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GFH375 produced responses and tumor shrinkage in heavily pretreated pancreatic ductal adenocarcinoma harboring KRAS G12D mutations.
The highly selective KRAS G12D inhibitor GFH375 generated responses and tumor shrinkage when given as monotherapy in heavily pretreated patients with pancreatic ductal adenocarcinoma (PDAC) harboring KRAS G12D mutations, according to data from a phase 1/2 trial (NCT06500676).1
Findings presented at the 2025 ESMO Congress showed that evaluable patients treated with GFH375 at 600 mg once per day (n = 59) achieved an overall response rate (ORR) of 40.7% (90% CI, 30%-52%). All responses were partial, and the disease control rate (DCR) was 96.7% (90% CI, 90%-99%). Notably, 91.5% of patients experienced reductions in target lesions.
Additionally, at a median follow-up of 5.65 months (90% CI, 4.96-6.08), this patient population experienced a median progression-free survival (PFS) of 5.52 months (90% CI, 4.27-7.20) and a 4-month PFS rate of 78.2% (90% CI, 69.8%-87.5%). At a median follow-up of 5.65 months (90% CI, 5.22-6.14), the median overall survival (OS) was not reached, and the 4-month OS rate was 92.2% (90% CI, 86.8%-97.9%).
“The efficacy and safety data support further advancing of clinical development for GFH375 as monotherapy in previously treated, advanced KRAS G12D–mutant PDAC,” lead study author Aiping Zhou, MD, of the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China, said in the conclusion of the presentation.
Among patients with PDAC, KRAS G12D mutations are the most common alteration, occurring in approximately 40% of patients. KRAS G12D mutations have been associated with shorter PFS and OS.2
GFH375 is an oral, potent, highly selective inhibitor of KRAS G12D in both the GDP-bound (off) and GTP-bound (on) positions.1
The phase 1/2 study enrolled patients with pathologically confirmed advanced solid tumors harboring KRAS G12D mutations who had received prior treatment with standard-of-care therapies. Patients also needed to have an ECOG performance status of 0 or 1.
During dose escalation in phase 1, patients received GFH375 monotherapy at 100 mg, 200 mg, 400 mg, 600 mg, 750 mg, or 900 mg once per day, or 300 mg twice per day. The once-daily, 600-mg dose was selected as the recommended phase 2 dose, which was further evaluated in the phase 2 indication expansion. The 4 tumor-specific cohorts in phase 2 were PDAC, non–small cell lung cancer, colorectal cancer, and other solid tumors.
Treatment continued until disease progression, unacceptable toxicity, or other withdrawal reasons.
The study’s end points included ORR, duration of response, DCR, and PFS per RECIST 1.1 criteria; safety and tolerability; and exploratory biomarkers.
Among patients with PDAC who received GFH375 at 600 mg once per day (n = 66), patients had a median age of 60 years (range, 35-74); 53.0% were above the age of 60, and 53.0% were male. The majority of patients had an ECOG performance status of 1 (100%), adenocarcinoma (97.0%), stage IV disease (95.5%), and received at least 2 prior lines of anticancer therapy (68.2%).
Baseline metastases included liver (78.8%), lung (28.8%), peritoneum (28.8%), and bone (18.2%). Prior therapies included a gemcitabine-containing regimen (92.4%), a fluorouracil-containing regimen (75.8%), an irinotecan-containing regimen (53.0%), and immune checkpoint inhibitors (33.3%).
At the data cutoff, 47.0% of patients remained on treatment, and the longest duration of treatment was 367 days. Among the 53.0% of patients who discontinued treatment, reasons for discontinuation included disease progression (31.8%), adverse effect (AE; 9.1%), investigator’s decision (3.0%), initiation of new therapy (1.5%), withdrawal of consent (1.5%), and other (6.1%).
At the 600-mg dose, any-grade treatment-emergent AEs (TEAEs) and treatment-related AEs (TRAEs) occurred in all patients. The grade 3 or higher TEAE and TRAE rates were 50.0% and 31.8%, respectively. Serious any-grade TEAEs and TRAEs occurred at rates of 25.8% and 13.6%, respectively. TEAEs led to treatment discontinuation, dose reductions, and dose interruptions in 7.6%, 6.1%, and 37.9% of patients, respectively. These respective rates were 3.0%, 6.1%, and 27.3% for TRAEs.
The most common any-grade TRAEs reported in at least 20% of patients comprised diarrhea (56.1%), decreased neutrophil count (48.5%), vomiting (47.0%), nausea (47.0%), anemia (42.4%), decreased white blood cell count (36.4%), decreased appetite (33.3%), hypoalbuminemia (33.3%), decreased platelet count (28.8%), asthenia (25.8%), increased aspartate aminotransferase levels (24.2%), and increased alanine transferase levels (22.7%).
Disclosures: Zhou did not report any conflicts of interest.
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