Table 1.
Similarities and differences among sotorasib and adagrasib (direct KRAS G12C inhibitors).
| Compound | Sotorasib (AMG 510) | Adagrasib (MRTX 849) |
|---|---|---|
| Mode of action and target | Covalent allosteric inhibitor KRAS G12C (OFF) | Covalent allosteric inhibitor KRAS G12C (OFF) |
| KRAS-GTP loading inhibition (IC50 value) | 47.9 nM | 89.9 nM |
| RP2D | 960mg QD | 600mg BID |
| Half-life | 5.5 hours | 24.7 hours |
| Study | Phase I/II study (CodeBreak 100; NCT03600883) in pretreated KRAS G12C mt solid tumors | Phase I/II study (KRYSTAL-1; NCT03785249) in pretreated KRAS G12C mt solid tumors |
| N | 124 evaluable patients with advanced NSCLC KRAS G12C mt | 51 evaluable patients |
| ORR | 37.1% | 45% |
| DCR | 80.6% | 96% |
| mPFS | 6.8 months | — |
| mOS | 12.5 months | — |
| Safety (TRAEs) | Any grade 69.8% | Any grade 85% |
| G3 19.8%. | G3-4 30% | |
| Most common any grade TRAEs: Diarrhea (31.7%), nausea (19%) and ALT/AST increased (15.1%) | Most common G3-4 TRAEs: fatigue (6%) and AST/ALT (5%) increased. | |
| Intracraneal activity | Patients with active brain metastases were ineligible | Adagrasib can penetrate the brain and cerebrospinal fluid (preclinical data) and has demonstrated antitumor activity against brain metastases (clinical data). |