Adagrasib has shown superior efficacy compared to docetaxel in patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC) who have previously undergone platinum-based chemotherapy and anti-PD1 or anti-PDL1 therapy. The Phase 3 KRYSTAL-12 trial demonstrated significant improvements in progression-free survival (PFS) and objective response rate (ORR) with adagrasib, highlighting its potential as a second-line treatment option. These findings, presented at the ASCO Annual Meeting 2024, mark a significant advancement in the treatment landscape for this specific NSCLC subgroup.
KRYSTAL-12 Trial Results
The KRYSTAL-12 trial (NCT04685135) randomized 453 patients in a 2:1 ratio to either oral adagrasib (600 mg twice daily) or IV docetaxel (75mg/m2 once every three weeks). The study focused on patients with locally advanced or metastatic NSCLC harboring the KRAS G12C mutation who had previously been treated with platinum-based chemotherapy and anti-PD1/PD-L1 therapy.
The median PFS (mPFS) was significantly longer with adagrasib at 5.49 months compared to 3.84 months with docetaxel (HR: 0.58, 95% CI: 0.45-0.76, P<0.0001). The ORR was also significantly improved with adagrasib (31.9%, 95% CI: 2.56-8.56) compared to docetaxel (9.2%, 95% CI: 5.1-15), with an odds ratio (OR) of 4.68 (95% CI: 2.56-8.56, P<0.0001).
Intracranial Activity
Notably, adagrasib demonstrated promising intracranial activity. The intracranial ORR was higher with adagrasib (24%, 19/78) than with docetaxel (11%, 4/36). Specifically, in the CNS evaluable population, defined as patients with at least one CNS target lesion at baseline and at least one post-baseline CNS tumor assessment, the intracranial ORR with adagrasib was 40% (10/25) compared to 11% (1/9) with docetaxel. This is particularly significant as neurological symptoms can greatly impact a patient’s quality of life.
Comparison with Sotorasib
Adagrasib is not the first KRASG12C inhibitor to be approved for NSCLC; sotorasib received FDA approval in May 2021. Both drugs selectively and irreversibly bind to the cysteine 12 in the S-IIP of KRAS protein, locking the protein in an inactive state. While both agents have shown efficacy, cross-trial comparisons suggest potential differences.
In the CodeBreaK 200 trial, sotorasib showed an mPFS of 5.6 months compared to 4.5 months for docetaxel (HR 0.66, 95% CI: 0.51-0.86, P=0.0017). The ORR was 28.1% for sotorasib versus 13.2% for docetaxel (P<0.001). Although both KRYSTAL-12 and CodeBreaK 200 demonstrated statistically significant improvements in mPFS and ORR compared to docetaxel, the numerical differences suggest adagrasib may offer a slightly more pronounced benefit in prolonging PFS and inducing overall response. However, caution should be exercised when performing cross-trial comparisons.
Safety Profile
The safety profiles of adagrasib and docetaxel were consistent with previous reports, with no new safety signals identified in the KRYSTAL-12 trial. Treatment discontinuation due to treatment-related adverse events (TRAEs) was similar between adagrasib and sotorasib. The most frequent TRAEs of both adagrasib and sotorasib included diarrhea and increased ALT and AST levels, whereas with docetaxel, neutropenia, fatigue, and febrile neutropenia were more common.
Emerging KRASG12C Inhibitors
Several other KRASG12C inhibitors are under development, including JDQ443, divarasib (GDC-6036), olomorasib (LY3537982), garsorasib (D-1553), and BI 1823911. These agents demonstrate encouraging antitumor activity and safety profiles, but have not yet been directly compared to docetaxel in the second-line setting. Additionally, data on CNS metastasis is lacking for many of these inhibitors, making adagrasib a more favorable option for patients with brain metastases.
Future Directions
Given the promising results of KRYSTAL-12, adagrasib is being evaluated as a first-line treatment in combination with pembrolizumab in the KRYSTAL-7 trial (NCT04613596). Preliminary data from the Phase II cohort showed that in patients with PD-L1 TPS ≥50%, the combination achieved an ORR of 63% and a disease control rate of 84%. A Phase III trial is planned to randomize patients with KRAS G12C-mutated NSCLC and TPS ≥50% to receive either a combination of adagrasib and pembrolizumab, or pembrolizumab alone in the first-line setting.
Conclusion
The KRYSTAL-12 trial confirms adagrasib's efficacy in improving PFS and ORR compared to docetaxel in previously treated KRAS G12C-mutated NSCLC. Its notable activity against CNS metastases further underscores its clinical significance. Ongoing studies are exploring adagrasib’s potential as a first-line therapy, which could further expand its role in the treatment of advanced NSCLC.
