrostatic matching. The ethynyl-naphthyridinone core is deeply embedded in the hydrophobic pocket induced by the SII, and establishes extensive hydrophobic/Van der Waals contact with Val9, Met72, Tyr64, Tyr96, Val103, and other residues. At the same time, its ethynyl substituent forms a water-mediated network with Gly10 and Thr58 through a conserved water molecule. Together with polar SII residues such as Asp69, these interactions collectively build a stable polar/hydrogen‑bonding environment. The picture is created in BioRender. Cheng, C. [2026]; https://BioRender.com/2kil3cp. DABO, 3,8-diazabicyclo[3.2.1] octane.

In animal experiments, MRTX-1133 exhibits poor pharmacokinetic characteristics. Studies have reported an oral bioavailability of approximately 2.9%, with plasma half-lives of 1.12 hours following oral administration and 2.88 hours following intravenous administration (36). This may be related to the poor solubility of non-covalent small molecules (12) and their absorption characteristics.

In preclinical models, MRTX-1133 binds GDP-loaded KRAS-G12D with approximately 700-fold higher affinity than wild-type KRAS (34). Robust tumor growth inhibition and, in some cases, tumor regression have been observed in xenograft models of NSCLC, pancreatic ductal adenocarcinoma (PDAC), and colorectal cancer (CRC) (34). However, sustained anti-tumor activity appears to be dependent on continuous drug exposure, as rapid tumor regrowth has been reported following treatment withdrawal in pancreatic cancer (37) and CRC models (38).

Combined drug studies indicate that MRTX-1133 and pan-erythroblastic oncogene B (pan-ERBB) inhibitors (afatinib) exert significant synergistic effects in PDAC (39). In addition, preliminary data presented in conference abstracts (AACR abstract) indicate that MEK inhibitors may enhance the efficacy of MRTX-1133 (NSCLC preclinical data) (40), and combined exportin 1 (XPO1) inhibitors also improve anti-tumor activity in in vitro models (PDAC preclinical data) (41).

In 2023, the FDA approved the initiation of a phase I/II clinical study (PDAC/CRC clinical data) for MRTX-1133 (NCT05737706), but the study was terminated before entering phase II. The clinical registration indicates that the reason for termination was “formulation challenges”, and an industry report further notes that its pharmacokinetic data were “highly variable and suboptimal”. This is consistent with the poor pharmacodynamic characteristics of MRTX-1133 described above, and the dependence of its anti-tumor effect on drug concentration.

To date, research has largely focused on preclinical strategies for overcoming resistance and improving drug delivery. The dual farnesyltransferase (FT)/geranylgeranyltransferase-1 (GGT-1) inhibitor FGTI-2734 was shown to suppress ERK-mediated feedback activation and enhance MRTX1133 efficacy in KRAS-G12D-mutant pancreatic cancer (42). Synthetic lethality-based approaches have also gained attention, as MRTX1133 increases sensitivity to homologous recombination (HR)-dependent DNA damage, and its combination with poly(ADP-ribose) polymerase (PARP) inhibitors (e.g., olaparib) further augments anti-tumor activity by exacerbating DNA damage stress in PDAC (43). In addition, the dual targeting of KRAS-G12D and PI3K/bromodomain-containing protein 4 (BRD4) overcomes resistance by co-inhibiting parallel survival pathways (PDAC preclinical data) (44). Advances in drug delivery (PDAC preclinical data), such as ferritin-based nanocarriers, may improve bioavailability and tumor-specific accumulation, potentially mitigating the pharmacokinetic limitations of MRTX1133 (45). Collectively, these findings highlight a shift from monotherapy toward combination and technology-enhanced strategies to improve the depth and durability of KRAS-G12D-targeted therapies.

RMC-9805 (zoldonrasib)

RMC-9805 (zoldonrasib) is a selectively targeted RAS (ON) G12D state triple complex [small molecule-CYPA-RAS (ON)] binding inhibitor developed by Revolution Medicines. The drug employs a “molecular glue” strategy to facilitate the engagement of an accessory protein, cyclophilin A, with GTP-bound (“ON” state) KRAS-G12D, thereby forming a new protein-protein interface. By leveraging this induced complex, the approach bypasses the traditional induction SII-P obstacle, enables covalent modification of the Asp12 site, and further specifically inhibits the mutant protein (46). The mechanism of action of RMC-9805 is summarized in Figure 3.

Figure 3 Mechanism of action of RMC-9805 (46). RMC-9805 first binds to CYPA and forms a high-affinity, stable binary complex; the complex then selectively identifies and binds with GTP-bound KRAS. The rigid linker precisely positions the aziridine near Asp12, and facilitates covalent modification of Asp12 by the aziridine warhead through local electrostatic interactions and desolvation. The picture is created in BioRender. Cheng, C. [2026]; https://BioRender.com/2imasbx.

The KRAS-G12D xenotransplantation model suggests that RMC-9805 has good systemic exposure and pharmacological consistency (46). Early clinical results [NCT06040541 and ASCO-Gastrointestinal Cancers (ASCO-GI) 2025] (PDAC clinical data) showed that its exposure increased linearly with the dose, which was consistent with preclinical predictions. Although the key pharmacokinetic parameters have not been reported, the existing data suggest that RMC-9805 has beneficial pharmacokinetic characteristics.

In preclinical studies, RMC-9805 has demonstrated significant tumor regression in KRAS-G12D-driven NSCLC and PDAC models in conference reports (47), although these findings remain to be fully peer-reviewed. Preliminary results from an ongoing phase I, open-label, non-randomized study (NCT06040541) presented at the 2025 American Association for Cancer Research Annual Meeting, suggest promising antitumor activity of RMC-9805 in patients with KRAS-G12D-mutant tumors (48,49) (NSCLC and other solid-tumor clinical data). In NSCLC patients (n≈18) with the KRAS-G12D mutation, the group receiving RMC-9805 at 1,200 mg once daily (qd) had an objective response rate (ORR) of 61%, a disease control rate (DCR) of 89%, and a median response time of 1.4 months. In patients with PDAC (n≈20), the ORR was approximately 30%, and the DCR was 80% (49,50). The overall tolerance was favorable, with no dose-restricted toxicities observed. These findings should be interpreted cautiously given the early-phase design, limited sample size, and immature follow-up. Recently, zoldonrasib has received Breakthrough Therapy Designation from the U.S. FDA, supporting its further clinical investigation in KRAS-G12D-mutant NSCLC. However, given the complexity of the tri-complex mechanism of its dependent auxiliary protein cyclophilin A, its long-term stability, tissue selectivity and potential drug-resistance mechanism still need to be further studied.

KRAS degraders

Distinct from combination inhibition, Astellas employs an E3-mediated targeted protein degradation (TPD) strategy, using PROteolysis TArgeting Chimera (PROTAC)-like molecules to recruit KRAS-G12D and E3 ubiquitin ligase into the same ternary complex, inducing ubiquitination and proteasomal degradation of the KRAS protein itself, thereby blocking downstream signaling (51). Representative drugs include ASP3082 and ASP4396 (52).

ASP3082 is the first KRAS-G12D protein degrader to enter clinical trials, using von Hippel-Lindau (VHL) as the E3 ligase, and has demonstrated significant downregulation of G12D and MAPK signaling in multiple cancer cell models (including NSCLC) (53). ESMO 2024 data showed that among 65 evaluable patients in the 10–300 mg dose range, the 300 mg group achieved an ORR of 33.3% and a DCR of 75%, with limited response at lower doses (NSCLC clinical data) (54). ASP3082 phase I trial results were reported in a news article by Cancer Discovery (55), which described the findings as “encouraging efficacy and safety”. Notably, the development of ASP3082 has gradually shifted from monotherapy exploration toward combination strategies. At the 2026 ASCO-Gastrointestinal Cancers Symposium (GI), it was reported that ASP3082 plus chemotherapy achieved an ORR of 58% in KRAS-G12D-mutant pancreatic cancer, suggesting that the TPD strategy may have greater clinical translational potential in combination regimens.

Building on ASP3082, Astellas developed another G12D degrader, ASP4396, which uses cereblon (CRBN) as the E3 ligase, and has demonstrated significant tumor growth inhibition and even “deep tumor regression” in a KRAS-G12D PDAC xenograft model (other solid-tumor preclinical data) (52). A phase I clinical trial (NCT06364696) has been initiated based on these findings.

The investigational drugs of the direct-targeting strategies are summarized in Table 2.

Multi-allelic coverage strategies

Multi-allelic targeting strategies block the combination of RAS and its effectors by identifying functional sites or inducing new protein-protein interfaces, thereby achieving the effect of “one drug covering multiple mutations”, as exemplified by RMC-6236 (61). Such drugs have a wide coverage, which can benefit a larger group of patients (especially those not limited to a single subtype), and lower selectivity for single points, which may theoretically reduce the risk of drug resistance. However, broader selectivity may also result in limited toxicity windows, differential sensitivity across subgroups, and the possibility of drug resistance dependent on bypass signaling (61). In addition, ensuring adequate oral pharmacokinetics and tissue exposure while maintaining broad-spectrum therapeutic effects poses a great challenge to chemical optimization.

RMC-6236 (daraxonrasib)

RMC-6236 is an active-state (RAS-ON) multi-selective (pan-RAS) inhibitor with a mechanism similar to that of RMC-9805. However, unlike RMC-9805—which requires covalent modification of Asp12 via an aziridine warhead (46)—RMC-6236 targets the relatively conserved SII-P and adjacent regions of GTP-bound RAS, enabling broader coverage across multiple isoforms and mutation sites (62). The mechanism of action of RMC-6236 is summarized in Figure 4.

Figure 4 Mechanism of action of RMC-6236 (63). RMC-6236 binds to CYPA to form a binary complex, and then binds to RAS-GTP. The large ring part of the drug straddles the interface between CYPA and RAS, forming hydrogen bonds, hydrophobic interactions, and π-π actions with conserved residues in RAS Switch I/Switch II. It forms multi-point non-covalent contacts on both sides of CYPA and RAS. It relies on broad-spectrum structural adaptation to achieve multi-allele inhibition without forming covalent modification. The picture is created in BioRender. Cheng, C. [2026]; https://BioRender.com/xjwkkco. CYPA, cyclophilin A; GTP, guanosine triphosphate.

Preclinical and I/Ib clinical trials (NCT05379985) suggest that RMC-6236 has good pharmacokinetics characteristics, manifested as dose-dependent systemic exposure, limited drug accumulation on repeated dosing, and good distribution to tumor and brain tissues (61). Preclinical studies have shown (61) that RMC-6236 significantly inhibits tumor growth in KRAS-G12X NSCLC cell lines and xenotransplantation models.

In an early-phase I/Ib single-agent study (NCT05379985), preliminary data presented in a conference abstract reported that at doses of 80–120 mg qd, the initial ORR across NSCLC and PDAC patients with KRAS-G12X mutations was 36%, and the DCR was 86% (64). In the same study, at higher dose ranges (160–300 mg once daily), RMC-6236 demonstrated additional clinical activity in PDAC cohorts harboring KRAS-G12X or other RAS mutations. Among treated patients, median progression-free survival (PFS) was 8.5 months [95% confidence interval (CI): 5.3–11.7] in the KRAS-G12X subgroup and 7.6 months (95% CI: 5.9–11.1) in the overall RAS-mutant PDAC population (65).

With the clinical advancement of the pan-RAS (ON) inhibitor RMC-6236, its resistance mechanisms are increasingly recognized as more complex and distinct from those of conventional KRAS-specific inhibitors. A PDAC-related study (66) suggests that AP-1 transcription factor subunit (JUN) upregulation represents a convergent resistance node to MAPK pathway inhibition [including SHP2 plus RAS (ON) blockade]. Although the combination of the SHP2 inhibitor RMC-4550 with RMC-6236 demonstrates synergistic effects, JUN-mediated resistance can still emerge (PDAC preclinical data) (66). Persistent activation of mTORC1 may also drive intrinsic or adaptive resistance (67); notably, the farnesyl transferase inhibitor darlifarnib (KO-2806) can block Ras homolog enriched in brain (RHEB)-mediated mTORC1 activation, thereby restoring sensitivity to RMC-6236 (NSCLC preclinical data).

BI-2865/BI-2493/BI-3706674

BI-2865 is a non-covalent pan-KRAS (OFF) inhibitor developed by Boehringer Ingelheim (68). It preferentially binds to the GDP state of KRAS with high affinity [and low affinity for HRas proto-oncogene (HRAS)/NRas proto-oncogene (NRAS)], occupies the SII-P, and prevents SOS-mediated catalysis of the transformation of GDP-bound KRAS to the GTP-bound state, thus widely suppressing a variety of KRAS alleles (e.g., G12C/D/V/F/S, and G13D) (69) (other solid-tumor preclinical data).

In in vitro studies, BI-2865 significantly inhibited the proliferation of Ba/F3 KRAS-G12D cells and significantly reduced RAS-MAPK signaling and transcriptional procedures in KRAS-G12D CRC and pancreatic cancer cells, showing high sensitivity in KRAS-G12C approximates (69). However, the pharmacological properties of BI-2865 are limited, and its orally optimized analog BI-2493 demonstrated robust in vivo antitumor activity in KRAS-mutant xenograft models (KRAS-G12V, KRAS-G12C), with limited impact on the body weight of mice (NSCLC preclinical data) (70). The feasibility of pan-KRAS (OFF) suppression strategy has thus been demonstrated. The oral multi-KRAS variant inhibitor BI-3706674 based on BI-2865 has entered a phase I clinical trial (NCT06056024) (71).

Notably, a recent study also reported that BI-2865 can reverse multi-drug resistance mediated by ATP-binding cassette (ABC) transporters in P-glycoprotein overexpression models by inhibiting drug excretion and increasing intracellular exposure to chemotherapy drugs (other solid-tumor preclinical data) (72). Additionally, BI-2865 can also be used as the “chemical matrix” of KRAS-targeted warheads: its Switch II binding skeleton is grafted onto a VHL ligand to construct the representative pan-KRAS PROTAC degradation agent ACBI3, achieving efficient degradation of a variety of KRAS mutants and wild-type KRAS (73,74) (KRAS-mutant solid tumors preclinical data), further expanding the application landscape of BI-2865-related molecules.

The investigational drugs of the multi-allelic coverage strategies are summarized in Table 3.

Indirect/upstream inhibition strategies

Given the intrinsic challenges associated with the direct targeting of KRAS-G12D, indirect blockade has become an important and feasible alternative and complementary strategy. Receptor tyrosine kinase (RTK)-mediated growth factor receptor-bound protein 2 (GRB2)/son of sevenless homolog 1 (SOS1) and SHP2-dependent signals are important sources of KRAS-GTP loading (80,81), and SOS1 and SHP2 have become the main research targets.

As direct-targeting strategies for KRAS-G12D—particularly RAS (ON) inhibitors and targeted protein degraders—continue to advance, upstream inhibition strategies are increasingly being repositioned from alternative therapeutic options to integral components of combination therapies.

SOS1 inhibitors

SOS1 inhibitors inhibit the exchange of GDP/GTP by blocking the interaction between SOS1 and KRAS, thus reducing active KRAS (RAS-GTP) and inhibiting downstream MAPK/PI3K and other signaling pathways (80). This represents an indirect yet broad-spectrum (pan-KRAS) upstream inhibition strategy, providing a robust mechanistic basis for targeting KRAS-mutant tumors and overcoming feedback resistance to MEK/ERK inhibition (82).

At present, typical SOS1 inhibitors include a variety of representative compounds at different stages of development. BI-3406 is the first highly efficient and selective SOS1-KRAS protein-protein interaction inhibitor reported in the literature. It blocks KRAS activation by combining with the SOS1 catalytic domain, and shows significant synergy with MEK inhibitors in a variety of KRAS-driven models (NSCLC preclinical data) (80). It also exhibited in vivo anti-tumor activity in a KRAS-G12D-driven mouse LUAD model (83). Its clinical candidate, BI-1701963, entered a phase I study as an oral pan-KRAS: SOS1 inhibitor (both as monotherapy and in combination with trametinib or irinotecan) (NCT04835714, NCT04111458, NCT04627142). However, a 2024–2025 Oncology Pipeline report titled “Bristol stops SOS1” revealed that its development had been terminated (84), although no official reason was provided.

MRTX-0902 (BMS-986509) is a second-generation oral, brain-penetrating, selective SOS1 inhibitor designed by Mirati, which disrupts the SOS1-KRAS interaction (85). It blocks the KRAS-SOS1 interaction and significantly enhances inhibition of the RAS-MAPK pathway when combined with KRAS-G12C inhibitor adagrasib or epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (NSCLC preclinical data) (86). However, its phase I/II trial (NCT05578092) has also recently been “closed to accrual”, and the “Bristol stops SOS1” report released by BMS on Oncology Pipeline in 2025 confirms the suspension of the SOS1 pipeline asset.

BAY-293 is a classic SOS1 tool molecule developed by Bayer. It specifically interferes with the KRAS-SOS1 interaction, inhibits pERK signaling (82), and shows synergistic effects with the covalent KRAS-G12C inhibitor ARS-853 (KRAS-G12C NSCLC preclinical data) (87).

BAY-3498264 is an oral SOS1 inhibitor independently developed by Bayer (88). According to Bayer’s official press release, it is currently being used in a phase I trial (NCT06659341) in combination with sotorasib, primarily in patients with KRAS-G12C-mutant advanced solid tumors. The approach aims to enhance MAPK pathway inhibition and prolong response duration through the longitudinal blocking of “KRAS inhibitor + SOS1 inhibitor”.

In addition, SOS1 PROTAC degradation agents based on ligands such as BI-3406 have also emerged at the preclinical stage, showing the potential to completely block upstream RAS activation by inducing ubiquitin-mediated degradation of SOS1 rather than simply occupying the SOS1 binding site (88,89) (other solid-tumor preclinical data), providing new directions for subsequent SOS1-targeting strategies. Overall, the development of SOS1 inhibitors as monotherapies faces certain translational challenges, and current research efforts are increasingly shifting toward combination therapeutic strategies.

SHP2 inhibitors

SHP2 inhibitors stabilize the self-inhibitory configuration of SHP2, block its phosphatase activity, and cut off the activation of RTK-mediated upstream signaling to RAS. This reduces RAS-GTP levels and downstream MAPK/PI3K and other signaling pathways, ultimately achieving the comprehensive inhibition of cancer cell proliferation, survival and signal transduction (90).

Currently, representative SHP2 inhibitors are predominantly oral allosteric small molecules, including the following types.

TNO-155 (batoprotafib), developed by Novartis and optimized from the classical lead compound SHP-099 (91), has been investigated in multiple phase I/Ib studies reported in conference abstracts as monotherapy or in combination with EGFR inhibitors or KRAS-G12C-directed agents across a range of advanced solid tumors (including NSCLC) (92,93).

RMC-4630, developed by Revolution Medicines, was reported to show early “on-pathway inhibition and biological activity” (94) for a variety of solid tumors (including KRAS-mutant NSCLC). In KRAS-mutant NSCLC, it is combined with KRAS-G12C inhibitors (95) and MEK/ERK inhibitors (trial number NCT04916236) to mitigate RTK-mediated feedback activation of the MAPK pathway.

GDC-1971 (RLY-1971, migoprotafib), developed by Genentech and Relay, is a highly selective allosteric SHP2 inhibitor. It is currently being combined with the KRAS-G12C inhibitor divarasib for the treatment of KRAS-G12C-driven solid tumors (96,97).

JAB-3312 (sitneprotafib), developed by Jacobio, is a highly potent allosteric SHP2 inhibitor. According to ClinicalTrialsArena News, China’s Center for Drug Evaluation has approved a phase III registration trial of glecirasib in combination with JAB-3312 for the first-line treatment of KRAS-G12C-mutant NSCLC. This regimen is considered one of the most advanced SHP2 inhibitor-based combination strategies currently in development.

In addition, a new generation of inhibitors, such as BBP-398, is also being explored in combination with KRAS-G12C or EGFR inhibitors in phase I/II trials (98). By blocking SHP2-mediated RTK-RAS-MAPK signaling and related immune pathways, these agents aim to overcome resistance to existing targeted and immunotherapeutic therapies.

Downstream/terminal pathway inhibition

The downstream pathway inhibition strategy for KRAS-driven tumors is mainly focused on two major effector axes: RAF-MEK-ERK and PI3K-AKT-mTOR (99). Although MEK inhibitors (e.g., trametinib and cobimetinib) can reduce ERK activity, extensive studies have demonstrated their limited efficacy as monotherapies and their susceptibility to ERK rebound activation through upstream RTK upregulation and SHP2/SOS1-mediated feedback activation (100,101). Thus, research has shifted toward combination strategies, involving simultaneous upstream and downstream targeting to enhance the amplitude of pathway suppression and delay feedback activation.

Currently, the main treatment approach involves vertical inhibition or dual vertical blockade. This approach simultaneously interrupts upstream signaling nodes (e.g., SOS1 or SHP2) that activate KRAS and the downstream MAPK cascade. The purpose is to produce a deeper and more sustained suppression of signaling. Many preclinical models have confirmed that combining the SHP2 inhibitor SHP-099 with the MEK inhibitor can significantly decrease ERK rebound. These combinations exhibit significantly better tumor suppressor activity than any single drug alone in KRAS-G12D-mutant (NSCLC preclinical data), KRAS-mutant, and pancreatic cancer models (81,100). Similarly, the SOS1 inhibitor BI-3406, when combined with MEK inhibition, can produce stable downward regulation of the MAPK pathway and also delay the emergence of drug resistance (80,102) (NSCLC preclinical data).

This mechanism has driven many clinical explorations. ClinicalTrials.gov (NCT03989115) evaluated the safety and pharmacology of RMC-4630 (the SHP2 inhibitor), in combination with cobimetinib (the MEK inhibitor), in a variety of KRAS-mutant solid tumors, with a focus on ERK inhibition, tolerability, and dose optimization. NCT04111458 explored the combination of BI-1701963 (the SOS1 inhibitor) and trametinib. NCT04111458 evaluated BI-1701963 in patients with advanced cancer (solid tumours) in whom previous chemotherapy was not successful. Available clinical data indicate a manageable safety profile with observed dose-limiting toxicities, and evidence of disease stabilization in a subset of patients (with approximately 23% achieving stable disease) (103,104).

In addition to the MAPK pathway, bypassing the PI3K-AKT-mTOR axis (105) has also prompted research into combinations of SHP2 inhibitors with PI3K/AKT/mTOR inhibitors (106). However, these approaches are primarily at the preclinical stage, with no corresponding clinical trials having entered the evaluation phase.

It should be noted that much of the current evidence supporting SHP2-, SOS1-, or MEK-based combination strategies originates from KRAS-G12C-mutant NSCLC, PDAC, CRC, or pan-KRAS models rather than KRAS-G12D-mutant NSCLC specifically. These findings therefore provide mechanistic rationale rather than direct clinical evidence for KRAS-G12D-mutant NSCLC.

Emerging strategies

In addition to the above mainstream strategies, recent research on KRAS-G12D mutations has gradually expanded into more innovative directions, including ideas such as immunotherapy, nucleic acid-based interventions, synthetic lethality, and gene editing. These strategies aim to overcome the structural challenges and drug-resistance limitations of traditional small-molecule drugs.

Tumor vaccines

KRAS-G12D mutations can produce tumor-specific new antigens, providing a basis for specific immunotherapy. Based on this, messenger RNA (mRNA) and peptide vaccines have emerged as important areas of research. The off-the-shelf peptide vaccine ELI-002 induces a strong T-cell response by directing the mutant KRAS peptide antigen and Adenosine Monophosphate-modified CpG oligonucleotide adjuvant to the lymph nodes. At present, its 2P version has obtained positive results in the AMPLIFY-201 phase I study (107,108) (PDAC/CRC clinical data), and the extended 7P version is currently being evaluated in the AMPLIFY-7P phase I/II randomized trial. Another mRNA vaccine, V941, uses lipid nanoparticles (LNPs) to deliver mutant mRNA into antigen-presenting cells, thereby stimulating specific T-cell immunity (109).

T-cell receptor engineered T cell (TCR-T) and chimeric antigen receptor T-cell (CAR-T)

By cloning and identifying high-affinity T-cell receptors (TCRs) corresponding to the KRAS-G12D mutant peptide human leukocyte antigen (HLA) complex, engineered TCR-T cells can be constructed for transitional transfer treatment. Early clinical evidence (PDAC clinical data) has shown (110) that in HLA-C*08:02-positive patients, KRAS-G12D-specific T cells can mediate tumor retraction. Currently, several clinical trials of TCR-T therapies for KRAS-G12D mutations under different HLA restrictions (e.g., HLA-C*08:02 and HLA-A*11:01) are being conducted (e.g., NCT06690281 and NCT06218914).

In addition, a CAR-T therapy targeting KRAS G12V/HLA-A*02:01 (B9 CAR-T) has been reported to effectively control tumor growth in subcutaneous, metastatic, and peritoneally disseminated PDAC models. Safety evaluations have revealed no significant in vivo toxicity signals (111), indicating that this strategy holds promise for providing precision cellular immunotherapy in selected patient populations.

Nucleic acid-based interventions

“Gene silencing” therapy based on RNA interference or antisense oligonucleotides (ASOs) is another emerging strategy, including small interfering RNA (siRNA), ASOs, peptide nucleic acids, and gene/RNA editing techniques. The siG12D-LODER system enables continuous delivery of siRNA targeting KRAS-G12D through a sustained-release device, and has been reported to show signals of tumor growth inhibition in early clinical studies (conference abstract) (PDAC clinical data) (112). In a randomized phase II trial in locally advanced pancreatic cancer, overall survival (OS) was not significantly improved; however, a more pronounced signal of benefit was observed in the KRAS-G12D/V subgroup (113), suggesting potential efficacy in mutation-enriched populations.

Synthetic lethality strategies

Synthetic lethality achieves selective killing in the context of specific genetic defects by simultaneously blocking two interdependent survival pathways in tumor cells. Ataxia telangiectasia and Rad3-related (ATR) (114) or Wee1-like protein kinase (42) inhibition can enhance replication pressure and induce apoptosis, and PARP inhibition and radiotherapy show synergistic effects (115). At present, combination therapy with the ATR inhibitor AZD-6738 has achieved tumor inhibition in preclinical models (116,117) (PDAC/CRC preclinical data). Current research efforts focus on combining synthetic lethality strategies with immunotherapy and chemotherapy, while also optimizing patient stratification through the use of biomarkers to achieve precision medicine (114,118,119).

Metabolic vulnerability-targeting strategies

KRAS-mutant tumors exhibit metabolic reprogramming, and depend on pathways such as glutamine and serine/one-carbon metabolism to form “metabolic vulnerabilities”. The glutaminase inhibitor CB-839 (telaglenastat) has shown activity in many preclinical experiments (NSCLC preclinical data) (120,121), and exerts a synergistic effect with metformin (other solid-tumor preclinical data) (122). Studies have shown that KRAS inhibitor treatment drives PDAC cells toward an oxidative phosphorylation-dependent resistant state, associated with ZBTB11 upregulation; targeting ZBTB11 with molecular glue degraders can restore sensitivity (123). In addition, class I Histone deacetylase (HDAC) inhibitors (e.g., IHCH9033) induce p53 and c-Myc acetylation, promote apoptosis, and overcome resistance by suppressing the Yes-associated transcription regulator (YAP)-c-Myc axis. Their combination with KRAS/MAPK inhibitors enhances anti-tumor activity and reduces the progression of brain metastasis in NSCLC (124).

Gene-editing and oncolytic virus approaches

Gene-editing technology provides a new avenue for directly targeting oncogenic mutations such as KRAS-G12D. The HiFi-Cas9 system has been shown to enable the specific resection of mutant genes and inhibit tumor growth in preclinical NSCLC models, with no obvious effect on wild-type KRAS (125). At the same time, oncolytic viruses destroy cells and activate immune responses through tumor selective replication (126) (CRC preclinical data), providing new ideas for NSCLC treatment. Recently, optimized LNPs have been reported for the pulmonary delivery of Cas9 mRNA and KRAS-G12S single-guide RNA. Both formulations achieved up to 90% targeted editing efficiency in A549 cells and induced apoptotic signaling (127).

Multiple additional directions currently under investigation have also been reported, including inhibitors targeting NF-κB-activating kinases, molecular chaperone inhibitors such as glucose-regulated protein 78 kDa and heat shock proteins and inhibitors of the ERBB family (2). Overall, the network of actionable pathways associated with KRAS-G12D continues to expand. As such, the strategies covered in this article inevitably have certain limitations, and further updates and refinements will be required as new mechanistic insights and clinical evidence continue to emerge.

Resistance mechanisms

With the significant advancement of a series of KRAS-G12D targeted drugs, drug resistance has also emerged as an important challenge. Despite limited data, insights from KRAS-G12C and broader RAS-targeted therapy research suggest several potential mechanisms of resistance.

On-target resistance

Research on KRAS-G12C-targeted drugs indicates that site-specific agents are prone to on-target resistance mechanisms (128), such as allele secondary mutations, KRAS amplification, increased mutational load, and switch mutations (129). Although reports of G12D secondary mutations are limited, preclinical models (130) and early clinical (conference) data (131) suggest that similar mechanisms may also exist. A recent site-specific mutagenesis screen of KRAS-G12D identified eight secondary KRAS-G12D mutations that confer marked resistance to MRTX1133, including V9E, V9W, V9Q, G13P, T58Y, R68G, Y96W, and Q99L, with V9W showing the most pronounced resistance (130).

Off-target and bypass signaling

The inhibition of KRAS or downstream MAPK signaling can lift its negative feedback on upstream pathways, enhancing signal conduction from RTKs to RAS, and leading to “vertical path return” or “adaptive feedback activation” (132). In addition, the preference of KRAS-G12D-driven tumors for the PI3K-AKT-mTOR pathway may further enable compensatory signaling when MAPK signaling is inhibited. A review noted that (133), following KRAS inhibition, adaptive resistance can be mediated by the activation of upstream RTKs, which in turn reactivates wild-type RAS (KRAS/NRAS/HRAS); this mechanism has been observed in KRAS-G12C NSCLC, CRC, and PDAC cell lines. A PDAC study on adaptive resistance further suggests that, following KRAS-G12D inhibition, RTK-mediated adaptive reactivation of the RAS-MAPK pathway occurs and is influenced by the cellular state. Thus, combining mutant-selective KRAS inhibitors with pan-RAS (ON) inhibitors may help overcome such resistance (134).

Co-mutation background and microenvironmental or metabolic mechanisms

G12D can induce an immunosuppressive microenvironment and reduce the reactivity of PD-1/PD-L1 monotherapy by upregulating TGF-β and IL-10, and by recruiting inhibitory cells (29,30); STK11/LKB1 co-mutations further weaken the immunotherapy effect (63). Metabolic reprogramming driven by pan-KRAS mutations also contributes to drug resistance, including (135): enhanced glycolysis and activation of the pentose phosphate pathway to support DNA repair and proliferation, glutamine-dependent increased resistance, and activation of the NF-E2-related factor 2 (Nrf2) pathway and mitochondrial DNA mutations that reduce apoptotic susceptibility. In addition, co-mutations can also trigger metabolic reprogramming. For example, Keap1 missing mutations can stably activate Nrf2 and increase glutamine dependence (30).

Epithelial-mesenchymal transition (EMT)

EMT confers phenotypic plasticity to tumor cells, enabling partial transformation between epithelial and mesenchymal states, which leads to enhanced invasiveness and signaling pathway reprogramming (136). EMT-mediated drug resistance has been reported in the clinical application of G12C (137). In a MRTX-1133 drug-resistance model, the tumors exhibited a partial EMT phenotype with PI3K-AKT-mTOR signal activation and RTK signal rewiring (8), suggesting that G12D mutations may follow a similar mechanism.

Aberrant subcellular localization of KRAS

The activity of the KRAS protein is highly dependent on the positioning of its plasma membrane (138,139). In a G12C model, Human EGFR 2 (Her2) amplification or other signal adaptation factors caused KRAS to abnormally locate from the plasma membrane to the cytoplasm, reducing its dependence on the MAPK pathway and conferring drug resistance (140). G12D inhibitors may be affected by similar mechanisms: KRAS protein misalignment can weaken inhibitor binding or impair downstream MAPK pathway inhibition, while promoting the survival of cell-dependent alternative pathways (e.g., PI3K-AKT-mTOR), thus facilitating the development of drug resistance.

Hippo pathway activation

Studies on G12C suggest that YAP1/transcription coactivator with PDZ-binding motif (TAZ) activation sustains the PI3K-AKT-mTOR pathway to maintain cell survival (141), and can be inhibited by transcriptional enhanced associate domain inhibitors. In G12C/G12D inhibitory drug-resistant cells, the YAP/TAZ pathway is activated, and proliferation is restored by the downregulation of apoptosis-promoting genes (e.g., BMF, BCL2L11, and PUMA) and the activation of the SLC7A5/mTORC1 axis (142). Another study suggests (143) that, under G12C inhibition, YAP can trigger MRAS expression, thereby replacing RAS and participating in the reactivation of the MAPK pathway.

Accumulating evidence suggests that multi-layered and non-mutually exclusive resistance mechanisms are emerging, including reactivation of signaling through parallel nodes (e.g., NRAS) (144) and the induction of cytoprotective autophagy (145). However, due to space limitations, the present article is unable to comprehensively cover all such mechanisms. With the continued accumulation of longitudinal molecular monitoring data and clinical studies of combination therapies, the resistance framework of KRAS-G12D-targeted treatment is expected to be further refined, providing an important basis for the rational design of future combination strategies.

Clinical implications for KRAS-G12D-mutated NSCLC

Although the development of KRAS-G12D-targeted therapies is rapidly progressing, these approaches remain in the early stages of investigation. To date, no KRAS-G12D-specific targeted therapy has been approved, and there are no dedicated treatment stratification guidelines for this molecular subtype. Current evidence is primarily derived from subgroup analyses of patients with KRAS-mutant or driver-negative NSCLC and retrospective studies, while prospective randomized controlled trials or systematic evaluations specifically focusing on KRAS-G12D-mutated NSCLC remain lacking.

In clinical practice, KRAS-G12D-mutated NSCLC is generally managed as a “non-actionable oncogenic driver” subtype, following the standard treatment algorithms for advanced NSCLC recommended by international guidelines (e.g., ESMO and NCCN). Treatment decisions are currently individualized based on PD-L1 expression, histological subtype, and patient-specific clinical factors (146-149). For patients without other actionable genomic alterations, first-line treatment typically consists of ICIs with or without platinum-based chemotherapy. Patients with PD-L1 expression ≥50% may be considered for ICI monotherapy, whereas those with PD-L1 expression of 1–49% are generally recommended to receive ICI combined with chemotherapy. For patients with PD-L1 expression <1%, platinum-based chemotherapy combined with immunotherapy remains the preferred approach, and anti-angiogenic therapy may be considered in combination regimens for selected non-squamous NSCLC patients. In addition, accumulating evidence suggests that co-mutations such as STK11 and KEAP1 may be associated with reduced responsiveness to immunotherapy; however, their predictive value requires further prospective validation, and these alterations have not yet modified the standard first-line treatment framework. Importantly, in the absence of an established actionable targeted therapy, the NCCN guidelines recommend considering clinical trial enrollment for all patients with NSCLC.

Despite substantial advances in NSCLC treatment driven by immunotherapy-based strategies, current guideline-directed approaches remain limited for patients with the KRAS-G12D subtype. A retrospective study demonstrated that, compared with other KRAS mutation subtypes, KRAS-G12D-mutated NSCLC exhibits lower PD-L1 expression, lower tumor mutational burden (TMB), and reduced CD8⁺ T-cell-associated immune infiltration, suggesting a relatively “immune-cold” TME (150,151). Among patients with advanced KRAS-mutant NSCLC treated with PD-L1 inhibitor monotherapy, the ORR for the G12D subtype was 15.8%, which was lower than that observed in non-G12D subtypes (28.4%), with a trend toward inferior PFS and OS outcomes (151). It should be noted that although KRAS-mutant NSCLC is more frequently associated with STK11/KEAP1 co-mutations compared with other oncogenic driver subtypes (152), and subgroup analyses from phase III randomized controlled trials (153) as well as large cohort studies (154,155) have demonstrated the association between STK11/KEAP1 alterations, immune-cold phenotypes, and primary resistance to immunotherapy, the frequency of these co-mutations appears relatively lower in the G12D subtype compared with other KRAS variants (16). Therefore, the immune-cold characteristics observed in KRAS-G12D NSCLC may be primarily attributable to intrinsic biological features of the G12D mutation itself rather than solely driven by STK11/KEAP1 alterations (156).

Based on these characteristics, KRAS-G12D-mutated NSCLC currently lacks effective precision therapeutic strategies within the existing standard-of-care framework, and its relatively immune-cold microenvironment may limit the durability of benefit from immunotherapy. Therefore, although KRAS-G12D-targeted therapy remains at a transitional stage from mechanistic exploration toward early clinical translation and has not yet established a mature therapeutic paradigm, drug development in this field remains of substantial scientific and clinical importance. Such approaches may not only directly inhibit a core oncogenic signaling pathway but may also overcome the limitations of current empirically stratified treatment strategies, ultimately providing more precise and effective therapeutic options for this patient population.

At present, for individual patients, management according to international guidelines (such as NCCN and ESMO recommendations) remains the optimal clinical approach, as these standard treatment strategies have demonstrated survival or disease-control benefits in multiple randomized controlled trials across broader NSCLC populations. However, for patients who experience disease progression after completion of guideline-recommended standard systemic therapies, enrollment in clinical trials evaluating KRAS-G12D-targeted agents should be prioritized whenever available.

Current promising research directions in KRAS-G12D-targeted therapy mainly include G12D-specific inhibitors, pan-KRAS inhibitors, and KRAS degraders. Additional potential strategies include immune-modulating approaches (such as cancer vaccines, TCR-T and CAR-T therapies), ASO-based strategies [e.g., siG12D-LODER and KRAS ASO combined with immune agonists (157)], gene-editing technologies, and synthetic lethal approaches. Furthermore, research efforts are increasingly expanding toward multidimensional combination strategies and mechanistically complementary therapeutic approaches; however, most of these strategies remain at the preclinical stage. Collectively, these advances indicate that KRAS-G12D-targeted therapy is gradually moving beyond a purely exploratory biological concept toward a clinically relevant therapeutic field.

Discussion

KRAS-G12D is an important gene mutation in NSCLC that has long lacked effective targeted therapies. Its unique structural characteristics, signaling preferences, and immune associations distinguish it from the more mature KRAS-G12C targeting system. In recent years, direct inhibitors (e.g., MRTX-1133 and RMC-9805), pan-RAS inhibitors (e.g., RMC-6236), nucleic acid-based interventions, synthetic lethality strategies, metabolic vulnerability targeting, and immunomodulatory strategies have collectively formed a more comprehensive treatment framework. Nevertheless, the long-term efficacy of KRAS-G12D-targeted therapies is likely to remain constrained by intrinsic tumor heterogeneity and the ongoing evolution of adaptive resistance mechanisms.

This review systematically summarized recent advances in targeted therapy for KRAS-G12D-mutant NSCLC, but several limitations should be acknowledged. First, this review focused on NSCLC, particularly LUAD, and did not comprehensively cover other KRAS-G12D-driven solid tumors; thus, the generalizability across tumor types remains to be further validated. Second, most KRAS-G12D-targeted therapies are still in early development or early-phase clinical trials, and some evidence was supplemented from studies on pancreatic cancer and CRC; more robust data are needed to establish long-term efficacy and safety in NSCLC. Third, the current understanding of resistance mechanisms was largely derived from preclinical models or extrapolated from KRAS-G12C inhibitor experience, and direct evidence specific to KRAS-G12D resistance remains limited.

Over the next 5–10 years, with advances in mechanism-driven combination therapies, metabolic and immunomicroenvironmental modulation, and refined patient stratification, KRAS-G12D-targeted therapy is expected to evolve from single-point breakthroughs to systematic approaches, thereby driving further progress in precision medicine for NSCLC. At the same time, achieving a more optimal balance among therapeutic efficacy, treatment-related toxicity, and overall patient benefit will remain a critical challenge in its clinical translation.

Conclusions

KRAS-G12D is a highly challenging but promising target in the field of precision treatment for NSCLC. With the development of new drugs and the advancement of diversified combination therapy strategies, it is expected that a more precise, effective, and durable KRAS-G12D-targeted treatment paradigm will be established in the future.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0639/rc

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0639/coif). The authors have no conflicts of interest to declare.

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(English Language Editor: L. Huleatt)