ESMO 2025 Showcases Promising First-in-Human Data for KRAS G12C and FGFR3 Inhibitors
核心洞察
HengRui (搜索)'s KRAS G12C (搜索) inhibitor HRS-7058 demonstrates impressive activity with 61% response rate in treatment-naive NSCLC (搜索) patients and notable 23% response rate in patients previously treated with other KRAS G12C inhibitors.
Lilly (搜索)'s FGFR3 (搜索) inhibitor vepugratinib (搜索) shows 29% overall response rate in FGFR3-positive urothelial cancer (搜索), including responses in patients previously treated with Balversa.
Moderna's mRNA-4359 immunotherapy reveals promising 67% response rate in PD-L1 (搜索)-positive checkpoint inhibitor-refractory melanoma (搜索) patients, though no responses were observed in PD-L1-negative patients.
The upcoming ESMO 2025 conference will feature several notable first-in-human clinical datasets, with HengRui (搜索)'s KRAS G12C (搜索) inhibitor HRS-7058 and Lilly (搜索)'s FGFR3 (搜索) inhibitor vepugratinib (搜索) delivering particularly impressive early clinical activity according to recently published abstracts.
KRAS G12C Inhibitor Shows Promise in Pretreated Patients
HengRui (搜索)'s HRS-7058 has emerged as a standout among new KRAS G12C (搜索) inhibitors, demonstrating significant clinical activity across different patient populations. In treatment-naive NSCLC (搜索) patients, the drug achieved a 61% overall response rate (ORR) among 42 patients. More notably, the inhibitor showed a 23% response rate among 19 NSCLC patients who had already been treated with another KRAS G12C inhibitor, suggesting potential utility in overcoming resistance to existing therapies.
This represents a marked improvement over HengRui (搜索)'s previous KRAS program, as the company's G12D asset HRS-4642 delivered only a 6% ORR at ESMO 2023, which was considered a significant disappointment.
FGFR3 Inhibitor Demonstrates Activity in Pretreated Urothelial Cancer
Lilly (搜索)'s vepugratinib (搜索), positioned as a highly isoform-selective FGFR3 (搜索) inhibitor and potential competitor to Johnson & Johnson's approved FGFR1/2/3/4 inhibitor Balversa, showed a 29% response rate in patients with FGFR3-positive urothelial cancer (搜索) receiving doses of 200mg BID or higher (n=82). The drug demonstrated particular promise at the 200mg BID dose level, achieving a 39% ORR among 28 patients.
Notably, vepugratinib (搜索) showed activity even in patients previously treated with Balversa, with three responses observed among seven such patients (43% response rate). An interesting observation from the data suggests that patients treated with relatively low doses appear to be performing better than the overall population.
mRNA Immunotherapy Shows Mixed Results in Melanoma
Moderna's mRNA-4359, an IDO (搜索)/PD-L1 (搜索) immunotherapy using mRNA-encoded peptides, presented its first clinical data in checkpoint inhibitor-resistant/refractory melanoma (搜索) patients. The treatment, given alongside Keytruda, achieved a 67% response rate among nine patients with PD-L1 expression ≥1%. However, no responses were observed among 13 patients with PD-L1 levels below 1%.
This contrasts with data from IO Biotech's competing IDO (搜索)/PD-L1 (搜索) peptide immunotherapy Cylembio, which reportedly showed "a profound effect" in PD-L1-negative tumors in a first-line melanoma (搜索) setting, yielding median progression-free survival of 16.6 months versus 3.0 months for Keytruda control.
Other Notable First-in-Human Programs
Several other programs will present early clinical data at ESMO 2025. Incyte's KRAS G12D inhibitor INCB161734 achieved a 30% ORR among 27 patients at doses ≥600mg daily. Daiichi Sankyo's anti-TA-MUC1 ADC DS-3939 showed a 26% ORR among 38 patients at dose levels 2-6.
Incyte's anti-PD-1 x TGFβR2 bispecific antibody INCA33890 demonstrated a 12% ORR in microsatellite stable colorectal cancer (搜索) patients (n=97), with additional responses observed in NSCLC (搜索) and head & neck cancer patients, including two patients who had previously received anti-PD-1 therapy.
Werner Helicase Inhibitor Disappoints
In contrast to these promising results, Novartis's Werner helicase (搜索) inhibitor HRO761 appears headed for discontinuation after delivering response rates of only 11% in colorectal cancer (搜索) patients (n=19) and 6% in non-colorectal patients (n=16), for an overall ORR of 9% among 35 patients with MSI-H/dMMR solid tumors. This follows a similar pattern to Roche's Werner helicase inhibitor RO7589831, which was handed back to Bayer in June.
ESMO 2025 will take place in Berlin from October 17-21, where these and other clinical datasets will be presented in detail to the oncology community.