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Clinical Trial
. 2025 Aug 9;406(10503):615-626.
doi: 10.1016/S0140-6736(25)00866-9.

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

Fabrice Barlesi  1 , Wenxiu Yao  2 , Michaël Duruisseaux  3 , Ludovic Doucet  4 , Aitor Azkárate Martínez  5 , Vanesa Gregorc  6 , Oscar Juan-Vidal  7 , Shun Lu  8 , Charlotte De Bondt  9 , Filippo de Marinis  10 , Helena Linardou  11 , Young-Chul Kim  12 , Robert Jotte  13 , Enriqueta Felip  14 , Giuseppe Lo Russo  15 , Martin Reck  16 , Mary F Michenzie  17 , Wenjing Yang  17 , Julie N Meade  17 , Beata Korytowsky  17 , Tony S K Mok  18 ; KRYSTAL-12 Investigators
Collaborators, Affiliations
Clinical Trial

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

Fabrice Barlesi et al. Lancet. .

Abstract

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.

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Conflict of interest statement

Declaration of interests FB reports personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, F. Hoffmann-La Roche, Lilly, Novartis, Merck, MSD, Pierre Fabre, Pfizer, and Takeda. MD reports consulting fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, F. Hoffmann-La Roche, Gamamabs Pharma, GSK, Guardant, MSD, Novartis, Pfizer, and Takeda; grants or contracts from Lilly; payment or honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, F. Hoffmann-La Roche, Guardant, MSD, Novartis, and Pfizer; and support for attending meetings or travel from F. Hoffmann-La Roche. LD reports payment or honoraria from Amgen; and support for attending meetings or travel from MSD. VG reports consulting fees from Bristol Myers Squibb, Pfizer, and Regeneron; payment for expert testimony from Boehringer Ingelheim, Pierre Fabre, and Regeneron; and support for travel from Genfleet and MSD. OJ-V reports payment or honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, F. Hoffmann-La Roche/Genentech, Johnson & Johnson, Lilly, Pfizer, and Takeda; and support for attending meetings or travel from AstraZeneca, F. Hoffmann-La Roche/Genentech, and Takeda. SL reports consulting fees from AstraZeneca, F. Hoffmann-La Roche, Hutchinson, and Simcere; independent director and member of Board for Innovent Biologics; participation on a Data Safety Monitoring Board or advisory board with Daiichi Sankyo, F. Hoffmann-La Roche, and Hengrui Therapeutics; payment or honoraria from AstraZeneca, F. Hoffmann-La Roche, Hansoh, and Hengrui Therapeutics; and research support from AstraZeneca, BeiGene, Bristol Myers Squibb, F, Hoffmann-La Roche, Hansoh, Hutchinson, and Hengrui Therapeutics. CDB reports consulting fees from Janssen; participation on a Data Safety Monitoring Board or advisory board with AstraZeneca, Janssen, and Merck; payment or honoraria from Medimix; and support for attending meetings or travel from Pfizer and Takeda. FdM reports consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, F. Hoffmann-La Roche, Johnson & Johnson, MSD, Pfizer, Pierre Fabre, and Regeneron. HL reports advisory board participation from Amgen, AstraZeneca, Bristol Myers Squibb, F. Hoffmann-La Roche, GSK, MSD, Novartis, and Pfizer; International Education Committee with Pfizer; personal fees for lectures from Amgen, AstraZeneca, Bristol Myers Squibb, F. Hoffmann-La Roche, MSD, Novartis, and Pfizer; personal support for attending meetings from F. Hoffmann-La Roche and Pfizer; principal investigator for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, F. Hoffmann-La Roche, GSK, Lilly, Mirati Therapeutics, a Bristol Myers Squibb company, MSD, and Novartis; speakers bureau with AstraZeneca; and an unpaid position in a non-profit organisation with ESMO Council (member), ESMO W40 Committee (Chair), Fairlife Lung Cancer Non-Profit Organisation (board member), Hellenic Cooperative Oncology Group (President of Scientific Committee and board member), and W40-Hellas non-profit organization (board member). Y-CK reports consulting fees from AstraZeneca, Boryung, Takeda, and Yuhan; and payment or honoraria from MSD. EF reports advisory role with AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, F. Hoffmann-La Roche, Gilead Sciences, GSK, iTeos Therapeutics, Janssen, Johnson & Johnson, MSD, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, and Turning Point Therapeutics; independent Member of the Board with Grifols; payment and honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Johnson & Johnson, Lilly, Medical Trends, MedScape, Merck Serono, MSD, Novartis, PeerVoice, Pfizer, Regeneron, Sanofi, Takeda, and Touch Oncology; and support for attending meetings or travel from AstraZeneca, F. Hoffmann-La Roche, and Janssen. GLR reports consulting fees and payments or honoraria from, principal investigator for, and participation on a Data Safety Monitoring Board or advisory board with Amgen, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, F. Hoffmann-La Roche, GSK, Johnson & Johnson, Lilly, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Regeneron, Sanofi, and Takeda; and support for attending meetings or travel from Amgen, Bristol Myers Squibb, F. Hoffmann-La Roche, and MSD. MR reports consulting fees, payment or honoraria, and support for attending meetings or travel from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, F. Hoffmann-La Roche, GSK, Janssen, Lilly, Merck, MSD, Mirati Therapeutics, a Bristol Myers Squibb company, Novartis, Pfizer, Regeneron, and Sanofi; and participation on a Data Safety Monitoring Board or advisory board with Daiichi Sankyo and Sanofi. MFM reports employment with Mirati Therapeutics, a Bristol Myers Squibb company, and Bristol Myers Squibb; and stock or stock options from Mirati Therapeutics, a Bristol Myers Squibb company. WYan reports employment with Mirati Therapeutics, a Bristol Myers Squibb company, and Bristol Myers Squibb. JNM reports employment with Mirati Therapeutics, a Bristol Myers Squibb company, and Bristol Myers Squibb; stock or stock options from Mirati Therapeutics, a Bristol Myers Squibb company; and support for attending meetings or travel from Mirati Therapeutics, a Bristol Myers Squibb company. BK reports stock or stock options from Mirati Therapeutics, a Bristol Myers Squibb company, Bristol Myers Squibb, and Pfizer. TSKM reports consulting fees from AbbVie, ACEA Pharma, Adagene, Alentis Therapeutics, Alpha Biopharma, Amgen, Amoy Diagnostics, AnHeart Therapeutics, AVEO Pharmaceuticals, Bayer, BeiGene, BerGenBio, Berry Oncology, Boehringer Ingelheim, Blueprint Medicines, Bridge Bio, Bristol Myers Squibb, Bowtie Life Insurance Company, Bridge Biotherapeutics, Covidien, C4 Therapeutics, Cirina, CStone Pharmaceuticals, Curio Science, D3 Bio, Da Volterra, Daiichi Sankyo, Eisai, Elevation Oncology, Erasca, F. Hoffmann-La Roche/Genentech, Fishawack Facilitate, G1 Therapeutics, geneDecode Co, Gilead Sciences, GLG's Healthcare, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, HiberCell, HutchMed, Ignyta, Illumina, Imagene AI, Incyte, Inivata, InxMed (Hong Kong), IQVIA, Janssen, Lakeshore Biotech, Lilly, Lunit, Loxo-Oncology, Lucence Health, Medscape/WebMD, Medtronic, Merck Serono, Mirati Therapeutics, a Bristol Myers Squibb company, MiRXES, MoreHealth, MSD, Novartis, Novocure, Ningbo NewBay Technology Development, Omega Therapeutics, OrigiMed, OSE Immunotherapeutics, PeerVoice, Phanes Therapeutics, Pfizer, PriME Oncology, Prenetics Global, Puma Biotechnology, Qiming Development (HK), Regen Medtech Holding, Regeneron Pharmaceuticals, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Schrödinger, Seagen International, SFJ Pharmaceutical, Simcere of America, Synergy Research, Summit Therapeutics Sub, Takeda, Tigermed, Vertex Pharmaceuticals, Virtus Medical Group, XENCOR, and Yuhan; grants or contracts (paid to institution) from AstraZeneca, Bristol Myers Squibb, F. Hoffmann-La Roche, G1 Therapeutics, Merck Serono, MSD, Novartis, Pfizer, SFJ Pharmaceutical, Takeda, and XCovery; leadership or fiduciary role in board, society, committee, or advocacy group with AstraZeneca, Aurora, Epoch Biosciences, HutchMed, and Insighta; participation of a Data Safety Monitoring Board or advisory board with AbbVie, ACEA Pharma, Amgen, AstraZeneca, Alentis Therapeutics, BerGenBio, Berry Oncology, Blueprint Medicines, Boehringer Ingelheim, Bowtie Life Insurance, Bristol Myers Squibb, C4 Therapeutics, Covidien, CStone Pharmaceuticals, Curio Science, D3 Bio, Daiichi Sankyo, Eisai, Erasca, F. Hoffmann-La Roche/Genentech, Fishawack Facilitate, G1 Therapeutics, Gilead Sciences, Gritstone Oncology, Guardant Health, geneDecode, Hengrui Therapeutics, HutchMed, Ignyta, Incyte, Imagene AI, Inivata, IQVIA, Janssen, LakeShore Biopharma, Lilly, Loxo-Oncology, Lumit, Merck Serono, Mirati Therapeutics, a Bristol Myers Squibb company, MiREXES, MSD, Novartis, OrigiMed, Phanes Therapeutics, Pfizer, Prenetics Global, Puma Biotechnology, Regeneron Pharmaceuticals, Sanofi-Aventis, SFJ Pharmaceuticals, Simcere of America, Simcere Zaiming, Takeda, Vertex Pharmaceuticals, Virtus Medical Group, DENCOR, and Yuhan; payment or honoraria from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Daz Group, Fishawack Facilitate, InMed Medical Communication, Janssen, Jiahui, LiangYiHui Healthcare, Lilly, Lucence Health, MD Health Brazil, Medscape, Merck Pharmaceuticals HK, MiRXES, MSD, Novartis, OrigiMed, P Permanyer, PeerVoice, Physicians' Education Resource, Pfizer, PriME Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostics, Foundation One, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting, Taiho Pharmaceutical, Takeda Oncology, and Touch Independent Medical Education; stock or stock options with Alentis Therapeutics, AstraZeneca, Aurora, Biolidics, Bowtie Life Insurance, D3 Bio, Epoch Biosciences, HutchMed, Insighta, LakeShore Biopharma, Loxo-Oncology, Lunit, Phanes Therapeutics, Prenetics, Virtus Medical Group, and Yinson Capital; and support for attending meetings or travel from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, F. Hoffmann-La Roche, LiangYiHui, MiRXES, MSD, Novartis, Pfizer, and ZaiLab. All other authors declare no competing interests.

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