Adagrasib versus docetaxel in KRASG12C-mutated non-small-cell lung cancer (KRYSTAL-12): a randomised, open-label, phase 3 trial

Author(s): Prof Fabrice Barlesi, MD PhD^a,b; Prof Wenxiu Yao, MD^c; Michaël Duruisseaux, MD PhD^d,e,f; Ludovic Doucet, MD^g; Aitor Azkárate Martínez, MD^h; Vanesa Gregorc, MDⁱ; Prof Oscar Juan-Vidal, MD PhD^j; Prof Shun Lu, MD PhD^k; Charlotte De Bondt, MD^l,*; Prof Filippo de Marinis, MD^m; Helena Linardou, MD PhDⁿ; Prof Young-Chul Kim, MD PhD^o; Robert Jotte, MD PhD^p; Prof Enriqueta Felip, MD PhD^q; Giuseppe Lo Russo, MD PhD^r; Prof Martin Reck, MD PhD^s; Mary F Michenzie, MSHS^t; Wenjing Yang, PhDt^*; Julie N Meade, MDt^*; Beata Korytowsky, MAt^*; Prof Tony S K Mok, MDu tony@clo.cuhk.edu.hk for the KRYSTAL-12 Investigators^†

Source: Volume 406, Issue 10503

Dr. Maen Hussein's Thoughts

Adagrasib demonstrated a median progression-free survival (PFS) of 5.5 months compared to 3.8 months with docetaxel in patients with KRAS G12C-mutated tumors. Treatment-related adverse events occurred in 47% of patients receiving Adagrasib and 46% in the docetaxel group. In my experience, Adagrasib is also more tolerable, making it a favorable option for this patient population.

BACKGROUND

Adagrasib is a KRASG12C inhibitor that demonstrated promising activity against KRASG12C-mutated advanced non-small-cell lung cancer (NSCLC) in a phase 2 trial. Here we aimed to compare the efficacy and safety of adagrasib versus docetaxel in patients with KRASG12C-mutated advanced NSCLC previously treated with chemotherapy and immunotherapy.

METHODS

KRYSTAL-12 is a randomised, multicentre, open-label, phase 3 trial conducted at 230 centres in 22 countries. Patients with Kirsten rat sarcoma viral oncogene homologue (KRAS)G12C-mutated locally advanced or metastatic NSCLC, who had previously received both platinum-based chemotherapy and anti-programmed cell death protein 1 or anti-programmed death ligand 1 therapy, were randomly allocated in a 2:1 ratio to receive 600 mg adagrasib (twice a day orally) or 75 mg/m2 docetaxel (every 3 weeks intravenously) using a centralised interactive web response system. Randomisation was stratified by region (non-Asia–Pacific vs Asia–Pacific) and previous treatment (sequential vs concurrent chemotherapy or immunotherapy). Treatment continued until disease progression, unacceptable toxicity, investigator or patient decision, or death. The primary endpoint was progression-free survival assessed by blinded independent central review in all randomised patients (intention-to-treat [ITT] population). Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov (NCT04685135), and is active but no longer recruiting.

FINDINGS

Between Feb 23, 2021, and Nov 16, 2023, 453 patients were randomly allocated to receive adagrasib (301 [66%]) or docetaxel (152 [34%]). In each group, 298 (99%) patients received adagrasib and 140 (92%) received docetaxel. In the ITT population (median follow-up 7·2 months [95% CI 5·8–8·7]), median progression-free survival was 5·5 months (95% CI 4·5–6·7) with adagrasib and 3·8 months (95% CI 2·7–4·7) with docetaxel (hazard ratio 0·58 [95% CI 0·45–0·76]; p<0·0001). Grade 3 and above treatment-related adverse events occurred in 140 (47%) of 298 patients treated with adagrasib and 64 (46%) of 140 with docetaxel. There were four (1%) treatment-related deaths in the adagrasib group and one (1%) treatment-related death in the docetaxel group.

INTERPRETATION

Adagrasib demonstrated a statistically significant improvement in progression-free survival over docetaxel in patients with previously treated KRASG12C-mutated NSCLC, without new safety signals.

FUNDING

Mirati Therapeutics, a Bristol Myers Squibb company.

Author Affiliations

^aGustave Roussy, Villejuif, France; ^bParis Saclay University, Le Kremlin-Bicêtre, France; ^cSichuan Cancer Hospital & Institute, Chengdu, China; ^dRespiratory Department and Early Phase (EPSILYON), Louis Pradel Hospital, Hospices Civils de Lyon Cancer Institute, Lyon, France; ^eCancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Lyon, France

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