Adagrasib Boosts PFS, Responses vs Docetaxel in KRAS G12C+ NSCLC

"Despite the current absence of overall survival data, these results reinforce adagrasib as an efficacious treatment option for patients with KRAS G12C-mutated advanced NSCLC after disease progression on previous chemotherapy and immunotherapy," according to the study authors.

Treatment with adagrasib (Krazati) significantly prolonged progression-free survival (PFS) and improved responses compared with docetaxel among patients with previously treated KRAS G12C-mutant non–small cell lung cancer (NSCLC), according to findings from the phase 3 KRYSTAL-12 trial (NCT04685135) published in The Lancet.¹

After a median follow-up of 7.2 months (95% CI, 5.8-8.7), data showed a median PFS of 5.5 months (95% CI, 4.5-6.7) with adagrasib vs 3.8 months (95% CI, 2.7-4.7) with docetaxel based on blinded independent central review (BICR; HR, 0.58; 95% CI, 0.45-0.76; P <.0001). Adagrasib improved PFS across all patient subgroups, which included those with brain metastases at baseline.

The objective response rate (ORR) was 32% (95% CI, 26.7%-37.5%) in the adagrasib arm vs 9% (95% CI, 5.1%-15.0%) in the docetaxel arm (OR, 4.68; 95% CI, 2.56-8.56; P <.0001), and the disease control rate (DCR) was 78% vs 59% in each arm. The median duration of response (DOR) was 8.3 months (95% CI, 6.1-10.4) with adagrasib vs 5.4 months (95% CI, 2.9-8.5) with docetaxel.

Among patients with measurable or non-measurable baseline brain metastases in the adagrasib arm (n = 78) and docetaxel arm (n = 36), the intracranial ORRs were 24% (95% CI, 15.3%-35.4%) vs 11% (95% CI, 3.1%-26.1%), respectively. Additionally, intracranial disease control occurred in 82% and 56% of patients in each arm. The median intracranial time to progression was 18.6 months (95% CI, 9.6-not evaluable [NE]) with adagrasib and NE (95% CI, 4.2-NE) with docetaxel (HR, 0.60; 95% CI, 0.26-1.40). Data showed an HR of 0.93 (95% CI, 0.50-1.73) for intracranial PFS.

“[A]dagrasib significantly improved [PFS] and [ORR] compared with docetaxel, confirming the initial results from KRYSTAL-1 [NCT03785249] that supported the accelerated or conditional approval of adagrasib for patients with previously treated KRAS G12C-mutated advanced NSCLC,” lead study author Fabrice Barlesi, MD, PhD, a professor from Gustave Roussy in Villejuif, France, and Paris Saclay University in Le Kremlin-Bicêtre, France, wrote with coauthors in the publication.^1,2 “The safety profile of adagrasib was manageable and consistent with previous reports. Despite the current absence of overall survival [OS] data, these results reinforce adagrasib as an efficacious treatment option for patients with KRAS G12C-mutated advanced NSCLC after disease progression on previous chemotherapy and immunotherapy.”

The FDA previously granted accelerated approval to adagrasib as a treatment for this NSCLC population in December 2022 based on data from the single-arm phase 2 KRYSTAL-1 trial.² At the time of the approval, adagrasib demonstrated a confirmed ORR of 43% (95% CI, 34%-53%) and a median DOR of 8.5 months (95% CI, 6.2-13.8) among 112 evaluable patients.

In the open-label KRYSTAL-12 trial, 453 patients were randomly assigned 2:1 to receive adagrasib at 600 mg orally twice a day (n = 301) or docetaxel at 75 mg/m² every 3 weeks intravenously (n = 152).

The trial’s primary end point was PFS per BICR across the intent-to-treat population. Secondary end points included ORR per RECIST v1.1 criteria, DOR, OS, 1-year OS rate, patient-reported outcomes, and safety.

Patients with locally advanced or metastatic NSCLC harboring a KRAS G12C mutation, prior treatment with a platinum-containing chemotherapy regimen plus an anti–PD-(L)1 agent, measurable lesions per RECIST v1.1 guidelines, and an ECOG performance status of 0 or 1 were eligible for study entry. Those with active brain metastases were ineligible to enroll.

The median age was 64.0 years (IQR, 59.0-69.0) in the adagrasib arm and 65.0 years (IQR, 59.0-69.5) in the docetaxel arm, and most patients in each arm were male (64% vs 72%) and White (45% vs 53%). Additionally, most patients in each respective group had an ECOG performance status of 1 (68% vs 68%), metastatic disease (94% vs 95%), adenocarcinoma (94% vs 97%), current or former smoking status (94% vs 93%), and 1 prior line of treatment in the advanced or metastatic setting (68% vs 72%).

Based on the Lung Cancer Symptom Scale (LCSS), patients who received adagrasib experienced a longer median time to deterioration at 3.0 months (95% CI, 2.7-4.1) vs 1.5 months (95% CI, 1.3-1.9) in the docetaxel arm (HR, 0.57; 95% CI, 0.45-0.74).

Treatment-related adverse effects (TRAEs) of any grade affected 94% of the adagrasib arm vs 86% of the docetaxel arm; 47% and 46% in each arm experienced grade 3 or higher toxicities. In the adagrasib and docetaxel arms, respectively, TRAEs led to dose reduction in 48% vs 24%, dose interruption in 59% vs 19%, and treatment discontinuation in 8% vs 14%.

The most common grade 3 or higher TRAEs in the adagrasib arm included increased alanine aminotransferase (8%), increased aspartate aminotransferase (6%), and diarrhea (5%). Four patients in the adagrasib arm experienced treatment-related deaths, including 1 instance each due to epilepsy, hepatic failure, hepatic ischemia, and an unknown cause.

References

1. Barlesi F, Yao W, Duruisseaux M, et al. Adagrasib versus docetaxel in KRASG12C-mutated non-small-cell lung cancer (KRYSTAL-12): a randomised, open-label, phase 3 trial. Lancet. 2025;406(10503):615-626. doi:10.1016/S0140-6736(25)00866-9
2. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. News release. FDA. December 12, 2022. Accessed August 12, 2025. https://bit.ly/3UUVphS