Divarasib Outperforms Approved KRAS G12C Inhibitors in Previously Treated NSCLC
Krascendo 1 (NCT06497556) is a global, randomized, open-label Phase III study evaluating oral divarasib against investigator’s choice of sotorasib or adagrasib in patients with previously treated, locally advanced or metastatic KRAS G12C-mutated NSCLC. A total of 338 patients were randomized to receive divarasib 400 mg once daily (n=167) or a comparator KRAS G12C inhibitor (n=171); sotorasib, (n=156), or adagrasib, (n=15). Eligible patients had received prior systemic treatment that included platinum-based chemotherapy and PD-1/PD-L1 inhibitor therapy. The primary endpoint was PFS assessed by blinded independent central review (BICR), with OS, objective response rate (ORR), duration of response (DoR), patient-reported outcomes and safety among the secondary endpoints. The primary analysis was based on a median follow-up of 14.3 months, with a data cutoff of May 19, 2026.
|
Key Efficacy and Safety Highlights | |||
|
Category |
Parameter |
Divarasib (n=167) |
Sotorasib or Adagrasib (n=171) |
|
Efficacy |
Median follow-up |
14.3 months |
14.3 months |
|
Median OS |
25.9 months |
17.4 months | |
|
Median PFS by BICR |
9.8 months |
5.7 months | |
|
PFS hazard ratio |
0.58 |
Comparator arm | |
|
PFS statistical significance |
p<0.0001 |
— | |
|
PFS rate at 12 months |
43.9% |
24% | |
|
Median OS |
17.7 months |
12.0 months | |
|
OS hazard ratio |
0.56 |
Comparator arm | |
|
OS statistical significance |
p=0.0005 | ||
|
Confirmed ORR |
58.4% |
32.3% | |
|
Safety |
Median duration of response |
11.9 months |
6.9 months |
|
Grade 3–4 treatment-related adverse events |
24.6% |
34.5% | |
|
Serious treatment-related adverse events |
7.8% |
15.2% | |
|
Treatment-related adverse events leading to discontinuation |
4.8% |
11.7% | |
|
Median treatment duration |
11.3 months |
5.0 months | |
Conclusion
The Phase III Krascendo 1 results establish a potentially important advance in the treatment of previously treated KRAS G12C-mutated advanced NSCLC. Divarasib significantly improved both PFS and OS compared with sotorasib or adagrasib, while nearly doubling the confirmed response rate and reducing treatment-related adverse events leading to discontinuation. The direct comparison with approved therapies makes these findings particularly relevant to treatment sequencing in this molecularly defined population. Nevertheless, divarasib remains investigational, and regulatory review will determine whether these results translate into a new standard treatment option. If approved, divarasib could represent a meaningful next-generation advance for patients whose disease progresses despite existing KRAS G12C-directed therapies.