Dr Luo on the Association Between ctDNA and Response to Daraxonrasib in RAS G12X–Mutant Advanced NSCLC

“The most interesting finding was that individuals who had more of a steep change from baseline to on-treatment circulating tumor DNA [ctDNA] had a better future result, and the change in the ctDNA actually predicted future outcomes in those patients.”

Jia Luo, MD, a physician at Dana-Farber Cancer Institute and an instructor in Medicine at Harvard Medical School, discussed the results from a circulating tumor DNA (ctDNA) analysis following the treatment of daraxonrasib (RMC-6236) in patients with advanced non–small cell lung cancer (NSCLC) harboring RAS G12X mutations.

The ctDNA analysis from a phase 1 trial (NCT05379985) showed that among ctDNA-evaluable patients (n = 35), 66% experienced complete ctDNA clearance, which was defined as a 100% reduction in RAS variant allele frequency (VAF). Of note, patients who received pretreatment and treatment early on had plasma collected for ctDNA analysis, Luo explained. In the analysis, mutations were distributed based on type, which included KRAS G12V, KRAS G12A, and KRAS G12D as the most common, she added.

Moreover, 11 ctDNA-evaluable patients achieved a partial response, and 82% of these patients experienced complete ctDNA clearance. Notably, patients who had a steeper change from baseline to on-treatment ctDNA also had better outcomes, Luo said. Therefore, the change in ctDNA helped predict future outcomes in respective patients, she emphasized.

Early efficacy findings from the phase 1 study revealed that patients with RAS G12X–mutant NSCLC treated with daraxonrasib in the second- or third-line setting at 120 mg to 220 mg once daily (n = 40) achieved a confirmed overall response rate of 38%, all of which were partial responses. The median duration of response was 15.1 months (95% CI, 11.1-not evaluable [NE]), with a median time to response of 1.5 months (range, 1.2-6.2). Additionally, the median progression-free survival was 9.8 months (95% CI, 6.0-12.3) and the median overall survival was 17.7 months (95% CI, 13.7-NE).

Any-grade and grade 3 treatment-related adverse effects (TRAEs) occurred in 97% and 16% of patients, respectively; however, there were no reported grade 4 or 5 TRAEs. Dose interruptions due to TRAEs occurred in 34% of patients, with dose reductions and treatment discontinuations reported in 21% and 4%, respectively. Between the findings from the ctDNA analysis and the early efficacy and safety data of daraxonrasib, the next steps are moving towards launching a phase 3, randomized study.