Results of the phase III KRYSTAL-12 trial demonstrate a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with adagrasib (ADA) compared to docetaxel in patients with previously-treated non-small cell lung cancer (NSCLC) harbouring a KRASG12C mutation. ADA also outperformed docetaxel in terms of response rate and induced deep and durable responses together with intracranial efficacy in patients with brain metastases at baseline.
ADA is a potent covalent inhibitor of KRASG12C with several favourable properties, including a long half-life, dose-dependent pharmacokinetics, and the potential to penetrate the blood-brain barrier. In the phase 1/2 KRYSTAL-1 trial, ADA demonstrated deep and durable responses leading to a promising PFS and overall survival (OS) in patients with previously treated KRASG12C-mutated NSCLC. In an attempt to confirm and strengthen these findings, the randomised, phase III KRYSTAL-12 study compared ADA to docetaxel in patients with KRASG12C-mutated locally advanced or metastatic NSCLC who had previously received a platinum-based chemotherapy, concurrently or sequentially with anti-PD-(L)1 therapy.
KRYSTAL-12 randomly (2:1) assigned 453 patients with KRASG12C-mutated locally advanced or metastatic NSCLC who were previously treated with platinum-based chemotherapy and anti-PD-(L)1 therapy, to receive ADA (600 mg BID orally) or docetaxel (75 mg/m2 q3w IV). Patients in the control arm were offered the chance to crossover to ADA upon disease progression. The primary endpoint of the study was PFS assessed per blinded independent central review (BICR), with objective response rate (ORR), duration of response (DoR), OS, and safety as key secondary objectives.
The median age of the patients in the study was 64 years and about 95% had metastatic disease. Brain metastases were present at baseline in 17% in the ADA arm and 18% in the docetaxel arm. About three quarters of patients in the study received concurrent chemo-immunotherapy (the remaining 25% received it sequentially). After a median follow-up of 9.4 months, ADA proved to be associated with a median PFS of 5.5 months, which was significantly better than the 3.8-month median PFS seen with docetaxel (HR[95CI]: 0.58[0.45-0.76]; p< 0.0001). At 6 months, 45% of patients in the ADA arm were alive and free of progression as compared to 30% in de docetaxel arm. This benefit in PFS was consistently seen across all investigated subgroups, irrespective of age, sex, smoking history, the presence of brain, liver or bone metastases and regardless of the level of PD-L1 expression. Similar findings were also seen for patients who received their prior chemo-immunotherapy sequentially or concurrently.
ADA induced a response in 32% of the patients, while this was only the case for 9% of patients in the docetaxel arm (OR[95%CI]: 4.68[2.56-8.56]; p< 0.0001). Furthermore, responses to ADA seemed to be more durable than with docetaxel, with a median DoR of 8.3 and 5.4 months, respectively. In the subgroup of patients with brain metastases at baseline, an intracranial response was obtained in 24% with ADA as compared to 11% with docetaxel. Corresponding intracranial disease control rates were 82% and 56%, respectively.
The incidence of grade ≥3 treatment-related adverse events (TRAEs) was similar with ADA and docetaxel at 47% and 46%, respectively. TRAEs led to dose reductions or interruptions in 48% and 59% of patients treated with ADA (vs. 24% and 19% with docetaxel). However, the rate of TRAEs leading to treatment discontinuation of ADA was low at 8% (vs. 14% with docetaxel). The most common TRAEs with ADA were diarrhoea (53% all grade, 5% grade ≥3), vomiting (35% all grade, 2% grade ≥3) and nausea (34% all grade, 3% grade ≥3).
Results of the phase III KRYSTAL-12 trial demonstrate a significantly better PFS with ADA compared to docetaxel in patients with advanced, KRASG12C-mutated NSCLC who were previously treated with chemo-immunotherapy (sequential or concurrent). ADA also induced a high rate of durable responses and displayed promising intracranial activity in patients with baseline brain metastases. The safety profile of ADA was consistent with previous reports. As such, these results reinforce ADA as an effective treatment option for patients with KRASG12C-mutated NSCLC who progressed on prior chemotherapy and immunotherapy. A phase III trial comparing ADA plus pembrolizumab to pembrolizumab alone in patients with previously untreated KRASG12C-mutated NSCLC and a PD-L1 expression level of ≥50% is currently enrolling patients (KRYSTAL-7).
Reference
Mok T, et al. KRYSTAL-12: Phase 3 study of adagrasib versus docetaxel in patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Presented at ASCO 2024; Abstract LBA8509.
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