02908nam a2200301   4500001000800000005001700008007000300025008004100028040000800069041000800077100002900085245007800114300002500192520200800217650001302225650004202238650002402280650001802304650001602322650002302338700001702361700002902378700002202407700002502429700002502454700002402479773010302503ESSALUD20260903144909.0ta      t        pe ||||| |||| 00| 0 spa d  aBMG  aeng  aWolpin, Brian M. eAutor  aDaraxonrasib in previously treated advanced RAS-Mutated pancreatic Cancer  apáginas: 1790-1802  aBackground: Current therapies for patients with pancreatic ductal adenocarcinoma (PDAC) provide modest benefit. Activating RAS mutations occur in more than 90% of PDAC tumors. Daraxonrasib (RMC-6236) is an oral RAS(ON) multiselective inhibitor that targets guanosine triphosphate–bound mutant and wild-type RAS. Methods: In this phase 1–2 study, we evaluated daraxonrasib in patients with advanced solid tumors with activating RAS mutations. Patients received 10 to 400 mg of daraxonrasib orally once daily; 300 mg was selected as the phase 3 dose. The primary end point was safety. Pharmacokinetics and antitumor activity were secondary end points. This report focuses on the 168 study patients with previously treated RAS-mutated PDAC. Results: Among the 168 patients with PDAC who received daraxonrasib at a dose of 300 mg or less, treatment-related adverse events of any grade were reported in 96%; such events of grade 3 or higher were reported in 30%. Treatment-related adverse events that occurred in at least 10% of the patients included rash, diarrhea, nausea, stomatitis or mucositis, vomiting, and fatigue. In a subgroup of 26 patients with RAS G12 mutations who were treated with second-line daraxonrasib at a dose of 300 mg, an objective response to therapy was reported in 35% (95% confidence interval [CI], 17 to 56). The median duration of response was 8.2 months (95% CI, 3.8 to not evaluable), with median values of 8.5 months for progression-free survival and 13.1 months for overall survival. Among the 38 patients with RAS G12, G13, or Q61 mutations, 29% (95% CI, 15 to 46) had an objective response. The median duration of response was 8.2 months (95% CI, 3.8 to 8.8), with median values of 8.1 months for progression-free survival and 15.6 months for overall survival. Conclusions: Daraxonrasib was associated with treatment-related adverse events of grade 3 or higher in one third of patients with previously treated RAS-mutated PDAC; antitumor activity was also reported. 

  aCÁNCER  aCÁNCER DEL TRACTO GASTROINTESTINAL   aGASTROENTEROLOGÍA  aHEMATOLOGÍA  aONCOLOGÍA  aGENÉTICA GENERAL  aPark, Wungki  aGarrido-Laguna, Ignacio   aSpira, Alexander   aStarodub, Alexander   aSommerhalder, David   aPunekar, Salman R. 0 022717dMassachusetts NEJM GroupoNEJM015tThe New England Journal of Medicine wESSALUDx0028-4793