A pan-RAS inhibitor reaches the clinic, and risk-stratified myeloma therapy holds at five years

The edition in brief

In a phase 1-2 dose-escalation and expansion study, 136 patients with previously treated advanced RAS-mutant non-small-cell lung cancer received daraxonrasib, an oral multiselective inhibitor of GTP-bound mutant and wild-type RAS, at 300 mg daily or less. Objective response was 31% at doses of 120 mg or less, 34% at 160 to 220 mg and 37% at 300 mg. Adverse events of any grade affected 99% and grade 3 or higher 54%, with pneumonia in 10% and four grade 5 events. The five-year OPTIMUM/MUKnine follow-up compared 107 patients with high-risk myeloma given intensified induction, extended consolidation and maintenance around autologous transplant with 120 genetically matched controls from Myeloma XI. At a median 71.1 months, median progression-free survival was not reached against 24.4 months (hazard ratio 0.32, 95% CI 0.22 to 0.45) and overall survival not reached against 57.4 months (HR 0.43, 0.28 to 0.65). Benefit was consistent except in patients with three or more high-risk cytogenetic abnormalities. A secondary analysis of 4,262 APHINITY tumour samples found manual stromal tumour-infiltrating lymphocyte scoring reproducible (intraclass correlation 0.84), with the largest six-year absolute pertuzumab benefit — 12.1 percentage points — in node-positive tumours scoring at least 70%. In KRAS G12C colorectal cancer, adding a focal adhesion kinase inhibitor to garsorasib raised response from 16.7% to 38.9%, a difference that did not reach significance in 36 patients. In 414,016 older patients with lung cancer, wildfire-derived fine particulate carried more risk per microgram than other PM2.5.