Daraxonrasib: 42% response rate in phase 1/2 RAS-mutant lung cancer

When platinum-based chemotherapy and immunotherapy stop controlling RAS-mutant non-small cell lung cancer, patients can be left with docetaxel and limited room to maneuver. In a phase 1/2 trial led by The University of Texas MD Anderson Cancer Center, the oral RAS inhibitor daraxonrasib produced a 42% objective response rate in a relevant group of previously treated patients.

The comparison is a difficult one. Docetaxel remains a common treatment after progression, but historical studies in this setting reported response rates of 9% to 14%, median progression-free survival of 3 to 4.5 months and median overall survival of approximately 9 to 12 months. David Hong, deputy chair of Investigational Cancer Therapeutics at MD Anderson, said the available options often bring modest benefit alongside substantial toxicities.

The most clinically relevant data came from 38 patients treated with 160–220 mg of daraxonrasib. They had already received platinum-based chemotherapy and immunotherapy, but not docetaxel. Their median duration of response was 11.5 months, median progression-free survival was 8.3 months and median overall survival was 16 months.

The price of that activity is a substantial side-effect burden. At the recommended phase 3 dose, 51% of patients experienced an adverse effect at grade 3 or higher, 71% needed dose modifications and 10% discontinued treatment. Rash affected 90% of patients, while diarrhea, nausea and vomiting affected 73%, 62% and 54%, respectively; each occurred in less than 10% of patients at grade 3 or higher. Hong described the toxicities as largely manageable compared with the alternatives, while stressing the need to optimize the dose.

So, concretely, daraxonrasib gives patients whose disease has progressed after two major treatment classes a candidate oral therapy with responses lasting a median of 11.5 months—but it is not yet established care. The initial data, presented at the 2025 European Lung Congress, prompted the ongoing phase 3 RASolve 301 trial, led at MD Anderson by Ferdinandos Skoulidis.