Coinhibition of the MEK/RTK pathway has high therapeutic efficacy in KRAS-mutant non-small cell lung cancer.

Oncogenic KRAS mutations are frequently detected in NSCLC. It remains a major challenge to target all KRAS mutants. MEK inhibitors are considered candidates for treating KRAS-mutant NSCLC; however, their easy adaptive resistance precludes further application. Here, we found that MEK inhibitor-trametinib treatment results in the feedback activation of multiple receptor tyrosine kinases (RTKs) and that treatment with the pan-RTK inhibitor anlotinib effectively inhibits the progression of KRAS-mutant NSCLC. Furthermore, we evaluated this strategy in a clinical study (NCT04967079) involving 33 advanced non-G12C KRAS-mutant NSCLC patients. The phase Ia containing 13 patients showed that the recommended phase 2 dose (RP2D) is trametinib (2 mg) plus anlotinib (8 mg), the objective response rate (ORR) is 69.2% (95% CI: 38.6-90.9), the median progression-free survival (PFS) is 6.9 months (95% CI: 3.9 to could not be evaluated), disease control rate (DCR) is 92% (95% CI: 64.0-99.8) and the rate of adverse events (AEs) ≥grade 3 is 23%. The phase Ib containing 20 patients demonstrated the high efficacy of this combinational therapy with RP2D, with the ORR at 65% (95% CI: 40.8-84.6), the median PFS is 11.5 months (95% CI: 8.3-15.5), the median overall survival (OS) is 15.5 months (95% CI: 15.5 to could not be evaluated), the DCR at 100% (95% CI: 83.2-100.0), the median duration of overall response (DoR) is 9.3 months (95% CI: 2.5-12.1), and the rate of AEs ≥ grade 3 at 35%. Overall, this study provides a potential combinational therapeutic strategy for KRAS-mutant NSCLC through the cotargeting of MEK and RTKs.