Daraxonrasib showed antitumor activity in previously treated RAS-mutant non–small-cell lung cancer

1. In patients with previously treated advanced RAS-mutant non–small-cell lung cancer, daraxonrasib produced objective responses in approximately one-third of subjects across the evaluated dose groups. 

2. Antitumor activity remained similar between lower and higher doses, while the lower dose range was associated with fewer severe adverse events. 

Evidence Rating Level: 2 (Good)

Study Rundown: Rat sarcoma virus (RAS) gene family mutations are among the most common oncogenic drivers of non–small-cell lung cancer (NSCLC), occurring in approximately 30% of patients. For patients whose disease progresses after platinum-based chemotherapy and programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) therapy, docetaxel-based treatment remains a standard option which is associated with modest but often nondurable clinical benefit. Although KRAS G12C inhibitors have expanded targeted treatment options, these agents are allele-specific and target the inactive, guanosine diphosphate–bound form of RAS. Daraxonrasib is an oral agent designed to inhibit active, guanosine triphosphate–bound mutant and wild-type RAS across multiple isoforms and variants. Hence, this phase 1–2 study evaluated the safety and preliminary antitumor activity of daraxonrasib in patients with previously treated advanced RAS-mutant NSCLC. Overall, objective responses were observed in more than three-tenths of patients in each evaluated dose range, including patients with several different RAS mutations. Responses were similar among patients receiving medium and high doses, but toxicity and the need for dose modification increased with the higher dose. Rash and gastrointestinal adverse events were especially common but were generally manageable with supportive measures and dose adjustments. The study was limited by its nonrandomized design, lack of a concurrent comparator, and small mutation-specific and co-mutation subgroups. Patients with previous RAS-targeted therapy were also excluded, limiting the number of participants with KRAS G12C-mutant disease. Nonetheless, these findings support further evaluation of daraxonirasib and led to the selection of 200mg as the dose for subsequent phase 3 trials.

Click to read the study in NEJM 

Relevant Reading: Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS G12C mutation: a randomised, open-label, phase 3 trial

In-Depth [prospective cohort]: This multicenter, open-label, nonrandomized dose-escalation and dose-expansion study enrolled adults with previously treated advanced NSCLC harboring specific KRAS, NRAS, or HRAS mutations. Eligible patients had measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST), and disease progression or unacceptable toxicity after platinum-based chemotherapy and anti–PD-1 or anti–PD-L1 therapy. Those with previous RAS-targeted therapy, untreated central nervous system metastases, interstitial lung disease, and recent thoracic radiotherapy were excluded. Daraxonrasib was administered orally once daily in 21-day cycles at doses ranging from 10 to 400 mg. Of 136 total patients, 26 received 120 mg or less, 59 received 160 to 220 mg, and 51 received 300 mg. The median age was 66 years, 38% of patients were male, 75% were White, and 79% had an ECOG performance-status score of 1. Nearly all patients had stage IV disease at enrollment and had received a median of two previous lines of therapy for metastatic disease. Adverse events of any grade occurred in 99% of patients, most commonly rash (90%), diarrhea (73%), and nausea (62%). Grade 3 or 4 adverse events occurred in 54% of patients, most commonly pneumonia (10%), diarrhea (9%), rash (8%), and anemia (5%). Treatment-related grade 3 or higher adverse events occurred in 30%, and serious adverse events occurred in 40%. A total of four grade 5 adverse events occurred, although none were considered treatment-related. Grade 3 or higher adverse events occurred in 51% of patients receiving 160 to 220 mg and 65% receiving 300 mg. Treatment-related adverse events led to dose modification in 47% and 75% and treatment discontinuation in 2% and 8%, respectively. Confirmed objective response occurred in 31% of patients receiving 120 mg or less (95% confidence interval [CI], 14% to 52%), 34% receiving 160 to 220 mg (95% CI, 22% to 47%), and 37% receiving 300 mg (95% CI, 24% to 52%). Median response duration was 11.5 months, median progression-free survival was 8.3 months (95% CI, 4.0 to 12.5), and median overall survival was 16.0 months. These safety and efficacy findings supported selection of 200 mg for subsequent phase 3 evaluation.

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