1306P - Trametinib plus anlotinib in non-G12C KRAS-mutant non-small cell lung cancer: A single-center, open-label, single-cohort study

Background

It remains as a big challenge to provide therapeutic regimen for the non-G12C KRAS-mutant non-small cell lung cancer (NSCLC) patients. The strategy of co-inhibition of MEK/RTKs pathways via trametinib and anlotinib showed preliminary activity in non-G12C KRAS-mutant NSCLC in preclinical. However, whether the strategy is effective in clinic remains elusive.

Methods

This phase I clinical trial enrolled patients with advanced non-G12C KRAS-mutant NSCLC patients from April 13, 2021, to May 13, 2023. The data cutoff date for this analysis was March 26, 2024. The trial was divided into 2 parts including phase Ia and phase Ib. Trametinib and anlotinib were administered orally once daily. The primary endpoint of phase Ia was to evaluate the determine the recommended phase 2 dose (RP2D), and the primary endpoint of phase Ib was to evaluate the objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of overall response (DoR), and adverse events (AEs).

Results

The phase Ia containing 13 patients showed that the RP2D is trametinib (2 mg) plus anlotinib (8 mg), the ORR is 69.2% (95% confidence interval [CI]: 38.6 to 90.9), the median PFS is 6.9 months (95% CI: 3.9 to could not be evaluated), DCR is 92% (95% CI: 64.0 to 99.8) and the rate of adverse events (AEs) ≥ grade 3 is 23%. The phase Ib containing 20 patients showed high efficacy of this combinational therapy (trametinib (2 mg) plus anlotinib (8 mg)), with the ORR at 65% (95% CI: 40.8 to 84.6), the median PFS is 11.5 months (95% CI: 8.3 to 15.5), the DCR at 100% (95% CI: 83.2 to 100.0), the median DoR is 9.3 months (95% CI: 2.5 to 12.1), and the rate of AEs ≥ grade 3 at 35%. An integrative analysis for the phase Ia plus phase Ib (33 patients) indicated that the ORR is 66.7% (95% CI: 42.1 to 77.1), the median PFS is 10.3 months (95% CI: 7.0 to 15.1), the DCR is 97% (95% CI: 89.4 to 100.0), the median DoR is 9.3 months (95% CI: 3.3 to 11.2), and the rate of AEs ≥ grade 3 is 30%.

Conclusions

This study provides a potential combinational therapeutic strategy for those non-G12C KRAS-mutant lung cancer patients via oral administration of trametinib and anlotinib.

Clinical trial identification

NCT04967079.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Chia Tai Tianqing Pharmaceutical Group Co., Ltd., and Novartis.

Disclosure

All authors have declared no conflicts of interest.