GFH375 in Patients with Previously Treated Non-Small Cell Lung Cancer and KRASG12D Mutations: A First-in-Human Study

GFH375 in Patients with Previously Treated Non-Small Cell Lung Cancer and KRASG12D Mutations: A First-in-Human Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article GFH375 in Patients with Previously Treated Non-Small Cell Lung Cancer and KRASG12D Mutations: A First-in-Human Study Shun Lu, Xinghao Ai, Ziming Li, Lin Wu, Peng Chen, Zuoxing Niu, and 23 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8540837/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract KRAS G12D mutations occur in approximately 2–4% of patients with non-small cell lung cancer (NSCLC). GFH375, a compound that targets both “ON” (GTP-bound) and “OFF” (GDP-bound) states of the KRAS G12D proteins, was evaluated in a phase 1/2 study among patients with advanced solid tumors harboring KRAS G12D mutations. The objectives were to evaluate safety and tolerability, characterize pharmacokinetics, and evaluate preliminary efficacy. A total of 86 patients with KRAS G12D -mutant advanced solid tumors, including 28 with advanced NSCLC, were treated with the single agent GFH375 administered orally once or twice daily. Overall, GFH375 was well tolerated and had a manageable safety profile. Treatment-related adverse events occurred in 97.7% of the patients: 37.2% experienced grade ≥3 adverse events, and 1 patient (1.2%) experienced a grade 5 adverse event. Encouraging antitumor activity was demonstrated in patients with previously treated NSCLC, with objective response rates of 57.7% (90% CI: 39.8–74.2) at all dose levels and 68.8% (90% CI: 45.2–86.8) at 600 mg once daily; the 6-month progression-free survival rates were 60.4% (90% CI: 46.2–78.8) and 77.4% (90% CI: 60.6–98.9), respectively. Co-occurring alterations were analyzed with circulating tumor DNA (ctDNA) collected at baseline and at the end of treatment. The study is ongoing (ClinicalTrials.gov identifier: NCT06500676). Biological sciences/Cancer/Lung cancer/Non-small-cell lung cancer Biological sciences/Cancer/Tumour biomarkers Figures Figure 1 Figure 2 Figure 3 Introduction Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and is the leading cause of cancer-related mortality worldwide, with an estimated 1.8 million deaths annually 1 . The clinical outcomes of late-line therapies are unsatisfactory, typically yielding response rates of 5–23% and progression-free survival of approximately 3–4 months, accompanied by substantial toxicity and limited overall benefits 2-7 . Mutations in the Kirsten rat sarcoma (KRAS) gene are among the most common oncogenic drivers in NSCLC, occurring in 20–30% of patients, predominantly in those with adenocarcinomas 8 . These mutations result in the constitutive activation of downstream pathways, including RAF/MEK/ERK and PI3K/AKT, driving tumor growth, survival, and metastasis. KRAS has historically been deemed “undruggable” because of the absence of tractable binding sites and its high GTP affinity and thus represents a major therapeutic challenge 9 ,10 . Advances in targeting KRAS G12C , the most prevalent subtype in NSCLC, have led to the approval of inhibitors such as sotorasib, adagrasib, fulzerasib, garsorasib and glecirasib, which covalently bind the mutant cysteine and improve outcomes in pretreated patients 11-16 . The KRAS G12D variant, which involves a glycine-to-aspartic acid substitution at codon 12, is present in approximately 2–4% of all NSCLC patients 17 ,18 . Compared with other types of KRAS-mutant or KRAS wild-type tumors, KRAS G12D mutation tumors are associated with aggressive disease, poor patient outcomes, and reduced responsiveness to conventional therapies 19-21 . MRTX1133, the first KRAS G12D inhibitor to enter clinical trials, exhibited preclinical high affinity, selectivity and antitumor activity; however, it was terminated for clinical development owing to unfavorable pharmacokinetic properties 22 . Many other KRAS G12D -selective agents, such as HRS-4642, zoldonrasib and setidegrasib, are under clinical development, underscoring a critical unmet need 23-29 . GFH375 is an orally bioavailable, noncovalent, selective KRAS G12D inhibitor that targets both the active (GTP-bound "ON") and inactive (GDP-bound "OFF") states of the mutant protein, demonstrating potent antitumor activity and signaling pathway inhibition in preclinical KRAS G12D -driven NSCLC models, with minimal off-target effects 30 . The first-in-human phase 1/2 trial (ClinicalTrials.gov NCT06500676) was conducted to evaluate GFH375 as a monotherapy in patients with advanced KRAS G12D -mutated solid tumors who had progressed on prior therapies. GFH375 monotherapy has demonstrated potential therapeutic benefits across multiple tumor types 31 . Here, we report the safety, tolerability, and pharmacokinetic profiles of GFH375, along with preliminary clinical activity and biomarker analyses specific to the NSCLC cohort. This study provides initial clinical insights into GFH375, advancing precision oncology for KRAS G12D -driven NSCLC and addressing a clinical therapeutic gap in this patient population. Results Trial description The safety endpoints included the incidence and severity of dose-limiting toxicities (DLTs), adverse events (AEs) and serious adverse events (SAEs), and changes from baseline in vital signs, electrocardiogram (ECG) results and laboratory parameters of GFH375 monotherapy in adult patients with KRAS G12D -mutant solid tumors. Clinical efficacy was assessed by the objective response rate (ORR), duration of response (DOR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by investigators, and overall survival (OS). Blood samples were collected for characterization of pharmacokinetics and for exploratory biomarker analyses of circulating tumor DNA (ctDNA). The key eligibility criteria were age ≥18 years, histologically or cytologically confirmed locally advanced or metastatic solid tumors, KRAS G12D mutation detected by local tests on tumor tissue or blood, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. Patients were required to have received at least one prior line of systemic therapy for advanced disease. A full list of eligibility criteria is provided in the Online Methods Patients. Patients A total of 86 patients were enrolled and received GFH375 as monotherapy. Twenty-eight patients had previously treated metastatic NSCLC for which standard therapies had failed. Among these patients with NSCLC, the majority (17; 60.7%) had never smoked. All had adenocarcinomas, and ten (35.7%) had pulmonary mucinous adenocarcinomas. Five (17.9%) had brain metastases at baseline. Among the 22 patients for whom baseline programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) data were available, none exhibited high PD-L1 expression: 13 (59.1%) had a TPS of <1%, and 9 (40.9%) had a TPS of 1–49%. Most patients (18 of 28; 64.3%) had received two or more prior lines of systemic therapy. All had received platinum-based chemotherapy, 27 (96.4%) had received immune checkpoint inhibitors (ICIs), and 25 (89.3%) had received concurrent ICI and platinum-based chemotherapy (Table 1). The median time from the last dose of ICI to the first administration of GFH375 was 2.8 months (range: 1.0–40.0 months). The median duration of ICI treatment was 4.3 months (range: 0.7–26.5 months). The demographic and baseline characteristics of all the patients are presented in Extended Data Table 1. Patients with NSCLC received GFH375 once daily at doses of 100 mg (n=1), 200 mg (n=1), 400 mg (n=7), 600 mg (n=16), 750 mg (n=1), or twice daily at 300 mg (n=2). The dosing regimens for all the patients are presented in Extended Data Table 3. Safety No DLTs were observed at doses ranging from 100–900 mg daily during the dose escalation phase. The majority of patients were in the 400 mg (29) and 600 mg (41) once daily dose cohorts. As of 09-October-2025, treatment-emergent adverse events (TEAEs) of any grade were reported in all 86 patients and were considered treatment related in 84 (97.7%) patients. The most common treatment-related adverse events (TRAEs; occurring in ≥20% of all patients) were diarrhea (59 of 86; 68.6%), nausea (59; 68.6%), vomiting (58; 67.4%), anemia (55; 64.0%), increased aspartate aminotransferase (39; 45.3%), decreased appetite (39; 45.3%), decreased neutrophil count (31; 36.0%), asthenia (31; 36.0%), hypoalbuminemia (30; 34.9%), decreased white blood cell count (30; 34.9%), increased alanine aminotransferase (28; 32.6%), hyponatremia (22; 25.6%), proteinuria (21; 24.4%) and decreased weight (19; 22.1%), primarily grade 1 or 2. These findings indicate that gastrointestinal, hematological, and hepatic toxicities represent the predominant categories in the GFH375 toxicity profile in the late-line clinical setting. Grade ≥3 TRAEs occurred in 32 of 86 patients (37.2%). The most common grade ≥ 3 TRAEs were a decreased neutrophil count (8 of 86; 9.3%), diarrhea (4; 4.7%), anemia (4; 4.7%), increased aspartate aminotransferase (4; 4.7%), asthenia (3; 3.5%), decreased white blood cell count (3; 3.5%), increased alanine aminotransferase (3; 3.5%) and abnormal hepatic function (3; 3.5%). One (1.2%) grade 5 TRAE was reported as septic shock (Table 2 and Extended Data Tables 2 and 3). Although presenting a safety/tolerability profile generally consistent with that of the whole study population, the NSCLC patients appeared to experience numerically higher rates and severities of AEs (Fig. 1 and Extended Data Fig. 1). All (28) patients with NSCLC experienced at least one TRAE. Grade 3 or 4 TRAEs occurred in 14 patients (50.0%), and serious TRAEs occurred in 4 (14.3%) (Table 2). In addition to the most common adverse events mentioned above, increased blood lactate dehydrogenase levels, increased gamma-glutamyl transferase levels, hyperglycemia, hypertriglyceridemia, increased amylase levels, hypochloremia, urinary tract infection and hyperuricemia were observed in more than 20% of patients with NSCLC. Hepatotoxicity appeared to be more prominent in patients with NSCLC. One patient had concurrent grade 3 aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) elevation and grade 1 bilirubin elevation. AST levels resolved to grade 1 within 4 days of dose interruption without deterioration of GGT or bilirubin levels. Another patient had concurrent grade 3 alanine aminotransferase (ALT) and AST elevation that resolved to grade 1 within 7 days after dose interruption. One patient with a partial response at the first tumor assessment developed grade 4 AST elevation (recorded as a hepatic function abnormality), accompanied by increases in ALT, GGT, alkaline phosphatase (ALP), and lactate dehydrogenase (LDH), 32 days after the initiation of the study drug. This event did not meet Hy's law criteria. Hepatic function abnormalities resolved within one month following drug interruption. Notably, the patient had received anti-PD-1 antibody therapy for 7 months, with the study drug administered 40 days after the last dose of immunotherapy. Pharmacokinetics GFH375 was rapidly absorbed after oral administration. The median T max at steady state ranged from 2.0 hours (h) to 4.2 h. Plasma exposure to GFH375 (AUC and C max ) increased with dose within the range of 100–600 mg, but there was no obvious increase in exposure above 600 mg. The accumulation ratios (RC max and RAUC) were less than two at 400 mg (n=27), 600 mg (n=27) and 750 mg (n=6), indicating limited accumulation following multiple doses of GFH375. The geometric mean of t 1/2 ranged from 14.0–20.7 h across dose cohorts. The C trough geometric means of 400 mg and 600 mg at steady state were 22.2 ng/mL and 37.1 ng/mL, respectively, which were approximately two- and threefold greater than 11 ng/mL, respectively, and the level required for >90% target inhibition (pERK IC 90 ) in tumor cells (Extended Data Figs. 2 and 3). Antitumor activity As of the efficacy data cutoff date of 27-November-2025, a total of 28 patients with KRAS G12D -mutant NSCLC had been treated. All patients had received their first dose of GFH375 at least 6 months before the cutoff date. The median exposure duration was 24.3 weeks (range: 3–72.4). One patient (200 mg) had no measurable disease at baseline but remained stable; one patient (400 mg) withdrew from the study following one cycle of treatment, with no postbaseline tumor assessment performed, and died 41 days after the final dose. Among the 26 patients with baseline target lesions and postbaseline tumor assessments, 21 (80.8%) experienced shrinkage of target lesions after approximately six weeks of treatment (Fig. 2b and c). Objective responses were achieved in 15 patients (ORR 57.7%, 90% CI: 39.8–74.2) and confirmed in 11 (confirmed ORR 42.3%). In the cohort treated with 600 mg once daily, the ORR was 68.8% (11 of 16, 90% CI: 45.2–86.8), and the confirmed rate was 50.0% (8 of 16) (Fig. 2b). The median TTR was 6.1 weeks (range: 6.0–48.0), and the median DOR was 11.0 months. Four patients achieved a partial response (PR) at the first postbaseline assessment without further confirmation: two with brain metastases at baseline (one each at 400 mg and 600 mg) had progressive disease at the second tumor assessment; one (600 mg) permanently discontinued treatment at week 5 due to grade 4 hepatic function abnormality; and one had a marginal tumor reduction of approximately 30% (Fig. 2a). The DCRs were 88.5% (23 of 26, 90% CI: 72.8–96.8) among all patients and 93.8% (15 of 16, 90% CI: 73.6–99.7) in the cohort receiving 600 mg once daily (Fig. 2b). The patient only with intracranial nontarget lesions at baseline continued treatment with 200 mg once daily for 16 months without disease progression. Eleven patients remained on treatment. The 6-month PFS rate was 60.4% (90% CI: 46.2–78.8) among the 28 patients and 77.4% (90% CI: 60.6–98.9) among the 16 patients treated with 600 mg once daily (Fig. 2d). Notably, the first patient treated with the starting dose (100 mg) experienced 23.1% tumor shrinkage at the first tumor assessment and achieved a PR at 11 months after initiating GFH375 treatment. As of the data cutoff date, this patient has remained on treatment for 16.7 months, with tumor reduction reaching 41% (Fig. 2a and c). Exploratory comutation analysis Among the 28 patients, 18 had available baseline ctDNA central testing results. Pathogenic alterations were identified and analyzed (Online Methods for ctDNA testing and comutation analysis). Although all the enrolled patients had documented KRAS G12D mutations, only 9 of 18 (50%) had a KRAS G12D mutation detected in the baseline ctDNA. The other identified pathogenic alterations were clustered in the cell cycle/transcription factor pathways, DNA damage response (DDR) and MAPK/RTK/PI3K pathways (Fig. 3a), which are commonly associated with tumorigenesis. Objective response rates and PFS were compared between patients with detectable KRAS G12D mutation in baseline ctDNA and those without it. The response rates were 66.7% (6 of 9) and 44.4% (4 of 9) in the two groups, respectively (Fig. 3b). However, the responses in the KRAS G12D -positive cohort appeared less durable, and the survival outcomes were worse than those in the KRAS G12D -negative cohort (Fig. 3c). Among the 18 patients, four harbored gene alterations (BRAF, PIK3CA, FGFR1 and YES1) in the RAS-upstream/downstream pathways (MAPK/RTK/PI3K). None of these four patients achieved an objective response. Only two patients with rapid disease progression carried BRAF and PIK3CA mutations, and had no detected alterations in the cell cycle/transcription factor or DDR pathways. In contrast, all patients who achieved responses had no detected alterations in the MAPK/RTK/PI3K pathway. TP53 (27.8%, 5 of 18), KEAP1 (22.2%, 4 of 18), and STK11 (16.7%, 3 of 18) were the most frequently reported pathogenic comutations in this analysis. Objective responses were observed in the subgroups with mutations in TP53 (3 of 5), KEAP1 (3 of 4), and STK11 (2 of 3), without significant differences from those among the patients who had no mutations detected in these genes—TP53 (7 of 13), KEAP1 (7 of 14), and STK11 (8 of 15) (Fig. 3b). Two patients with concomitant KEAP1 and STK11 mutations—including one with a concomitant TP53 mutation—both achieved PR. The association between these comutations and the durability of this antitumor activity was analyzed among the 14 patients without observed alterations in the MAPK/RTK/PI3K pathway. Six had at least one comutation detected in TP53, KEAP1 or STK11. The duration of response and survival outcomes of these patients generally appeared to be worse than those of patients without such comutations (Fig. 3d). Three patients had paired ctDNA test reports available for samples collected at baseline and at the end of treatment (EOT). Among these patients, two had negative KRAS G12D status at both baseline and EOT: one had no potential pathogenic mutations detected, and the other had only BRAF amplification identified at baseline. In the third patient, a KRAS G12D mutation was detected at baseline, accompanied by comutations in KEAP1, STK11, TP53 and RB1. Compared with baseline, no new genetic alterations were detected at the time of disease progression, except that the allelic frequency of KRAS G12D increased by approximately threefold (3.69% at baseline vs. 14.19% at EOT) (Fig. 3e). Discussion Novel small molecules targeting KRAS G12D are under development through ongoing research and clinical efforts. Preclinical profiling indicates that GFH375 is a highly selective KRAS G12D (ON/OFF) inhibitor that, compared with other KRAS G12D inhibitors, demonstrates superior potency and bioavailability in reducing the levels of RAF1-bound active KRAS G12D -GTP (ON) and inhibiting cell proliferation 30 ,32 . In this clinical study, orally administered GFH375 demonstrated good pharmacokinetic characteristics with a manageable safety profile. Substantial and durable clinical responses were observed in patients with previously treated NSCLC. Despite originating from a single-arm phase I/II study constrained by a small cohort size, these results offer preliminary but compelling evidence that GFH375 holds substantial therapeutic promise for the treatment of KRAS G12D -mutated NSCLC. To date, limited effective second-line or later options are available following disease progression on immunotherapy, with an ORR of approximately 10% and a median PFS of less than 4 months 7 ,33-35 . Although this is a single-arm study lacking a direct comparator, the efficacy of GFH375 appears to surpass those of currently available treatments, such as ramucirumab plus docetaxel, as reported 7 . For patients with newly diagnosed NSCLC, the current standard of care commonly includes chemoimmunotherapy, the clinical benefit of which is strongly associated with the tumor PD-L1 expression level. However, studies suggest that KRAS G12D mutations promote immune suppression and primary resistance to anti-PD-1/PD-L1 immunotherapy in NSCLC, especially in patients also harboring a TP53 mutation 21 ,36 ,37 . In this clinical study, the clinicopathologic characteristics of patients with KRAS G12D -mutated NSCLC—such as a predominance of light or never smokers and mucinous adenocarcinoma—aligned with those reported in the literature 38 ,39 . Although conflicting data exist, the proportion of tumor tissue samples with negative or low PD-L1 expression (TPS) tested in this study was significantly greater than that reported in the general population of patients with NSCLC 40 ,41 . These findings suggest that immunotherapy-based standard treatment may be inadequate for patients with KRAS G12D -mutated NSCLC. In this study, GFH375 treatment induced rapid and durable responses irrespective of PD-L1 expression levels, suggesting that PD-L1 expression is not a predictive marker of GFH375 efficacy. These results provide compelling evidence to support the potential advancement of GFH375 to first-line therapy for patients with KRAS G12D -mutated NSCLC. Given the encouraging antitumor activity of GFH375 monotherapy, combination strategies should be explored to overcome resistance and further enhance clinical efficacy. Although it remains unknown whether KRAS G12D inhibition can sensitize tumor cells to immune checkpoint inhibitors, combining it with immunotherapy or chemoimmunotherapy represents a logical option given the current standard of care. However, existing studies on KRAS G12 C inhibitors have generally shown that such combinations present challenging safety and tolerability profiles 42 ,43 . Alternative synergistic combination strategies that have been tested in clinical studies for KRAS G12 C inhibitors could also be considered, such as those involving anti-EGFR antibodies, SHP2 inhibitors, FAK inhibitors, or chemotherapy 44 ,45 . In light of emerging evidence suggesting a negative correlation between KRAS G12D mutations and PD-L1 expression/tumor mutation burden, these combinations may hold greater biological relevance. Baseline ctDNA analysis of the 18 patients revealed that TP53, STK11, and KEAP1 were the most frequently co-occurring mutations, findings that align with the observations from other studies of KRAS-mutated NSCLC. In our study, although patients harboring these comutations exhibited initial responses to GFH375 treatment at a remarkably high rate, the survival outcomes appeared to be substantially worse than those of patients without these comutations. This finding is consistent with the existing reports that both STK11 and KEAP1 are generally associated with poorer prognosis and inferior treatment outcomes in this population 46 ,47 . In addition, subgroup analysis of response and survival outcomes suggested that baseline ctDNA KRAS G12D positivity, as a marker of tumor burden, may predict a poorer prognosis in patients with NSCLC, and similar results were reported in studies of patients with KRAS G12C mutation 48 ,49 . Another intriguing finding was the association between co-occurring genetic alterations in the MAPK/RTK/PI3K pathway and tumor response to GFH375 treatment. This link highlights the dominant role of RAS and its upstream/downstream pathways in tumorigenesis. Specifically, co-occurring pathogenic alterations in these RAS-related pathways promote primary resistance to KRAS G12D inhibitors, suggesting that simultaneous inhibition of signaling from these alterations is necessary to achieve favorable clinical outcomes 50-52 . This pattern aligns with observations in other indications, such as colorectal cancer, where such comutations are more prevalent and insensitive to KRAS inhibitors 53 . In particular, activation of the PI3K pathway in KRAS-mutant tumors—including those with G12C or G12D mutations—has been reported as a key primary resistance mechanism 54 . Moreover, the acquired KRAS G12D amplification observed in one patient after disease progression suggests a potential mechanism of resistance, resembling the findings of allele amplification after treatment with sotorasib 55 . Certainly, these analyses are limited by the sensitivity of ctDNA sequencing and small sample size, particularly the insufficient collection of samples following disease progression. Many confounding factors essentially compromised the interpretability of the exploratory study results. As the study advances, cumulative data will be generated to provide more robust insights into resistance mechanisms and guide the development of corresponding therapeutic strategies to further improve treatment efficacy. In this study, GFH375 exhibited a generally well-tolerated clinical safety profile in patients with heavily pretreated cancer. Further analysis revealed that 62.8% of the patients had received prior ICI-containing treatment (Extended Data Table 1), including 96.4% of those with NSCLC (Table 1) and 46.6% with other tumor types. The median time from the last ICI dose to the initiation of GFH375 treatment was 2.9 months (2.8 months in patients with NSCLC and 3.1 months in others). Among patients previously treated with ICIs, toxicity events of high clinical severity were generally more frequent, and the tolerability of GFH375 appeared to be worse (Extended Data Table 4). Notably, compared with its use as a single agent in a second-line setting following front-line immunochemotherapy failure, fulzerasib—an approved KRAS G12 C inhibitor—demonstrated a superior safety profile when combined with cetuximab in the first-line setting for NSCLC 56 . These integrated findings suggest that prior ICI use, without sufficient washout periods, may increase the safety risks of subsequent therapies, potentially explaining the numerically higher frequency of clinically relevant safety events observed in patients with NSCLC in this study. The risk should not be neglected when considering the optimal combination strategy in the 1st-line setting. In conclusion, the KRAS G12D mutation represents a critical oncogenic driver and a promising therapeutic target for advanced NSCLC. The data reported herein demonstrate the encouraging antitumor efficacy and manageable safety of GFH375, an oral KRAS G12D inhibitor, in patients with NSCLC, thereby underscoring its clinical druggability. Moving forward, advancing research into resistance mechanisms—including coexisting genetic alterations and PD-L1 expression levels in tumor cells will be central to identifying optimal combination strategies to augment therapeutic efficacy. To this end, clinical studies investigating GFH375 in combination with other agents, such as anti-EGFR therapy, chemotherapy, and immunotherapy, are slated to initiate. Furthermore, ongoing clinical investigations in GFH375 are underway in patients with KRAS G12D -mutated solid tumors, encompassing diverse disease settings and larger patient cohorts, with the aim of further validating its therapeutic effects and addressing unmet medical needs. Online Methods Study design and treatment This is a first-in-human, multicenter, open-label, phase 1/2 trial to evaluate the safety, tolerability, pharmacokinetics, and efficacy of GFH375 in patients with KRAS G12D -mutant advanced solid tumors. The study is conducted in two parts, comprising GFH375 monotherapy dose escalation and back-filling (phase 1) and GFH375 monotherapy indication expansion (phase 2). GFH375 was administered orally once daily (QD) or twice daily (BID) in 21-day treatment cycles, and treatment was continued until disease progression, unmanageable toxicity or patient withdrawal. The study is ongoing. In phase 1, dose escalation was performed using accelerated titration at the first two dose levels followed by a Bayesian optimal interval (BOIN) design to determine the maximum tolerated dose (MTD). The starting dose of GFH375 was 100 mg once daily in cohort 1, with a planned dose escalation of up to 1200 mg once daily over seven additional cohorts. Decisions to expand the number of patients at a given dose level, proceed to the next dose level, stop dose escalation or de-escalate to a lower dose level were made by a safety monitoring committee. Additional patients would be backfilled to selected cohorts after confirmation of safety and observation of preliminary antitumor activities for further evaluation across dose levels and determination of the recommended phase 2 dose (RP2D). Dose intraescalation was not allowed in phase 1. An evaluation of the efficacy and safety of GFH375 monotherapy at the RP2D in an expanded patient population with previously treated NSCLC, pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and other solid tumors is ongoing. The patients reported in this article were enrolled before 27-May-2025. Trial oversight The institutional ethics committee at each study site approved the trial protocol. The trial was conducted in accordance with the Good Clinical Practice guidelines of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, the principles of the Declaration of Helsinki, and local regulations regarding the conduct of clinical research. All patients provided written informed consent before participating in the trial. Safety oversight was provided by the safety monitoring committee, which reviewed the safety profile and additional data if available during the dose-escalation period and dose backfilling or expansion. All the authors ensured the completeness and accuracy of the data and analyses and the fidelity of the trial to the protocol. Patients Eligible patients were aged 18–75 years, had a life expectancy of ≥12 weeks according to the investigator, were able to comprehend and willing to sign an informed consent form, had histologically or cytologically confirmed locally advanced or metastatic solid tumors, had KRAS G12D mutation documented by local tests on tumor tissue or blood, had evaluable disease (phase 1) or measurable disease (phase 2) per the Response Evaluation Criteria in Solid Tumors v.1.1, had an ECOG performance status equal to or less than 1, and must have had adequate organ and marrow function during the screening period. Treatment-related toxicity events (except alopecia) from previous anticancer treatments needed to be resolved to baseline or ≤ grade 1 (to ≤ grade 2 for nervous system toxicities). Patients must have been able to take oral medication. Eligible patients must have progressive disease after receiving standard-of-care treatment for locally advanced and unresectable or metastatic disease or intolerance of the standard-of-care treatment. Patients with brain metastases were eligible for inclusion if the brain metastases were stable (i.e., no residual neurologic symptoms, without receiving corticosteroids >10 mg per day prednisone or equivalent). Other key exclusion criteria were uncontrolled intercurrent illness, current interstitial lung disease or pneumonitis or uncontrolled pleural effusion, pericardial effusion or ascites requiring more than one placement of a catheter or concomitant superior vena cava syndrome. Patients should not have active gastrointestinal disease or other conditions that could interfere with the absorption, distribution, metabolism or excretion of oral therapy. No history of allogeneic organ transplantation was allowed, and patients must not have active infection requiring treatment with systemic antibacterial, antifungal or antiviral therapy within 7 days before receiving the first dose of the study treatment. Patients should not have active hepatitis B or hepatitis C or have a history of human immunodeficiency virus infection. Patients should not have a history of other malignancies except for the current malignancy, should have been treated with curative intent and no known active disease for at least 3 years, should have a low risk of recurrence, and should have been adequately treated for basal cell carcinoma, skin cancer or adequately treated for carcinoma in situ without evidence of disease. Patients were excluded if they had a corrected QT interval >470 ms, an increased risk of QT interval prolongations or arrythmias, or clinically important electrocardiogram abnormalities or other cardiovascular diseases. Patients who had received other KRAS G12D inhibitors or pan-RAS inhibitors were excluded. Patients had to stop other anticancer therapies for at least 28 days or five half-lives before initiating the study treatment. Concomitant medication should be following the pharmacological requirements of avoiding strong CYP3A or P-gp inhibitors or inducers and CYP3A or OAT1 sensitive substrates and concomitant antacid drugs should be paused for at least 7 days before receiving the first dose of the study treatment. Assessments Safety and tolerability were assessed by treatment-emergent AEs, treatment-related AEs and clinically significant changes in vital signs, physical exams, electrocardiograms and clinical laboratory tests. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v.5.0 (CTCAE5.0). DLTs were defined as any of the following events judged as related to the study treatment occurring during the first cycle of treatment (21 days) in the dose-escalation phase: febrile neutropenia; grade 4 neutropenia lasting ≥5 days; grade 4 thrombocytopenia lasting ≥5 days; grade ≥3 thrombocytopenia with grade ≥ 2 bleeding; grade 4 anemia; grade ≥ 3 increase in ALT or AST lasting >7 days if ALT or AST ≤grade 1 at baseline or ALT or AST more than ten times the upper limit of normal lasting >7 days if ALT or AST was grade 2 at baseline; grade ≥3 increased blood bilirubin; ALT or AST ≥ three times the upper limit of normal with concurrent total bilirubin more than two times the upper limit of normal without evidence of cholestasis or alternative explanations; any other grade ≥3 AE except grade ≥3 nausea, vomiting or diarrhea lasting >3 days despite optimal support; grade 3 fatigue lasting >3 days; and asymptomatic transient isolated laboratory abnormalities lasting >7 days with intervention, e.g., increased serum amylase GGT, or ALP. The MTD was defined as the dose at which the estimated probability of a DLT was closest to 30% according to an isotonic regression model. RP2D was determined based on the integrated information, including the MTD, general safety profile, pharmacokinetics, and preliminary antitumor activity. Antitumor activity was measured by the ORR (rate of complete or partial response), DCR (rate of complete or partial response, or stable disease), DOR (time from first documentation of response until disease progression or death from any cause), TTR (time from first dose of study treatment to first documentation of response), PFS (time from first dose of study treatment to disease progression or death from any cause) per RECIST v.1.1, and OS (time from first dose of study treatment to death from any cause). Tumor assessments were performed by computed tomography or MRI every 6 weeks until week 48 and then every 12 weeks thereafter. Pharmacokinetic parameters, including C max , T max , t 1/2 , CL/F, V z /F, C trough and AUC, were determined using standard noncompartmental methods. The PK analysis included patients who received at least one dose of GFH375 and had measurable plasma concentrations. Patients enrolled in phase 1 received a dose on Day 1 and then continuous dosing starting from Day 4. PK blood samples were collected at cycle (C) 1 Day (D) 1 predose, 0.5, 1, 2, 4, 6, 8, and 12 h postdose; Day 2 (24 h), D3 (48 h), and D4 predose (72 h) for single-dose PK profiling; and at D21 predose, 0.5, 1, 2, 4, 6, 8, and 12 h postdose, C2D1 predose (24 h) for steady-state PK profiling. Predose blood samples were also collected at C1D8; C1D15, C2D10, C4D1, C5D1 and C6D1 to test trough concentrations. Plasma ctDNA samples were collected at baseline (C1D1 predose) and at EOT for exploratory study of genetic biomarkers and potential relationships with clinical responses to treatment. Methods for ctDNA testing and comutation a nalysis Plasma was collected from 8–10 mL of peripheral blood in CWBIO cell-free DNA storage tubes (CWbio) by centrifugation for 10 min at 2,000×g at 4 °C, after which the supernatant was transferred to a new tube and centrifuged again at 16,000×g at 4 °C for 10 min. Plasma cell-free DNA (cfDNA) was extracted according to the manufacturer’s instructions. Briefly, cfDNA was extracted from plasma samples using a HiPure Circulating DNA Kit (Magen, Cat# IVD3182), and the quantification of cfDNA was performed using a Qubit 2.0 fluorimeter with a Qubit dsDNA HS Assay Kit (Life Technologies, CA, USA). A minimum of 30 ng of cfDNA was required for library construction using a commercial OncoCompass ® Target kit (Burning Rock Dx, Guangzhou, China), a hybrid capture-based NGS panel targeting the genomic alterations of 168 genes in solid tumors. The cfDNA was subjected to end repair, phosphorylation, dA addition and adaptor ligation. The DNA library was purified with the magnetic beads provided with the abovementioned kits (Burning Rock Dx), followed by hybridization with capture probe baits, hybrid selection with magnetic beads and PCR amplification. The indexed samples were sequenced on a NextSeq550Dx/NovaSeq 6000 (Illumina, CA, USA) with paired-end reads at a target sequencing depth of 10,000× for cfDNA. The raw sequencing data were preprocessed using the in-house developed software one-loop-trimmer for trimming adaptors and low-quality reads. Preprocessed sequencing data were then mapped to the human genome (hg19) using Burrows–Wheeler Aligner v0.7.10 . Variant calling was performed using Vardict , the in-house developed software/algorithm BRCNV v4.2.3 , markSV v0.2.5 and prettyMSI v2.0 . In accordance with the ExAC, 1,000 Genomes, dbSNP, and gnomAD databases, variants with a population frequency greater than 0.1% were grouped as germline mutations and excluded from further analysis. The remaining variants were annotated using the in-house software BrasAnnotation . Analysis of the co-occurring genetic alterations in ctDNA: In this study, the genetic alterations were reported according to the predefined cutoff value and criteria of the designated OncoCompass ® Target Kit (Burning Rock Dx, Guangzhou, China). For co-occurring alterations analysis, the identified genetic alterations were further annotated, and only the somatic alterations with “clear/potential/uncertain clinical significance” and the germline alterations with “clear pathogenic/likely pathogenic/uncertain clinical significance” were included in this analysis. Statistical analysis The sample size of this study was determined by practical considerations common in early oncology trials rather than a formal statistical hypothesis. All treated patients (those who received at least 1 dose of GFH375) were included in the safety assessment. Efficacy was evaluated in patients who received at least 1 dose of GFH375. Pharmacokinetics were assessed in all patients who received at least one dose of GFH375 and provided at least one blood sample with evaluable pharmacokinetic data. The 90% CIs for the ORR and DCR were calculated using the Clopper‒Pearson method. Time-to-event endpoints were summarized with Kaplan–Meier estimates and 90% CIs at select timepoints. For time-to-event endpoints, the DoR and PFS were censored at the last disease assessment if no progression or death was documented, whereas if PD or death occurred after the initiation of new antitumor therapy, these endpoints were censored at the last assessment prior to the new therapy. Data were collected using Taimei eCollect v6 EDC. Analyses were performed using SAS v.9.4 and R v.4.4.3 (http://www.R-project.org/). Pharmacokinetic parameters were determined using noncompartmental analysis methods and calculated using Phoenix WinNonlin Version 8.3.1 (Certara, Princeton, NJ, USA). Declarations DATA AVAILABILITY Deidentified participant data that underlie the results reported in this article, the protocol and statistical analysis plan may be available upon reasonable request to the corresponding author from qualified researchers following completion of the first-in human study with the clinical study reports finalization. Data is only available upon request to protect the privacy of the company and clinical trial participants. Full details are available at http://www.genfleet.com/. ACKNOWLEDGEMENTS The study was funded by GenFleet Therapeutic (Shanghai) Inc. We thank the participants and their families, investigators, and study staff who contributed to this study, and ClinChoice study team for their contributions. We would like to thank Springer Nature for English language editing (Springer Nature Go | Author Services from Springer Nature EN). A UTHOR CONTRIBUTIONS S.L., Y.W., H.S. were responsible for the study conception or design. S.L., X.A., Z.M.L., L. W., P.C., Z.N., Y.S., Z.S., W.Y., J.H., Q.Y., A.Z., D.C., Y.H.D., Z.W.L., L.Z., H.Z., H.W., Y.Y., H.T.Z., Y.Y.D., X.Q., Y.W., H.S., H.Q.Z., C.L.Z., S.W., Z.C., C.Q.Z. conducted the study and were involved in acquisition, analysis or interpretation of data. S.W. and Z.C. performed statistical analysis. C.L.Z. and Z.C. analyzed the biomarker data. C.L.Z., S.W. and C.Q.Z. provided medical writing. S.L., X.A., Z.M.L., Y.W., H.S., H.Q.Z., C.L.Z., S.W., Z.C., C.Q.Z. drafted the working manuscript or critically reviewed it for important intellectual content. S.L., X.A., Z.M.L., L.W., P.C., Z.N., Y.S., Z.S., W.Y., J.H., Q.Y., A.Z., D.C., Y.H.D., Z.W.L., L.Z., H.Z., H.W., Y.Y., H.T.Z., Y.Y.D., X.Q., Y.W., H.S., H.Q.Z., C.L.Z., S.W., Z.C., C.Q.Z. approved the final version for publication and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. C OMPETING INTERESTS S.L. reports research funding from AstraZeneca, Hutchison, Bristol Myers Squibb (BMS), Heng Rui, BeOne Medicines, Roche and Hansoh pharma; consulting fees from AstraZeneca, Pfizer, Boehringer Ingelheim, Hutchison MediPharma, Simcere, Zai Lab, GenomiCare Consulting, Yuhan Corporation, PRIME Oncology, Menarini group and Roche; honorarias as an invited speaker from AstraZeneca, Roche, Hansoh pharma and Hengrui Therapeutics. Y.Y.D reports research funding from Innovent Biologics and Anke Biotechnology. 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Demographics and baseline characteristics of patients with NSCLC Characteristic All NSCLC, n (%) (n = 28) NSCLC at 600 mg, n (%) (n = 16) Age, median (range), years 61 (36–74) 60.5 (36–74) Sex Female 13 (46.4) 8 (50) Male 15 (53.6) 8 (50) Smoking status Current or former 11 (39.3) 8 (50) Never 17 (60.7) 8 (50) ECOG PS 0 2 (7.1) 2 (12.5) 1 26 (92.9) 14 (87.5) Pathology adenocarcinoma 28 (100) 16 (100) Pulmonary mucinous adenocarcinoma 10 (35.7) 8 (50) Baseline metastasis 28 (100) 16 (100) Bone 12 (42.9) 4 (25) Brain 5 (17.9) 1 (6.3) Liver 3 (10.7) 2 (12.5) PD-L1 TPS Known 22 (78.6) 11 (68.8) < 1% 13 (59.1) a 6 (54.5) b 1–49% 9 (40.9) a 5 (45.5) b ≥ 50% 0 0 Prior lines of therapies, median (range) 2 (1–4) 1.5 (1–4) 1 10 (35.7) 8 (50) ≥ 2 18 (64.3) 8 (50) Prior ICI 27 (96.4) 16 (100) Prior platinum 28 (100) 16 (100) Prior ICI + platinum 25 (89.3) 16 (100) Notes: a Denominator is 22. b Denominator is 11. ECOG PS, Eastern Cooperative Oncology Group performance status; ICI, Immune checkpoint inhibitor; NSCLC, Non-small cell lung cancer；PD-L1 TPS, Programmed death ligand 1 tumor cell proportion score. Table 2. Adverse events in all patients and in patients with NSCLC Adverse events All patients, n (%) (n = 86) NSCLC, n (%) (n = 28) TEAEs All grades 86 (100) 28 (100) Grade ≥ 3 46 (53.5) 16 (57.1) SAE 24 (27.9) 8 (28.6) TRAEs All grades 84 (97.7) 28 (100) Grade ≥ 3 32 (37.2) 14 (50) SAE 9 (10.5) 4 (14.3) Grade ≥ 3 TRAEs occurring in ≥ 3% of all patients * Decreased neutrophil count 8 (9.3) 3 (10.7) Diarrhea 4 (4.7) 2 (7.1) Increased aspartate aminotransferase 4 (4.7) 2 (7.1) Anemia 4 (4.7) 0 Increased alanine aminotransferase 3 (3.5) 2 (7.1) Decreased white blood cell count 3 (3.5) 2 (7.1) Abnormal hepatic function 3 (3.5) 1 (3.6) Asthenia 3 (3.5) 1 (3.6) Notes: * Among the listed terms, there was one grade 4 case of decreased neutrophil count and one grade 4 case of abnormal hepatic function; no grade 5 cases occurred. NSCLC, Non-small cell lung cancer；SAE, Serious adverse events; TEAEs, Treatment-emergent adverse events; TRAEs, Treatment-related adverse events. Additional Declarations Yes there is potential Competing Interest. S.L. reports research funding from AstraZeneca, Hutchison, Bristol Myers Squibb (BMS), Heng Rui, BeOne Medicines, Roche and Hansoh pharma; consulting fees from AstraZeneca, Pfizer, Boehringer Ingelheim, Hutchison MediPharma, Simcere, Zai Lab, GenomiCare Consulting, Yuhan Corporation, PRIME Oncology, Menarini group and Roche; honorarias as an invited speaker from AstraZeneca, Roche, Hansoh pharma and Hengrui Therapeutics. Y.Y.D reports research funding from Innovent Biologics and Anke Biotechnology. Y.W., H.S., H.Q.Z., C.L.Z., S.W., Z.C., C.Q.Z. report employment and stock or stock options with GenFleet Therapeutics. Supplementary Files EXTENDEDDATAFIGURES.docx EXTENDED DATA FIGURES Flowdiagram.pdf CONSORT Flow diagram nrreportingsummaryflat.pdf Reporting Summary GFH375X1101SAPV0.9CleanEN.pdf SAP GFH375X1101XXXXXXXXXXXXXXXXXXV2.020250124CleanEN.pdf Protocol CONSORTchecklist2025.docx CONSORT Checklist ExtendedDataTables.docx Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Yu","email":"","orcid":"","institution":"Affiliated Tumour Hospital of Guangxi Medical University, Nanning, Guangxi","correspondingAuthor":false,"prefix":"","firstName":"Qitao","middleName":"","lastName":"Yu","suffix":""},{"id":585368534,"identity":"6903ea30-4f9c-4493-97ff-88ee958f118a","order_by":11,"name":"Aiping Zhou","email":"","orcid":"","institution":"Cancer Hospital Chinese Academy of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Aiping","middleName":"","lastName":"Zhou","suffix":""},{"id":585368535,"identity":"f643bb17-0a65-4ac1-b2c2-ef531103cd72","order_by":12,"name":"Di Cheng","email":"","orcid":"","institution":"Department of Medical Oncology, Sun Yat-sen Memorial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Di","middleName":"","lastName":"Cheng","suffix":""},{"id":585368536,"identity":"9c976caf-4714-4ded-aabe-c7a2fc7dada6","order_by":13,"name":"Yanhong Deng","email":"","orcid":"","institution":"The Sixth Affiliated Hospital, Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Yanhong","middleName":"","lastName":"Deng","suffix":""},{"id":585368537,"identity":"60444610-4f8d-48c2-88d0-168f83d24582","order_by":14,"name":"Zhiwei Li","email":"","orcid":"","institution":"Department of Gastroenterology, Harbin Medical University Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhiwei","middleName":"","lastName":"Li","suffix":""},{"id":585368538,"identity":"4f1f605c-b5c5-4699-a24b-7115f2032176","order_by":15,"name":"Lingjun Zhu","email":"","orcid":"","institution":"Department of Oncology, The First Affiliated Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lingjun","middleName":"","lastName":"Zhu","suffix":""},{"id":585368539,"identity":"fc64eddf-4821-410f-8248-b254c862311c","order_by":16,"name":"Hong Zong","email":"","orcid":"","institution":"Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University","correspondingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Zong","suffix":""},{"id":585368540,"identity":"7c1a7537-644c-4f6a-8e04-a2afb09dc79a","order_by":17,"name":"Heshui Wu","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Heshui","middleName":"","lastName":"Wu","suffix":""},{"id":585368541,"identity":"7034792f-7e25-46b4-afaf-cc881f0470fb","order_by":18,"name":"Ying Yuan","email":"","orcid":"https://orcid.org/0000-0002-3922-9553","institution":"Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Yuan","suffix":""},{"id":585368542,"identity":"8e9f8c82-3375-4424-acb0-b41a41cf5bf0","order_by":19,"name":"Haitao Zhao","email":"","orcid":"","institution":"Department of Liver Surgery, Peking Union Medical College Hospital/Chinese Academy of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Haitao","middleName":"","lastName":"Zhao","suffix":""},{"id":585368543,"identity":"75337439-b4aa-4889-882b-4891ed48e5ad","order_by":20,"name":"Yingying Du","email":"","orcid":"","institution":"Department of Oncology, The First Affiliated Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yingying","middleName":"","lastName":"Du","suffix":""},{"id":585368544,"identity":"40f42783-51ea-4d8f-8483-b17536217320","order_by":21,"name":"Xiujuan Qu","email":"","orcid":"","institution":"The First Affiliated Hospital of China Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiujuan","middleName":"","lastName":"Qu","suffix":""},{"id":585368545,"identity":"0a1c1572-116b-4763-a5c4-073a454bc46b","order_by":22,"name":"Yu Wang","email":"","orcid":"","institution":"GenFleet Therapeutics (Shanghai) Inc.","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Wang","suffix":""},{"id":585368546,"identity":"9135ad50-c893-497e-a908-95e2eef53591","order_by":23,"name":"Hiage Shen","email":"","orcid":"","institution":"GenFleet Therapeutics (Shanghai) Inc.","correspondingAuthor":false,"prefix":"","firstName":"Hiage","middleName":"","lastName":"Shen","suffix":""},{"id":585368547,"identity":"903de6b7-9750-4cf4-85d7-9edcd529d92e","order_by":24,"name":"Huaqiang Zhu","email":"","orcid":"","institution":"GenFleet Therapeutics (Shanghai) Inc.","correspondingAuthor":false,"prefix":"","firstName":"Huaqiang","middleName":"","lastName":"Zhu","suffix":""},{"id":585368548,"identity":"e99aa346-50eb-42c2-8b51-9669649b0a7c","order_by":25,"name":"Chanli Zheng","email":"","orcid":"","institution":"GenFleet Therapeutics (Shanghai) Inc.","correspondingAuthor":false,"prefix":"","firstName":"Chanli","middleName":"","lastName":"Zheng","suffix":""},{"id":585368549,"identity":"ef0e564a-1ce4-427f-b9be-5f29e0b4b34d","order_by":26,"name":"Shuang Wang","email":"","orcid":"","institution":"GenFleet Therapeutics (Shanghai) Inc.","correspondingAuthor":false,"prefix":"","firstName":"Shuang","middleName":"","lastName":"Wang","suffix":""},{"id":585368550,"identity":"0f8b14c6-b9cb-48fc-aef5-d970179b2d04","order_by":27,"name":"Zhao Cui","email":"","orcid":"","institution":"GenFleet Therapeutics (Shanghai) Inc.","correspondingAuthor":false,"prefix":"","firstName":"Zhao","middleName":"","lastName":"Cui","suffix":""},{"id":585368551,"identity":"9f2fe14d-b186-4cb7-b02f-ce2a8facf300","order_by":28,"name":"Congqiao Zhao","email":"","orcid":"","institution":"GenFleet Therapeutics (Shanghai) Inc.","correspondingAuthor":false,"prefix":"","firstName":"Congqiao","middleName":"","lastName":"Zhao","suffix":""}],"badges":[],"createdAt":"2026-01-07 11:36:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8540837/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8540837/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105034373,"identity":"80c8d997-c028-4386-9b09-2b86d180c754","added_by":"auto","created_at":"2026-03-20 07:23:13","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":182944,"visible":true,"origin":"","legend":"\u003cp\u003eMost frequent TEAEs in the whole population (left bar) and patients with NSCLC (right bar).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8540837/v1/77a8074f1c248d9b5db8b438.png"},{"id":105034567,"identity":"5a08568b-7b1b-40f6-9887-5077a1233079","added_by":"auto","created_at":"2026-03-20 07:23:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":80423,"visible":true,"origin":"","legend":"\u003cp\u003eAntitumor activity of GFH375 in NSCLC.\u003c/p\u003e\n\u003cp\u003ea. Swimlane plot of treatment duration and tumor assessments in individual patients; the number in parentheses on the y-axis refers to the number of prior lines of therapy at baseline. b. Waterfall plot of the maximum percentage change from baseline in the sum of target lesion diameters in individual patients; the right arrow indicates ongoing treatment. c. Spider plot of the percentage change from baseline in the sum of target lesion diameters over time in individual patients. d. PFS Kaplan‒Meier plots for all patients and for the cohort treated with 600 mg once daily. The waterfall (b) and spider (c) plots were based on the response-evaluable set (n=26), which included patients who had measurable disease at baseline according to RECIST v1.1 and at least one postbaseline tumor assessment. Two patients—one with no measurable disease at baseline and one who dropped out of the study early without adequate treatment and postbaseline tumor assessment—are not displayed on either plot. Abbreviations: BM, Brain metastasis at baseline; BOR, Best overall response; PD, Progressive disease; PDL1-L, Low PD-L1 expression (PD-L1 TPS \u0026lt; 1%); PDL1-M, Medium PD-L1 expression (PD-L1 TPS 1–49%); PLoT, Number of prior lines of therapy; PFS, Progression-free survival; PR, Partial response; SD, Stable disease; UK, Unknown.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8540837/v1/81f7eeb9e4871129ff3cf0a6.png"},{"id":104888220,"identity":"5a2dc021-a1c4-499e-9dc0-4affd14d140d","added_by":"auto","created_at":"2026-03-18 10:14:02","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":113071,"visible":true,"origin":"","legend":"\u003cp\u003eCo-occurring gene alterations detected in ctDNA and patient clinical responses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea\u003c/strong\u003e. Genetic alterations detected in ctDNA at baseline are categorized by clinical response and molecular pathway; the number in parentheses on the left side of the y-axis refers to the number of prior lines of therapy; the horizontal bars on the right side are the treatment duration with the clinical outcome of each individual patient. \u003cstrong\u003eb. \u003c/strong\u003eObjective response rates of patient subgroups according to the status of KRAS\u003csup\u003eG12D\u003c/sup\u003e mutation (detectable vs. undetectable) and co-occurring KEAP1, STK11 and TP53 mutations (mutant vs. wild type) in ctDNA. \u003cstrong\u003ec.\u003c/strong\u003e PFS Kaplan‒Meier plots of patient subgroups according to the status of KRAS\u003csup\u003eG12D\u003c/sup\u003e mutation in ctDNA (detectable vs. undetectable). \u003cstrong\u003ed.\u003c/strong\u003e PFS Kaplan‒Meier plots of patient subgroups with vs. without KEAP1, STK11 and/or TP53 comutations (mutant vs. wild type). \u003cstrong\u003ee. \u003c/strong\u003eGene mutations of one patient detected at baseline and at the end of treatment (EOT) after disease progression. Abbreviations: BM, Brain metastasis at baseline; CNV, Copy number variation; COMPLEX, Complex variant; DDR, DNA Damage response; DEL, Deletion; INDEL, Insertion/deletion; RAS, Rat sarcoma; SNV, Single-nucleotide variant; TDUP, Tandem duplication.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8540837/v1/36c6b80574bc08c794d8d751.png"},{"id":105036616,"identity":"aedfd76f-0d37-418f-bf8b-a7c3a5aea5e1","added_by":"auto","created_at":"2026-03-20 07:34:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1244525,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8540837/v1/6c5f88cb-2f7e-46b4-b6a3-5f9e11dba278.pdf"},{"id":105033984,"identity":"45b93f0e-33cc-4965-945d-f7f9dcd43c96","added_by":"auto","created_at":"2026-03-20 07:22:21","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1760877,"visible":true,"origin":"","legend":"EXTENDED DATA FIGURES","description":"","filename":"EXTENDEDDATAFIGURES.docx","url":"https://assets-eu.researchsquare.com/files/rs-8540837/v1/3a1d139bede69dc17dfe8e01.docx"},{"id":104888218,"identity":"63e8acaa-1bb8-48fa-afd2-b7d223d0ca4f","added_by":"auto","created_at":"2026-03-18 10:14:02","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":68887,"visible":true,"origin":"","legend":"CONSORT Flow diagram","description":"","filename":"Flowdiagram.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8540837/v1/dbe062ec51b8a46837bfbc33.pdf"},{"id":104888223,"identity":"25fe9dc9-a664-4b2f-b251-8191167589df","added_by":"auto","created_at":"2026-03-18 10:14:02","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":1316849,"visible":true,"origin":"","legend":"Reporting Summary","description":"","filename":"nrreportingsummaryflat.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8540837/v1/b0b7ac0ba90fb361048b582a.pdf"},{"id":105033945,"identity":"fc8efd64-df27-4bd2-8b1a-57944c2934c6","added_by":"auto","created_at":"2026-03-20 07:22:14","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":858995,"visible":true,"origin":"","legend":"SAP","description":"","filename":"GFH375X1101SAPV0.9CleanEN.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8540837/v1/283f8d74cc9505a8e61328e4.pdf"},{"id":104888225,"identity":"cb2797f5-933c-4d97-847f-1d44292821b1","added_by":"auto","created_at":"2026-03-18 10:14:02","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":2171922,"visible":true,"origin":"","legend":"Protocol","description":"","filename":"GFH375X1101XXXXXXXXXXXXXXXXXXV2.020250124CleanEN.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8540837/v1/6635e051234417ad9217cbd8.pdf"},{"id":105034047,"identity":"9d0bc0a7-6c51-46c5-a24a-1810976d4b9c","added_by":"auto","created_at":"2026-03-20 07:22:31","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":28685,"visible":true,"origin":"","legend":"CONSORT Checklist","description":"","filename":"CONSORTchecklist2025.docx","url":"https://assets-eu.researchsquare.com/files/rs-8540837/v1/ad331f3c159d1d284d136915.docx"},{"id":105034295,"identity":"38dd47ee-1cda-44da-ab38-e709881a071e","added_by":"auto","created_at":"2026-03-20 07:23:02","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":29079,"visible":true,"origin":"","legend":"","description":"","filename":"ExtendedDataTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8540837/v1/7ba1a68f0d2224b3dde78473.docx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nS.L. reports research funding from AstraZeneca, Hutchison, Bristol Myers Squibb (BMS), Heng Rui, BeOne Medicines, Roche and Hansoh pharma; consulting fees from AstraZeneca, Pfizer, Boehringer Ingelheim, Hutchison MediPharma, Simcere, Zai Lab, GenomiCare Consulting, Yuhan Corporation, PRIME Oncology, Menarini group and Roche; honorarias as an invited speaker from AstraZeneca, Roche, Hansoh pharma and Hengrui Therapeutics. Y.Y.D reports research funding from Innovent Biologics and Anke Biotechnology. Y.W., H.S., H.Q.Z., C.L.Z., S.W., Z.C., C.Q.Z. report employment and stock or stock options with GenFleet Therapeutics.","formattedTitle":"GFH375 in Patients with Previously Treated Non-Small Cell Lung Cancer and KRASG12D Mutations: A First-in-Human Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNon-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and is the leading cause of cancer-related mortality worldwide, with an estimated 1.8 million deaths annually\u003csup\u003e1\u003c/sup\u003e. The clinical outcomes of late-line therapies are unsatisfactory, typically yielding response rates of 5\u0026ndash;23% and progression-free survival of approximately 3\u0026ndash;4 months, accompanied by substantial toxicity and limited overall benefits\u003csup\u003e2-7\u003c/sup\u003e. Mutations in the Kirsten rat sarcoma (KRAS) gene are among the most common oncogenic drivers in NSCLC, occurring in 20\u0026ndash;30% of patients, predominantly in those with adenocarcinomas\u003csup\u003e8\u003c/sup\u003e. These mutations result in the constitutive activation of downstream pathways, including RAF/MEK/ERK and PI3K/AKT, driving tumor growth, survival, and metastasis. KRAS has historically been deemed \u0026ldquo;undruggable\u0026rdquo; because of the absence of tractable binding sites and its high GTP affinity and thus represents a major therapeutic challenge\u003csup\u003e9\u003c/sup\u003e\u003csup\u003e,10\u003c/sup\u003e. Advances in targeting KRAS\u003csup\u003eG12C\u003c/sup\u003e, the most prevalent subtype in NSCLC, have led to the approval of inhibitors such as sotorasib, adagrasib, fulzerasib,\u0026nbsp;garsorasib and\u0026nbsp;glecirasib,\u0026nbsp;which covalently bind the mutant cysteine and improve outcomes in pretreated patients\u003csup\u003e11-16\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe KRAS\u003csup\u003eG12D\u003c/sup\u003e variant, which involves a glycine-to-aspartic acid substitution at codon 12, is present in approximately 2\u0026ndash;4% of all NSCLC patients\u003csup\u003e17\u003c/sup\u003e\u003csup\u003e,18\u003c/sup\u003e. Compared with other types of KRAS-mutant or KRAS wild-type tumors, KRAS\u003csup\u003eG12D\u003c/sup\u003e mutation tumors are associated with aggressive disease, poor patient outcomes, and reduced responsiveness to conventional therapies\u003csup\u003e19-21\u003c/sup\u003e. MRTX1133, the first KRAS\u003csup\u003eG12D\u003c/sup\u003e inhibitor to enter clinical trials, exhibited preclinical high affinity, selectivity and antitumor activity; however, it was terminated for clinical development owing to unfavorable pharmacokinetic properties\u003csup\u003e22\u003c/sup\u003e. Many other\u0026nbsp;KRAS\u003csup\u003eG12D\u003c/sup\u003e-selective agents, such as HRS-4642,\u0026nbsp;zoldonrasib\u0026nbsp;and\u0026nbsp;setidegrasib, are under clinical development, underscoring a critical unmet need\u003csup\u003e23-29\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eGFH375 is an orally bioavailable, noncovalent, selective KRAS\u003csup\u003eG12D\u003c/sup\u003e inhibitor that targets both the active (GTP-bound \u0026quot;ON\u0026quot;) and inactive (GDP-bound \u0026quot;OFF\u0026quot;) states of the mutant protein, demonstrating potent antitumor activity and signaling pathway inhibition in preclinical KRAS\u003csup\u003eG12D\u003c/sup\u003e-driven NSCLC models, with minimal off-target effects\u003csup\u003e30\u003c/sup\u003e.\u0026nbsp;The first-in-human phase 1/2 trial\u0026nbsp;(ClinicalTrials.gov\u0026nbsp;NCT06500676)\u0026nbsp;was\u0026nbsp;conducted to evaluate GFH375 as a monotherapy in patients with advanced KRAS\u003csup\u003eG12D\u003c/sup\u003e-mutated solid tumors who had\u0026nbsp;progressed on prior therapies.\u0026nbsp;GFH375 monotherapy has demonstrated potential therapeutic benefits across multiple tumor types\u003csup\u003e31\u003c/sup\u003e.\u0026nbsp;Here, we report the safety,\u0026nbsp;tolerability,\u0026nbsp;and\u0026nbsp;pharmacokinetic\u0026nbsp;profiles of GFH375,\u0026nbsp;along\u0026nbsp;with\u0026nbsp;preliminary\u0026nbsp;clinical activity\u0026nbsp;and biomarker analyses\u0026nbsp;specific to\u0026nbsp;the NSCLC cohort. This study provides initial clinical insights into GFH375, advancing precision oncology for KRAS\u003csup\u003eG12D\u003c/sup\u003e-driven NSCLC and addressing a clinical therapeutic gap in this patient population.\u003c/p\u003e"},{"header":"Results","content":"\u003ch2\u003e\u003cem\u003eTrial description\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eThe safety endpoints included the incidence and severity of dose-limiting toxicities (DLTs), adverse events (AEs) and serious adverse events (SAEs), and changes from baseline in vital signs, electrocardiogram (ECG) results and laboratory parameters of GFH375 monotherapy in adult patients with KRAS\u003csup\u003eG12D\u003c/sup\u003e-mutant solid tumors. Clinical efficacy was assessed by the objective response rate (ORR), duration of response (DOR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by investigators, and overall survival (OS). Blood samples were collected for characterization of pharmacokinetics and for exploratory biomarker analyses of circulating tumor DNA (ctDNA). The key eligibility criteria were age ≥18 years, histologically or cytologically confirmed locally advanced or metastatic solid tumors, KRAS\u003csup\u003eG12D\u003c/sup\u003e mutation detected by local tests on tumor tissue or blood, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. Patients were required to have received at least one prior line of systemic therapy for advanced disease. A full list of eligibility criteria is provided in the Online Methods\u0026nbsp;Patients.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003ePatients\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eA total of 86 patients were enrolled and received GFH375 as monotherapy. Twenty-eight patients had previously treated metastatic NSCLC for which standard therapies had failed. Among these patients with NSCLC, the majority (17; 60.7%) had never smoked. All had adenocarcinomas, and ten (35.7%) had pulmonary mucinous adenocarcinomas. Five (17.9%) had brain metastases at baseline. Among the 22 patients for whom baseline programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) data were available, none exhibited high PD-L1 expression: 13 (59.1%) had a TPS of \u0026lt;1%, and 9 (40.9%) had a TPS of 1–49%. Most patients (18 of 28; 64.3%) had received two or more prior lines of systemic therapy. All had received platinum-based chemotherapy, 27 (96.4%) had received immune checkpoint inhibitors (ICIs), and 25 (89.3%) had received concurrent ICI and platinum-based chemotherapy (Table 1). The median time from the last dose of ICI to the first administration of GFH375 was 2.8 months (range: 1.0–40.0\u0026nbsp;months). The median duration of ICI treatment was 4.3 months (range: 0.7–26.5\u0026nbsp;months). The demographic\u0026nbsp;and baseline characteristics of all\u0026nbsp;the\u0026nbsp;patients are presented in\u0026nbsp;Extended Data Table 1.\u003c/p\u003e\n\u003cp\u003ePatients with NSCLC received GFH375 once daily at doses of 100 mg (n=1), 200 mg (n=1), 400 mg (n=7), 600 mg (n=16), 750 mg (n=1), or twice daily at 300 mg (n=2). The dosing regimens for all the patients are presented in\u0026nbsp;Extended Data Table\u0026nbsp;3.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003eSafety\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eNo DLTs were observed at doses ranging from 100–900 mg daily during the dose escalation phase. The majority of patients were in the 400 mg (29) and 600 mg (41) once daily dose cohorts. As of 09-October-2025, treatment-emergent adverse events (TEAEs) of any grade were reported in all 86 patients and were considered treatment related in 84 (97.7%) patients. The most common treatment-related adverse events (TRAEs; occurring in ≥20% of all patients) were diarrhea (59 of 86; 68.6%), nausea (59; 68.6%), vomiting (58; 67.4%), anemia (55; 64.0%), increased aspartate aminotransferase (39; 45.3%), decreased appetite (39; 45.3%), decreased neutrophil count (31; 36.0%), asthenia (31; 36.0%), hypoalbuminemia (30; 34.9%), decreased white blood cell count (30; 34.9%), increased alanine aminotransferase (28; 32.6%), hyponatremia (22; 25.6%), proteinuria (21; 24.4%) and decreased weight (19; 22.1%), primarily grade 1 or 2. These findings indicate that gastrointestinal, hematological, and hepatic toxicities represent the predominant categories in the GFH375 toxicity profile in the late-line clinical setting. Grade ≥3 TRAEs occurred in 32 of 86 patients (37.2%). The most common grade ≥ 3 TRAEs were a decreased neutrophil count (8 of 86; 9.3%), diarrhea (4; 4.7%), anemia (4; 4.7%), increased aspartate aminotransferase (4; 4.7%), asthenia (3; 3.5%), decreased white blood cell count (3; 3.5%), increased alanine aminotransferase (3; 3.5%) and abnormal hepatic function (3; 3.5%). One (1.2%) grade 5 TRAE was reported as septic shock (Table 2\u0026nbsp;and\u0026nbsp;Extended Data Tables 2\u0026nbsp;and\u0026nbsp;3).\u003c/p\u003e\n\u003cp\u003eAlthough presenting a safety/tolerability profile generally consistent with that of the whole study population, the NSCLC patients appeared to experience numerically higher rates and severities of AEs (Fig. 1\u0026nbsp;and\u0026nbsp;Extended Data Fig. 1). All (28) patients with NSCLC experienced at least one TRAE. Grade 3 or 4 TRAEs occurred in 14 patients (50.0%),\u0026nbsp;and serious TRAEs\u0026nbsp;occurred\u0026nbsp;in 4 (14.3%) (Table 2).\u0026nbsp;In addition to\u0026nbsp;the most common adverse events\u0026nbsp;mentioned above, increased\u0026nbsp;blood lactate dehydrogenase\u0026nbsp;levels, increased\u0026nbsp;gamma-glutamyl transferase\u0026nbsp;levels,\u0026nbsp;hyperglycemia,\u0026nbsp;hypertriglyceridemia,\u0026nbsp;increased\u0026nbsp;amylase\u0026nbsp;levels, hypochloremia, urinary tract infection and hyperuricemia\u0026nbsp;were observed in more than 20% of patients with NSCLC. Hepatotoxicity appeared to be more prominent in patients with NSCLC. One patient had concurrent grade 3\u0026nbsp;aspartate\u0026nbsp;aminotransferase\u0026nbsp;(AST)\u0026nbsp;and gamma-glutamyl transferase\u0026nbsp;(GGT)\u0026nbsp;elevation and grade 1 bilirubin elevation. AST\u0026nbsp;levels resolved\u0026nbsp;to grade 1\u0026nbsp;within\u0026nbsp;4 days of dose interruption without deterioration of GGT\u0026nbsp;or\u0026nbsp;bilirubin\u0026nbsp;levels. Another patient had concurrent grade 3\u0026nbsp;alanine\u0026nbsp;aminotransferase\u0026nbsp;(ALT)\u0026nbsp;and AST elevation that\u0026nbsp;resolved\u0026nbsp;to grade 1\u0026nbsp;within\u0026nbsp;7 days after dose interruption. One patient with\u0026nbsp;a\u0026nbsp;partial response at\u0026nbsp;the\u0026nbsp;first tumor assessment developed grade 4 AST elevation (recorded as\u0026nbsp;a\u0026nbsp;hepatic function abnormality), accompanied by increases in ALT, GGT, alkaline phosphatase (ALP), and lactate dehydrogenase (LDH), 32 days after\u0026nbsp;the\u0026nbsp;initiation of the study drug. This event did not meet Hy's law criteria. Hepatic function abnormalities resolved within one month following drug interruption. Notably, the patient had received anti-PD-1 antibody therapy for 7 months, with the study drug administered 40 days after the last dose of immunotherapy.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003ePharmacokinetics\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eGFH375 was rapidly absorbed after oral administration. The median T\u003csub\u003emax\u003c/sub\u003e at steady state ranged from 2.0 hours (h) to 4.2 h. Plasma exposure to GFH375 (AUC and C\u003csub\u003emax\u003c/sub\u003e) increased with dose within the range of 100–600 mg, but there was no obvious increase in exposure above 600 mg. The accumulation ratios (RC\u003csub\u003emax\u003c/sub\u003e and RAUC) were less than two at 400 mg (n=27), 600 mg (n=27) and 750 mg (n=6), indicating limited accumulation following multiple doses of GFH375. The geometric mean of t\u003csub\u003e1/2\u003c/sub\u003e ranged from 14.0–20.7 h across dose cohorts. The C\u003csub\u003etrough\u003c/sub\u003e geometric means of 400 mg and 600 mg at steady state were 22.2 ng/mL and 37.1\u0026nbsp;ng/mL, respectively,\u0026nbsp;which were\u0026nbsp;approximately\u0026nbsp;two- and\u0026nbsp;threefold\u0026nbsp;greater than\u0026nbsp;11 ng/mL,\u0026nbsp;respectively, and\u0026nbsp;the level required for \u0026gt;90% target inhibition (pERK IC\u003csub\u003e90\u003c/sub\u003e) in tumor cells\u0026nbsp;(Extended Data Figs. 2\u0026nbsp;and\u0026nbsp;3).\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003eAntitumor\u003c/em\u003e\u003cem\u003e\u0026nbsp;activity\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eAs of the efficacy data cutoff date of 27-November-2025, a total of 28 patients with KRAS\u003csup\u003eG12D\u003c/sup\u003e-mutant NSCLC had been treated. All patients had received their first dose of GFH375 at least 6 months before the cutoff date. The median exposure duration was 24.3 weeks (range: 3–72.4). One patient (200 mg) had no measurable disease at baseline but remained stable; one patient (400 mg) withdrew from the study following one cycle of treatment, with no postbaseline tumor assessment performed, and died 41 days after the final dose. Among the 26 patients with baseline target lesions and postbaseline tumor assessments, 21 (80.8%) experienced shrinkage of target lesions after approximately six weeks of treatment (Fig. 2b\u0026nbsp;and\u0026nbsp;c). Objective responses were achieved in 15 patients (ORR 57.7%, 90% CI: 39.8–74.2) and confirmed in 11 (confirmed ORR 42.3%). In the cohort treated with 600 mg once daily, the ORR was 68.8% (11 of 16, 90% CI: 45.2–86.8),\u0026nbsp;and\u0026nbsp;the\u0026nbsp;confirmed rate was 50.0% (8 of 16) (Fig.\u0026nbsp;2b). The median\u0026nbsp;TTR\u0026nbsp;was 6.1 weeks (range: 6.0–48.0), and\u0026nbsp;the\u0026nbsp;median DOR was 11.0 months. Four patients achieved a partial response (PR) at the first postbaseline assessment without further confirmation: two with brain metastases at baseline (one each at 400 mg and 600 mg) had\u0026nbsp;progressive disease at the second tumor assessment; one (600 mg) permanently discontinued treatment at week 5 due to grade 4 hepatic function abnormality;\u0026nbsp;and\u0026nbsp;one had\u0026nbsp;a\u0026nbsp;marginal tumor reduction\u0026nbsp;of approximately\u0026nbsp;30% (Fig.\u0026nbsp;2a). The DCRs were 88.5% (23 of 26, 90% CI: 72.8–96.8) among all patients and 93.8% (15 of 16, 90% CI:\u0026nbsp;73.6–99.7) in the cohort receiving 600 mg once daily (Fig.\u0026nbsp;2b). The patient only with intracranial\u0026nbsp;nontarget lesions at baseline continued treatment with 200 mg once daily for 16 months without disease progression.\u003c/p\u003e\n\u003cp\u003eEleven patients remained on treatment. The 6-month PFS rate was 60.4% (90% CI: 46.2–78.8) among the 28 patients and 77.4% (90% CI: 60.6–98.9) among the 16 patients treated with 600 mg once daily (Fig. 2d).\u0026nbsp;Notably, the\u0026nbsp;first patient\u0026nbsp;treated with the starting dose (100 mg)\u0026nbsp;experienced\u0026nbsp;23.1% tumor shrinkage at the first\u0026nbsp;tumor\u0026nbsp;assessment and achieved a\u0026nbsp;PR\u0026nbsp;at\u0026nbsp;11\u0026nbsp;months after initiating GFH375 treatment. As of the data\u0026nbsp;cutoff\u0026nbsp;date, this\u0026nbsp;patient has remained on treatment\u0026nbsp;for\u0026nbsp;16.7 months,\u0026nbsp;with\u0026nbsp;tumor reduction reaching 41% (Fig.\u0026nbsp;2a\u0026nbsp;and\u0026nbsp;c).\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003eExploratory\u0026nbsp;\u003c/em\u003e\u003cem\u003ecomutation\u003c/em\u003e\u003cem\u003e\u0026nbsp;analysis\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eAmong the 28 patients, 18 had available baseline ctDNA central testing results. Pathogenic alterations were identified and analyzed (Online\u0026nbsp;Methods for ctDNA testing and comutation\u0026nbsp;analysis). Although all\u0026nbsp;the\u0026nbsp;enrolled patients had\u0026nbsp;documented KRAS\u003csup\u003eG12D\u003c/sup\u003e mutations, only 9 of 18\u0026nbsp;(50%)\u0026nbsp;had a KRAS\u003csup\u003eG12D\u003c/sup\u003e mutation\u0026nbsp;detected in the baseline ctDNA. The other identified pathogenic alterations were clustered in the cell cycle/transcription factor pathways, DNA damage response (DDR) and MAPK/RTK/PI3K pathways (Fig. 3a), which are commonly associated with tumorigenesis.\u003c/p\u003e\n\u003cp\u003eObjective response rates and PFS were compared between patients with detectable KRAS\u003csup\u003eG12D\u003c/sup\u003e mutation in baseline ctDNA and those without it. The response rates were 66.7% (6 of 9) and 44.4% (4 of 9) in the two groups, respectively (Fig. 3b). However, the responses in the\u0026nbsp;KRAS\u003csup\u003eG12D\u003c/sup\u003e-positive cohort appeared less durable, and the survival outcomes were worse than those in the\u0026nbsp;KRAS\u003csup\u003eG12D\u003c/sup\u003e-negative cohort (Fig. 3c).\u003c/p\u003e\n\u003cp\u003eAmong the 18 patients, four harbored gene alterations (BRAF, PIK3CA, FGFR1 and YES1) in the RAS-upstream/downstream pathways (MAPK/RTK/PI3K). None of these four patients achieved an objective response. Only two patients with rapid disease progression carried BRAF and PIK3CA mutations, and had no detected alterations in the cell cycle/transcription factor or DDR pathways. In contrast, all patients who achieved responses had no detected alterations in the MAPK/RTK/PI3K pathway.\u003c/p\u003e\n\u003cp\u003eTP53 (27.8%, 5 of 18), KEAP1 (22.2%, 4 of 18), and STK11 (16.7%, 3 of 18) were the most frequently reported pathogenic comutations in this analysis. Objective responses were observed in the subgroups with mutations in TP53 (3 of 5), KEAP1 (3 of 4), and STK11 (2 of 3), without significant differences from those among the patients who had no mutations detected in these genes—TP53 (7 of 13), KEAP1 (7 of 14), and STK11 (8 of 15) (Fig. 3b).\u0026nbsp;Two patients with concomitant KEAP1 and STK11 mutations—including one with a concomitant TP53 mutation—both achieved PR. The association between these comutations and the durability of this antitumor activity was analyzed among the 14 patients without observed alterations in the MAPK/RTK/PI3K\u0026nbsp;pathway. Six had at least one\u0026nbsp;comutation\u0026nbsp;detected in TP53, KEAP1 or STK11. The\u0026nbsp;duration of response and survival outcomes of these patients generally appeared to be worse than those of patients without such comutations (Fig. 3d).\u003c/p\u003e\n\u003cp\u003eThree patients had paired ctDNA test reports available for samples collected at baseline and at the end of treatment (EOT). Among these patients, two had negative KRAS\u003csup\u003eG12D\u003c/sup\u003e status at both baseline and EOT: one had no potential pathogenic mutations detected, and the other had only BRAF amplification identified at baseline. In the third patient, a KRAS\u003csup\u003eG12D\u003c/sup\u003e mutation was detected at baseline, accompanied by comutations in KEAP1, STK11, TP53 and RB1. Compared with baseline, no new genetic alterations were detected at the time of disease progression, except that the allelic frequency of KRAS\u003csup\u003eG12D\u003c/sup\u003e increased by approximately threefold (3.69% at baseline vs. 14.19% at EOT) (Fig. 3e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eNovel small molecules targeting KRAS\u003csup\u003eG12D\u003c/sup\u003e are under development through ongoing research and clinical efforts. Preclinical profiling indicates that GFH375 is a highly selective KRAS\u003csup\u003eG12D\u003c/sup\u003e (ON/OFF) inhibitor that, compared with other KRAS\u003csup\u003eG12D\u003c/sup\u003e inhibitors, demonstrates superior potency and bioavailability in reducing the levels of RAF1-bound active KRAS\u003csup\u003eG12D\u003c/sup\u003e-GTP (ON) and inhibiting cell proliferation\u003csup\u003e30\u003c/sup\u003e\u003csup\u003e,32\u003c/sup\u003e.\u0026nbsp;In this clinical study, orally administered GFH375 demonstrated good\u0026nbsp;pharmacokinetic\u0026nbsp;characteristics with a manageable safety profile. Substantial and durable clinical responses were observed in patients with previously treated NSCLC. Despite originating from a single-arm phase I/II study constrained by a small cohort size, these results offer preliminary but compelling evidence that GFH375 holds substantial therapeutic promise for the treatment of KRAS\u003csup\u003eG12D\u003c/sup\u003e-mutated NSCLC.\u003c/p\u003e\n\u003cp\u003eTo date, limited effective second-line or later options are available following disease progression on immunotherapy, with an ORR of approximately 10% and a median PFS of less than 4 months\u003csup\u003e7\u003c/sup\u003e\u003csup\u003e,33-35\u003c/sup\u003e. Although this is a single-arm study lacking a direct comparator, the efficacy of GFH375 appears to surpass those of currently available treatments, such as ramucirumab plus docetaxel, as reported\u003csup\u003e7\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eFor patients with newly diagnosed NSCLC, the current standard of care commonly includes chemoimmunotherapy, the clinical benefit of which is strongly associated with the tumor PD-L1 expression level. However, studies suggest that KRAS\u003csup\u003eG12D\u003c/sup\u003e mutations promote immune suppression and primary resistance to anti-PD-1/PD-L1 immunotherapy in NSCLC, especially in patients also harboring a TP53 mutation\u003csup\u003e21\u003c/sup\u003e\u003csup\u003e,36\u003c/sup\u003e\u003csup\u003e,37\u003c/sup\u003e. In this clinical study, the clinicopathologic characteristics of patients with KRAS\u003csup\u003eG12D\u003c/sup\u003e-mutated NSCLC\u0026mdash;such as a predominance of light or never smokers and mucinous adenocarcinoma\u0026mdash;aligned with those reported in the literature\u003csup\u003e38\u003c/sup\u003e\u003csup\u003e,39\u003c/sup\u003e. Although conflicting data exist, the proportion of tumor tissue samples with negative or low\u0026nbsp;PD-L1\u0026nbsp;expression (TPS) tested in this study was significantly greater than that reported in the general population of patients with NSCLC\u003csup\u003e40\u003c/sup\u003e\u003csup\u003e,41\u003c/sup\u003e.\u0026nbsp;These findings suggest that immunotherapy-based standard treatment may be inadequate for patients with\u0026nbsp;KRAS\u003csup\u003eG12D\u003c/sup\u003e-mutated NSCLC. In this study, GFH375 treatment induced rapid and durable responses irrespective of PD-L1 expression levels, suggesting that PD-L1 expression is not a predictive marker of GFH375 efficacy.\u0026nbsp;These results provide compelling evidence to support the potential advancement of GFH375 to first-line therapy for patients with\u0026nbsp;KRAS\u003csup\u003eG12D\u003c/sup\u003e-mutated NSCLC.\u003c/p\u003e\n\u003cp\u003eGiven the encouraging antitumor activity of GFH375 monotherapy, combination strategies should be explored to overcome resistance and further enhance clinical efficacy. Although it remains unknown whether KRAS\u003csup\u003eG12D\u003c/sup\u003e inhibition can sensitize tumor cells to immune checkpoint inhibitors, combining it with immunotherapy or chemoimmunotherapy represents a logical option given the current standard of care. However, existing studies on KRAS\u003csup\u003eG12\u003c/sup\u003e\u003csup\u003eC\u003c/sup\u003e inhibitors have generally shown that such combinations present challenging safety and tolerability profiles\u003csup\u003e42\u003c/sup\u003e\u003csup\u003e,43\u003c/sup\u003e. Alternative synergistic combination strategies that have been tested in clinical studies for\u0026nbsp;KRAS\u003csup\u003eG12\u003c/sup\u003e\u003csup\u003eC\u003c/sup\u003e inhibitors could also be considered, such as those involving anti-EGFR antibodies, SHP2 inhibitors, FAK inhibitors, or chemotherapy\u003csup\u003e44\u003c/sup\u003e\u003csup\u003e,45\u003c/sup\u003e. In light of emerging evidence suggesting a negative correlation between KRAS\u003csup\u003eG12D\u003c/sup\u003e mutations and PD-L1 expression/tumor mutation burden, these combinations may hold greater biological relevance.\u003c/p\u003e\n\u003cp\u003eBaseline ctDNA analysis of the 18 patients revealed that TP53, STK11, and KEAP1 were the most frequently co-occurring mutations, findings that align with the observations from other studies of KRAS-mutated NSCLC. In our study, although patients harboring these comutations exhibited initial responses to GFH375 treatment at a remarkably high rate, the survival outcomes appeared to be substantially worse than those of patients without these comutations. This finding is consistent with the existing reports that both STK11 and KEAP1 are generally associated with poorer prognosis and inferior treatment outcomes in this population\u003csup\u003e46\u003c/sup\u003e\u003csup\u003e,47\u003c/sup\u003e.\u0026nbsp;In addition, subgroup analysis of response and survival outcomes suggested that baseline ctDNA\u0026nbsp;KRAS\u003csup\u003eG12D\u003c/sup\u003e positivity, as a marker of tumor burden, may predict a poorer prognosis in patients with NSCLC, and similar results were reported in studies of patients with KRAS\u003csup\u003eG12C\u003c/sup\u003e mutation\u003csup\u003e48\u003c/sup\u003e\u003csup\u003e,49\u003c/sup\u003e. Another intriguing finding was the association between co-occurring genetic alterations in the MAPK/RTK/PI3K pathway and tumor response to GFH375 treatment. This link highlights the dominant role of RAS and its upstream/downstream pathways in tumorigenesis. Specifically, co-occurring pathogenic alterations in these RAS-related pathways promote primary resistance to KRAS\u003csup\u003eG12D\u003c/sup\u003e inhibitors, suggesting that simultaneous inhibition of signaling from these alterations is necessary to achieve favorable clinical outcomes\u003csup\u003e50-52\u003c/sup\u003e. This pattern aligns with observations in other indications, such as colorectal cancer, where such comutations are more prevalent and insensitive to KRAS inhibitors\u003csup\u003e53\u003c/sup\u003e. In particular, activation of the PI3K pathway in KRAS-mutant tumors\u0026mdash;including those with G12C or G12D mutations\u0026mdash;has been reported as a key primary resistance mechanism\u003csup\u003e54\u003c/sup\u003e. Moreover, the acquired KRAS\u003csup\u003eG12D\u003c/sup\u003e amplification observed in one patient after disease progression suggests a potential mechanism of resistance, resembling the findings of allele amplification after treatment with sotorasib\u003csup\u003e55\u003c/sup\u003e.\u0026nbsp;Certainly, these analyses are limited by the sensitivity of ctDNA sequencing and small sample size, particularly the insufficient collection of samples following disease progression. Many confounding factors essentially compromised the interpretability of the exploratory study results. As the study advances, cumulative data will be generated to provide more robust insights into resistance mechanisms and guide the development of corresponding therapeutic strategies to further improve treatment efficacy.\u003c/p\u003e\n\u003cp\u003eIn this study, GFH375 exhibited a generally well-tolerated clinical safety profile in patients with heavily pretreated cancer. Further analysis revealed that 62.8% of the patients had received prior ICI-containing treatment (Extended Data Table 1), including 96.4% of those with NSCLC (Table 1) and 46.6% with other tumor types. The median time from the last ICI dose to the initiation of GFH375 treatment was 2.9 months (2.8 months in patients with NSCLC and 3.1 months in others). Among patients previously treated with ICIs, toxicity events of high clinical severity were generally more frequent, and the tolerability of GFH375 appeared to be worse (Extended Data Table\u0026nbsp;4). Notably, compared with its use as a single agent in a second-line setting following front-line immunochemotherapy failure, fulzerasib\u0026mdash;an approved\u0026nbsp;KRAS\u003csup\u003eG12\u003c/sup\u003e\u003csup\u003eC\u003c/sup\u003e inhibitor\u0026mdash;demonstrated a superior safety profile when combined with cetuximab in the first-line setting for NSCLC\u003csup\u003e56\u003c/sup\u003e. These integrated findings suggest that prior ICI use, without sufficient washout periods, may increase the safety risks of subsequent therapies, potentially explaining the numerically higher frequency of clinically relevant safety events observed in patients with NSCLC in this study. The risk should not be neglected when considering the optimal combination strategy in the 1st-line setting.\u003c/p\u003e\n\u003cp\u003eIn conclusion, the KRAS\u003csup\u003eG12D\u003c/sup\u003e mutation represents a critical oncogenic driver and a promising therapeutic target for advanced NSCLC. The data reported herein demonstrate the encouraging antitumor efficacy and manageable safety of GFH375, an oral KRAS\u003csup\u003eG12D\u003c/sup\u003e inhibitor, in patients with NSCLC, thereby underscoring its clinical druggability. Moving forward, advancing research into resistance mechanisms\u0026mdash;including coexisting genetic alterations and PD-L1 expression levels in tumor cells will be central to identifying optimal combination strategies to augment therapeutic efficacy. To this end, clinical studies investigating GFH375 in combination with other agents, such as anti-EGFR therapy, chemotherapy, and immunotherapy, are slated to initiate. Furthermore, ongoing clinical investigations in GFH375 are underway in patients with KRAS\u003csup\u003eG12D\u003c/sup\u003e-mutated solid tumors, encompassing diverse disease settings and larger patient cohorts, with the aim of further validating its therapeutic effects and addressing unmet medical needs.\u003c/p\u003e"},{"header":"Online Methods","content":"\u003ch2\u003e\u003cem\u003eStudy design and treatment\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eThis is a first-in-human, multicenter, open-label, phase 1/2 trial to evaluate the safety, tolerability, pharmacokinetics, and efficacy of GFH375 in patients with KRAS\u003csup\u003eG12D\u003c/sup\u003e-mutant advanced solid tumors. The study is conducted in two parts, comprising GFH375 monotherapy dose escalation and back-filling (phase 1) and GFH375 monotherapy indication expansion (phase 2). GFH375 was administered orally once daily (QD) or twice daily (BID) in 21-day treatment cycles, and treatment was continued until disease progression, unmanageable toxicity or patient withdrawal. The study is ongoing.\u003c/p\u003e\n\u003cp\u003eIn phase 1, dose escalation was performed using accelerated titration at the first two dose levels followed by a Bayesian optimal interval (BOIN) design to determine the maximum tolerated dose (MTD). The starting dose of GFH375 was 100 mg once daily in cohort 1, with a planned dose escalation of up to 1200 mg once daily over seven additional cohorts. Decisions to expand the number of patients at a given dose level, proceed to the next dose level, stop dose escalation or de-escalate to a lower dose level were made by a safety monitoring committee. Additional patients would be backfilled to selected cohorts after confirmation of safety and observation of preliminary antitumor activities for further evaluation across dose levels and determination of the recommended phase 2 dose (RP2D). Dose intraescalation was not allowed in phase 1. An evaluation of the efficacy and safety of GFH375 monotherapy at the RP2D in an expanded patient population with previously treated NSCLC, pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and other solid tumors is ongoing. The patients reported in this article were enrolled before 27-May-2025.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003eTrial oversight\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eThe institutional ethics committee at each study site approved the trial protocol. The trial was conducted in accordance with the Good Clinical Practice guidelines of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, the principles of the Declaration of Helsinki, and local regulations regarding the conduct of clinical research. All patients provided written informed consent before participating in the trial. Safety oversight was provided by the safety monitoring committee, which reviewed the safety profile and additional data if available during the dose-escalation period and dose backfilling or expansion. All the authors ensured the completeness and accuracy of the data and analyses and the fidelity of the trial to the protocol.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003ePatients\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eEligible patients were aged 18–75 years, had a life expectancy of ≥12 weeks according to the investigator, were able to comprehend and willing to sign an informed consent form, had histologically or cytologically confirmed locally advanced or metastatic solid tumors, had KRAS\u003csup\u003eG12D\u003c/sup\u003e mutation documented by local tests on tumor tissue or blood, had evaluable disease (phase 1) or measurable disease (phase 2) per the Response Evaluation Criteria in Solid Tumors v.1.1, had an ECOG performance status equal to or less than 1, and must have had adequate organ and marrow function during the screening period. Treatment-related toxicity events (except alopecia) from previous anticancer treatments needed to be resolved to baseline or ≤ grade 1 (to ≤ grade 2 for nervous system toxicities). Patients must have been able to take oral medication. Eligible patients must have progressive disease after receiving standard-of-care treatment for locally advanced and unresectable or metastatic disease or intolerance of the standard-of-care treatment.\u003c/p\u003e\n\u003cp\u003ePatients with brain metastases were eligible for inclusion if the brain metastases were stable (i.e., no residual neurologic symptoms, without receiving corticosteroids \u0026gt;10 mg per day prednisone or equivalent). Other key exclusion criteria were uncontrolled intercurrent illness, current interstitial lung disease or pneumonitis or uncontrolled pleural effusion, pericardial effusion or ascites requiring more than one placement of a catheter or concomitant superior vena cava syndrome. Patients should not have active gastrointestinal disease or other conditions that could interfere with the absorption, distribution, metabolism or excretion of oral therapy. No history of allogeneic organ transplantation was allowed, and patients must not have active infection requiring treatment with systemic antibacterial, antifungal or antiviral therapy within 7 days before receiving the first dose of the study treatment. Patients should not have active hepatitis B or hepatitis C or have a history of human immunodeficiency virus infection. Patients should not have a history of other malignancies except for the current malignancy, should have been treated with curative intent and no known active disease for at least 3 years, should have a low risk of recurrence, and should have been adequately treated for basal cell carcinoma, skin cancer or adequately treated for carcinoma in situ without evidence of disease. Patients were excluded if they had a corrected QT interval \u0026gt;470 ms, an increased risk of QT interval prolongations or arrythmias, or clinically important electrocardiogram abnormalities or other cardiovascular diseases. Patients who had received other KRAS\u003csup\u003eG12D\u003c/sup\u003e inhibitors or pan-RAS inhibitors were excluded. Patients had to stop other anticancer therapies for at least 28 days or five half-lives before initiating the study treatment. Concomitant medication should be following the pharmacological requirements of avoiding strong CYP3A or P-gp inhibitors or inducers and CYP3A or OAT1 sensitive substrates and concomitant antacid drugs should be paused for at least 7 days before receiving the first dose of the study treatment.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003eAssessments\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eSafety and tolerability were assessed by treatment-emergent AEs, treatment-related AEs and clinically significant changes in vital signs, physical exams, electrocardiograms and clinical laboratory tests. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v.5.0 (CTCAE5.0). DLTs were defined as any of the following events judged as related to the study treatment occurring during the first cycle of treatment (21 days) in the dose-escalation phase: febrile neutropenia; grade 4 neutropenia lasting ≥5 days; grade 4 thrombocytopenia lasting ≥5 days; grade ≥3 thrombocytopenia with grade ≥ 2 bleeding; grade 4 anemia; grade ≥ 3 increase in ALT or AST lasting \u0026gt;7 days if ALT or AST ≤grade 1 at baseline or ALT or AST more than ten times the upper limit of normal lasting \u0026gt;7 days if ALT or AST was grade 2 at baseline; grade ≥3 increased blood bilirubin; ALT or AST ≥ three times the upper limit of normal with concurrent total bilirubin more than two times the upper limit of normal without evidence of cholestasis or alternative explanations; any other grade ≥3 AE except grade ≥3 nausea, vomiting or diarrhea lasting \u0026gt;3 days despite optimal support; grade 3 fatigue lasting \u0026gt;3 days; and asymptomatic transient isolated laboratory abnormalities lasting \u0026gt;7 days with intervention, e.g., increased serum amylase GGT, or ALP. The MTD was defined as the dose at which the estimated probability of a DLT was closest to 30% according to an isotonic regression model. RP2D was determined based on the integrated information, including the MTD, general safety profile, pharmacokinetics, and preliminary antitumor activity.\u003c/p\u003e\n\u003cp\u003eAntitumor activity was measured by the ORR (rate of complete or partial response), DCR (rate of complete or partial response, or stable disease), DOR (time from first documentation of response until disease progression or death from any cause), TTR (time from first dose of study treatment to first documentation of response), PFS (time from first dose of study treatment to disease progression or death from any cause) per RECIST v.1.1, and OS (time from first dose of study treatment to death from any cause). Tumor assessments were performed by computed tomography or MRI every 6 weeks until week 48 and then every 12 weeks thereafter.\u003c/p\u003e\n\u003cp\u003ePharmacokinetic parameters, including C\u003csub\u003emax\u003c/sub\u003e, T\u003csub\u003emax\u003c/sub\u003e, t\u003csub\u003e1/2\u003c/sub\u003e,\u0026nbsp;CL/F,\u0026nbsp;V\u003csub\u003ez\u003c/sub\u003e/F,\u0026nbsp;C\u003csub\u003etrough\u003c/sub\u003e and AUC,\u0026nbsp;were\u0026nbsp;determined using standard noncompartmental methods.\u0026nbsp;The\u0026nbsp;PK analysis included patients who received at least one\u0026nbsp;dose of GFH375\u0026nbsp;and had measurable plasma concentrations.\u0026nbsp;Patients enrolled in\u0026nbsp;phase 1\u0026nbsp;received a dose on Day 1 and then continuous dosing starting from Day 4.\u0026nbsp;PK blood samples were collected at\u0026nbsp;cycle\u0026nbsp;(C) 1 Day (D) 1\u0026nbsp;predose,\u0026nbsp;0.5,\u0026nbsp;1, 2, 4,\u0026nbsp;6,\u0026nbsp;8, and 12\u0026nbsp;h\u0026nbsp;postdose; Day\u0026nbsp;2 (24\u0026nbsp;h),\u0026nbsp;D3\u0026nbsp;(48\u0026nbsp;h),\u0026nbsp;and\u0026nbsp;D4\u0026nbsp;predose\u0026nbsp;(72\u0026nbsp;h)\u0026nbsp;for single-dose PK profiling;\u0026nbsp;and at\u0026nbsp;D21\u0026nbsp;predose,\u0026nbsp;0.5,\u0026nbsp;1, 2, 4,\u0026nbsp;6,\u0026nbsp;8, and 12\u0026nbsp;h\u0026nbsp;postdose, C2D1 predose (24 h) for steady-state PK profiling. Predose blood samples were also collected at C1D8;\u0026nbsp;C1D15, C2D10, C4D1, C5D1 and C6D1 to test trough concentrations.\u003c/p\u003e\n\u003cp\u003ePlasma ctDNA samples were collected at baseline (C1D1 predose) and at EOT for exploratory study of genetic biomarkers and potential relationships with clinical responses to treatment.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003eMethods for ctDNA testing and\u0026nbsp;\u003c/em\u003e\u003cem\u003ecomutation\u003c/em\u003e\u003cem\u003ea\u003c/em\u003e\u003cem\u003enalysis\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003ePlasma was collected from 8–10 mL of peripheral blood in CWBIO cell-free DNA storage tubes (CWbio) by centrifugation for 10 min at 2,000×g at 4 °C, after which the supernatant was transferred to a new tube and centrifuged again at 16,000×g at 4 °C for 10 min. Plasma cell-free DNA (cfDNA) was extracted according to the manufacturer’s instructions. Briefly, cfDNA was extracted from plasma samples using a HiPure Circulating DNA Kit (Magen, Cat# IVD3182), and the quantification of cfDNA was performed using a Qubit 2.0 fluorimeter with a Qubit dsDNA HS Assay Kit (Life Technologies, CA, USA). A minimum of 30 ng of cfDNA was required for library construction using a commercial OncoCompass\u003csup\u003e®\u003c/sup\u003e Target kit (Burning Rock Dx, Guangzhou, China), a hybrid capture-based NGS panel targeting\u0026nbsp;the\u0026nbsp;genomic alterations of 168 genes in solid\u0026nbsp;tumors. The cfDNA was subjected to end repair, phosphorylation, dA addition and adaptor ligation. The DNA library was purified with the magnetic beads provided with the\u0026nbsp;abovementioned\u0026nbsp;kits (Burning Rock Dx), followed by hybridization with capture probe baits, hybrid selection with magnetic beads and PCR amplification.\u0026nbsp;The\u0026nbsp;indexed samples were sequenced on\u0026nbsp;a\u0026nbsp;NextSeq550Dx/NovaSeq 6000 (Illumina, CA, USA) with paired-end reads at a target sequencing depth of 10,000× for cfDNA.\u003c/p\u003e\n\u003cp\u003eThe raw sequencing data were preprocessed using the in-house developed software \u003cem\u003eone-loop-trimmer\u003c/em\u003e for trimming adaptors and low-quality reads. Preprocessed sequencing data were then mapped to the human genome (hg19) using \u003cem\u003eBurrows–Wheeler Aligner v0.7.10\u003c/em\u003e. Variant calling was performed using \u003cem\u003eVardict\u003c/em\u003e, the in-house developed software/algorithm \u003cem\u003eBRCNV v4.2.3\u003c/em\u003e, \u003cem\u003emarkSV v0.2.5\u003c/em\u003e and \u003cem\u003eprettyMSI v2.0\u003c/em\u003e. In accordance with the ExAC, 1,000 Genomes, dbSNP, and gnomAD databases, variants with a population frequency greater than 0.1% were grouped as germline mutations and excluded from further analysis. The remaining variants were annotated using the in-house software \u003cem\u003eBrasAnnotation\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003eAnalysis of the co-occurring genetic alterations in ctDNA: In this study, the genetic alterations were reported according to the predefined cutoff value and criteria of the designated OncoCompass\u003csup\u003e®\u003c/sup\u003e Target Kit (Burning Rock Dx, Guangzhou, China). For co-occurring alterations analysis, the identified genetic alterations were further annotated, and only the somatic alterations with “clear/potential/uncertain clinical significance” and the germline alterations with “clear pathogenic/likely pathogenic/uncertain clinical significance” were included in this analysis.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eThe sample size of this study was determined by practical considerations common in early oncology trials rather than a formal statistical hypothesis. All treated patients (those who received at least 1 dose of GFH375) were included in the safety assessment. Efficacy was evaluated in patients who received at least 1 dose of GFH375. Pharmacokinetics were assessed in all patients who received at least one dose of GFH375 and provided at least one blood sample with evaluable pharmacokinetic data. The 90% CIs for the ORR and DCR were calculated using the Clopper‒Pearson method. Time-to-event endpoints were summarized with Kaplan–Meier estimates and 90% CIs at select timepoints. For time-to-event endpoints, the DoR and PFS were censored at the last disease assessment if no progression or death was documented, whereas if PD or death occurred after the initiation of new antitumor therapy, these endpoints were censored at the last assessment prior to the new therapy. Data were collected using Taimei eCollect v6 EDC. Analyses were performed using SAS v.9.4 and R v.4.4.3 (http://www.R-project.org/). Pharmacokinetic parameters were determined using noncompartmental analysis methods and calculated using Phoenix WinNonlin Version 8.3.1 (Certara, Princeton, NJ, USA).\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDeidentified participant data that underlie the results reported in this article, the protocol and statistical analysis plan may be available upon reasonable request to the corresponding author from qualified researchers following completion of the first-in human study with the clinical study reports finalization. Data is only available upon request to protect the privacy of the company and clinical trial participants. Full details are available at http://www.genfleet.com/.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was funded by GenFleet Therapeutic (Shanghai) Inc. We thank the participants and their families, investigators, and study staff who contributed to this study, and ClinChoice study team for their contributions. We would like to thank Springer Nature for English language editing (Springer Nature Go | Author Services from Springer Nature EN).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e\u003cstrong\u003eUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eS.L., Y.W., H.S. were responsible for the study conception or design. S.L., X.A., Z.M.L., L. W., P.C., Z.N., Y.S., Z.S., W.Y., J.H., Q.Y., A.Z., D.C., Y.H.D., Z.W.L., L.Z., H.Z., H.W., Y.Y., H.T.Z., Y.Y.D., X.Q., Y.W., H.S., H.Q.Z., C.L.Z., S.W., Z.C., C.Q.Z. conducted the study and were involved in acquisition, analysis or interpretation of data. S.W. and Z.C. performed statistical analysis. C.L.Z. and Z.C. analyzed the biomarker data. C.L.Z., S.W. and C.Q.Z. provided medical writing. S.L., X.A., Z.M.L., Y.W., H.S., H.Q.Z., C.L.Z., S.W., Z.C., C.Q.Z. drafted the working manuscript or critically reviewed it for important intellectual content. S.L., X.A., Z.M.L., L.W., P.C., Z.N., Y.S., Z.S., W.Y., J.H., Q.Y., A.Z., D.C., Y.H.D., Z.W.L., L.Z., H.Z., H.W., Y.Y., H.T.Z., Y.Y.D., X.Q., Y.W., H.S., H.Q.Z., C.L.Z., S.W., Z.C., C.Q.Z. approved the final version for publication and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003cstrong\u003eOMPETING INTERESTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eS.L. reports research funding from AstraZeneca, Hutchison, Bristol Myers Squibb (BMS), Heng Rui, BeOne Medicines, Roche and Hansoh pharma; consulting fees from AstraZeneca, Pfizer, Boehringer Ingelheim, Hutchison MediPharma, Simcere, Zai Lab, GenomiCare Consulting, Yuhan Corporation, PRIME Oncology, Menarini group and Roche; honorarias as an invited speaker from AstraZeneca, Roche, Hansoh pharma and Hengrui Therapeutics. Y.Y.D reports research funding from Innovent Biologics and Anke Biotechnology. Y.W., H.S., H.Q.Z., C.L.Z., S.W., Z.C., C.Q.Z. report employment and stock or stock options with GenFleet Therapeutics.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLi, C.\u003cem\u003e, et al.\u003c/em\u003e Global burden and trends of lung cancer incidence and mortality. \u003cem\u003eChin. Med. J.\u003c/em\u003e \u003cstrong\u003e136\u003c/strong\u003e, 1583\u0026ndash;1590 (2023).\u003c/li\u003e\n\u003cli\u003eHerbst, R.S.\u003cem\u003e, et al.\u003c/em\u003e Five year survival update from KEYNOTE-010: pembrolizumab versus docetaxel for previously treated, programmed death-ligand 1-positive advanced NSCLC. \u003cem\u003eJ. Thorac. 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Oncol.\u003c/em\u003e \u003cstrong\u003e19\u003c/strong\u003e, 995\u0026ndash;1006 (2024).\u003c/li\u003e\n\u003cli\u003eEspinosa-Olarte, P.\u003cem\u003e, et al.\u003c/em\u003e 367P: clinical characteristics and ctDNA as prognostic tools in KRAS-mutated NSCLC during first line treatment (1L). \u003cem\u003eJ. Thorac. Oncol.\u003c/em\u003e \u003cstrong\u003e20\u003c/strong\u003e, S217 (2025).\u003c/li\u003e\n\u003cli\u003eMcDaid, W.J.\u003cem\u003e, et al.\u003c/em\u003e The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRAS\u003csup\u003eG12D\u003c/sup\u003e-driven non-small cell lung cancer. \u003cem\u003eMol. Cancer\u003c/em\u003e \u003cstrong\u003e23\u003c/strong\u003e, 253 (2024).\u003c/li\u003e\n\u003cli\u003eLi, Y., Zhao, J. \u0026amp; Li, Y. New exploration of KRAS\u003csup\u003eG12D\u003c/sup\u003e inhibitors and the mechanisms of resistance. \u003cem\u003eExp. Hematol. Oncol.\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, 39 (2025).\u003c/li\u003e\n\u003cli\u003eDiehl, A.C.\u003cem\u003e, et al.\u003c/em\u003e KRAS mutation variants and co-occurring PI3K pathway alterations impact survival for patients with pancreatic ductal adenocarcinomas. \u003cem\u003eOncologist\u003c/em\u003e \u003cstrong\u003e27\u003c/strong\u003e, 1025\u0026ndash;1033 (2022).\u003c/li\u003e\n\u003cli\u003eLuo, Q.\u003cem\u003e, et al.\u003c/em\u003e KRAS and PIK3CA bi-mutations predict a poor prognosis in colorectal cancer patients: a single-site report. \u003cem\u003eTransl. Oncol.\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e, 100874 (2020).\u003c/li\u003e\n\u003cli\u003eQi, W.L.\u003cem\u003e, et al.\u003c/em\u003e Targeting PI3K\u0026alpha; overcomes resistance to KRAS\u003csup\u003eG12C\u003c/sup\u003e inhibitors mediated by activation of EGFR and/or IGF1R. \u003cem\u003eActa Pharmacol. Sin.\u003c/em\u003e \u003cstrong\u003e44\u003c/strong\u003e, 1083\u0026ndash;1094 (2023).\u003c/li\u003e\n\u003cli\u003eAwad, M.M.\u003cem\u003e, et al.\u003c/em\u003e Acquired Resistance to KRAS(G12C) Inhibition in Cancer. \u003cem\u003eN Engl J Med\u003c/em\u003e \u003cstrong\u003e384\u003c/strong\u003e, 2382-2393 (2021).\u003c/li\u003e\n\u003cli\u003eGregorc, V.\u003cem\u003e, et al.\u003c/em\u003e KROCUS: A phase II study investigating the efficacy and safety of fulzerasib (GFH925) in combination with cetuximab in patients with previously untreated advanced KRAS G12C mutated NSCLC. \u003cem\u003eJournal of Clinical Oncology\u003c/em\u003e (2024).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Demographics and baseline characteristics of patients with NSCLC\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003eAll NSCLC, n (%)\u003cbr\u003e\u0026nbsp;(n = 28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eNSCLC at 600 mg, n (%)\u003cbr\u003e\u0026nbsp;(n = 16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003eAge, median (range), years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e61 (36\u0026ndash;74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e60.5 (36\u0026ndash;74)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e13 (46.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e8 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e15 (53.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e8 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003eSmoking status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003eCurrent or former\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e11 (39.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e8 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003eNever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e17 (60.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e8 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003eECOG PS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e2 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e26 (92.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e14 (87.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003ePathology adenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e28 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e16 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003ePulmonary mucinous adenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e10 (35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e8 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003eBaseline metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e28 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e16 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003eBone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e12 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e4 (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003eBrain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e5 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e3 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e2 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003ePD-L1 TPS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003eKnown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e22 (78.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e11 (68.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e\u0026lt; 1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e13 (59.1)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e6 (54.5)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e1\u0026ndash;49%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e9 (40.9)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e5 (45.5)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e\u0026ge; 50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003ePrior lines of therapies, median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e2 (1\u0026ndash;4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e1.5 (1\u0026ndash;4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e10 (35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e8 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003e\u0026ge; 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e18 (64.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e8 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003ePrior ICI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e27 (96.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e16 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003ePrior platinum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e28 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e16 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44px;\"\u003e\n \u003cp\u003ePrior ICI + platinum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e25 (89.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e16 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNotes:\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Denominator is 22.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Denominator is 11.\u003c/p\u003e\n\u003cp\u003eECOG PS, Eastern Cooperative Oncology Group performance status; ICI, Immune checkpoint inhibitor; NSCLC, Non-small cell lung cancer；PD-L1 TPS, Programmed death ligand 1 tumor cell proportion score.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003eAdverse events in all patients and in patients with NSCLC\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eAdverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003eAll patients, n (%)\u003cbr\u003e(n = 86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003eNSCLC, n (%)\u003cbr\u003e\u0026nbsp;(n = 28)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eTEAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eAll grades\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e86 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e28 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eGrade \u0026ge; 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e46 (53.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e16 (57.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eSAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e24 (27.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e8 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eTRAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eAll grades\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e84 (97.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e28 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eGrade \u0026ge; 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e32 (37.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e14 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eSAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e9 (10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e4 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eGrade \u0026ge; 3 TRAEs occurring in \u0026ge; 3% of all patients\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eDecreased neutrophil count\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e8 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e3 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e4 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eIncreased aspartate aminotransferase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e4 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e4 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eIncreased alanine aminotransferase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e3 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eDecreased white blood cell count\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e3 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eAbnormal hepatic function\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e3 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003eAsthenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e3 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22px;\"\u003e\n \u003cp\u003e1 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNotes:\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e*\u0026nbsp;\u003c/sup\u003eAmong the listed terms, there was one grade 4 case of decreased neutrophil count and one grade 4 case of abnormal hepatic function; no grade 5 cases occurred.\u003c/p\u003e\n\u003cp\u003eNSCLC, Non-small cell lung cancer；SAE, Serious adverse events; TEAEs, Treatment-emergent adverse events; TRAEs, Treatment-related adverse events.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8540837/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8540837/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eKRAS\u003csup\u003eG12D\u003c/sup\u003e mutations occur in approximately 2–4% of patients with non-small cell lung cancer (NSCLC). GFH375, a compound that targets both “ON” (GTP-bound) and “OFF” (GDP-bound) states of the KRAS\u003csup\u003eG12D\u003c/sup\u003e proteins, was evaluated in a phase 1/2 study among patients with advanced solid tumors harboring KRAS\u003csup\u003eG12D\u003c/sup\u003e mutations. The objectives were to evaluate safety and tolerability, characterize pharmacokinetics, and evaluate preliminary efficacy. A total of 86 patients with KRAS\u003csup\u003eG12D\u003c/sup\u003e-mutant advanced solid tumors, including 28 with advanced NSCLC, were treated with the single agent GFH375 administered orally once or twice daily. Overall, GFH375 was well tolerated and had a manageable safety profile. Treatment-related adverse events occurred in 97.7% of the patients: 37.2% experienced grade ≥3 adverse events, and 1 patient (1.2%) experienced a grade 5 adverse event. Encouraging antitumor activity was demonstrated in patients with previously treated NSCLC, with objective response rates of 57.7% (90% CI: 39.8–74.2) at all dose levels and 68.8% (90% CI: 45.2–86.8) at 600 mg once daily; the 6-month progression-free survival rates were 60.4% (90% CI: 46.2–78.8) and 77.4% (90% CI: 60.6–98.9), respectively. Co-occurring alterations were analyzed with circulating tumor DNA (ctDNA) collected at baseline and at the end of treatment. The study is ongoing (ClinicalTrials.gov identifier: NCT06500676).\u003c/p\u003e","manuscriptTitle":"GFH375 in Patients with Previously Treated Non-Small Cell Lung Cancer and KRASG12D Mutations: A First-in-Human Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-18 10:13:57","doi":"10.21203/rs.3.rs-8540837/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nm","sideBox":"Learn more about [Nature Medicine](http://www.nature.com/nm/)","snPcode":"","submissionUrl":"","title":"Nature Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"eb78cda7-9011-494c-a1ca-b3adb96b2514","owner":[],"postedDate":"March 18th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":62273938,"name":"Biological sciences/Cancer/Lung cancer/Non-small-cell lung cancer"},{"id":62273939,"name":"Biological sciences/Cancer/Tumour biomarkers"}],"tags":[],"updatedAt":"2026-03-18T10:13:57+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-18 10:13:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8540837","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8540837","identity":"rs-8540837","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}