3113 Background: Studies have shown that combining RAS inhibitors (RASi) with appropriate partners may enhance efficacy. Ifebemtinib (ifebe) is a potent and selective oral focal adhesion kinase (FAK) inhibitor demonstrating synergy with RASi. D-1553 is a KRAS G12C inhibitor approved in China for KRAS G12C –mutant NSCLC. We previously reported encouraging antitumor activity with ifebe plus D-1553. Here we present updated 2-year efficacy and safety results, including exploratory TP53 subgroup analyses. Methods: This is a phase Ib/II, open-label study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of D-1553 in combination with ifebe in patients with locally advanced or metastatic NSCLC harboring KRAS G12C mutations regardless of PD-L1 expression. Patients received ifebe 100 mg once daily (QD) plus D-1553 600 mg twice daily (BID). Results: As of January 4, 2026, 33 treatment-naïve NSCLC patients (81.8% stage IV) were enrolled; median follow-up was 24.9 months (Range: 1.05, 31.77). The objective response rate (ORR) was 90.3% (95% CI: 74.2, 98.0) and disease control rate (DCR) was 96.8% (95% CI: 83.3, 99.9). The median progression free survival (PFS) was 22.14 months (95% CI: 9.63, NE) with the 12- and 24-month PFS rates were 67.9% and 40.0%, respectively. The median duration of response (DOR) was 19.38 months (95% CI: 12.85, NE). The 24-month overall survival (OS) rate was 69.7%, and mOS was not reached (95% CI: 27.76, NE). TP53 wild-type patients (n=17) showed more favorable outcomes, with higher ORR (94.1% vs. 81.8%), unreached mPFS (vs. 14.2 months), and unreached mOS (vs. 17.7 months) compared with TP53-mutant patients (n=13). The safety profile of ifebe plus D-1553 was generally comparable to that of each single agent. SAEs were reported in 33.3% of patients, with 18.2% experiencing ifebe-related SAEs. Most TRAEs were grade 1–2; grade ≥3 TRAEs occurred in 24.2% of patients, including one grade 4 event. No treatment-related deaths or discontinuations were reported. Conclusions: Ifebe plus D-1553 exhibited robust, durable antitumor activity and a favorable safety profile in treatment-naïve KRAS G12C -mutant NSCLC patients regardless of PD-L1 expression. Notably, TP53-wild-type KRAS G12C tumors typically show poor responsiveness and short durability to ICI therapies, likely due to reduced PD-L1 expression and lower tumor mutational burden. The superior outcomes in TP53 wild-type patients suggest this combination may address an unmet need in this distinct population. Further studies are needed to validate these findings and define the regimen’s optimal role in the evolving treatment landscape. Clinical trial information: NCT06166836; NCT05379946 .
Wang et al. (Wed,) studied this question.
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