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Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial
Open accessAbstract
Background Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRAS G12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRAS G12C mutation who had been previously treated with other anticancer drugs.Methods We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRAS G12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRAS G12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRAS G12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m 2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting.Findings Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4-20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months [95% CI 4·3-7·8] vs 4·5 months [3·0-5·7]; hazard ratio 0·66 [0·51-0·86]; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34 [23%]). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%]).Interpretation Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRAS G12C mutation and who had been previously treated with other anticancer drugs.Funding Amgen.
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“Clinical trials of multiple KRASG12C inhibitors have shown promising efficacy in advanced, previously treated non–small cell lung cancer (NSCLC), leading to United States Food and Drug Administration (FDA) accelerated approval of two of these therapies (adagrasib and sotorasib) and many others being investigated in this setting (9–17).”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [15]
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“For example, sotorasib, adagrasib, and divarasib monotherapies have demonstrated objective response rates ranging from 7.1% to 53.4% and median progression-free survival of 4.0-13.1 months, 13-20”
From Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer (2024) · cites this paper as [15]
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“This is further supported by a numerically higher ORR seen with divarasib in patients with non-small cell lung cancer (56.4%) compared with sotorasib (37% in a phase 2 trial and 28% in a phase 3 trial) and adagrasib (43% in a phase 2 trial)11,23–25.”
From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [23]
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“while median overall survival was not improved with sotorasib compared with docetaxel (10.6 vs. 11.3 months; HR, 1.01) [25]”
From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [25]
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“In the randomized phase III CodeBreaK 200 trial, sotorasib significantly improved progression-free survival compared with docetaxel in previously treated KRAS G12C-mutant NSCLC (median PFS, 5.6 vs. 4.5 months; HR, 0.66).”
From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [25]
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“In addition, some patients selected for these trials may have preexisting multidrug resistance (9, 37, 74), which could contribute to treatment failure.”
From SRC kinase drives multidrug resistance induced by KRAS-G12C inhibition (2024) · cites this paper as [74]
Experimental — accuracy not yet measuredIn the citing paper
“Despite this success, disease progression occurs in many patients4,5,7, with development of resistance to KRASG12Ci recapitulated in preclinical studies9–11.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [5]
In the citing paper
“Multiple mechanisms of intrinsic and acquired resistance (10,12,13), have been identified; hence, drug combinations will likely be needed to maximize the clinical efficacy of G12Cis (and probably other, emerging KRAS inhibitors) in NSCLC and other diseases.”
From Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy (2023) · cites this paper as [13]
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Metadata
- Authors
- de Langen, A. J., Johnson, M. L., Mazieres, J., Dingemans, A.-M. C., Mountzios, G., Pless, M., Wolf, J., Schuler, M., Lena, H., Skoulidis, F., Yoneshima, Y., Kim, S.-W., Linardou, H., Novello, S., van der Wekken, A. J., Chen, Y., Peters, S., Felip, E., Solomon, B. J., Ramalingam, S. S., Dooms, C., Lindsay, C. R., Ferreira, C. G., Blais, N., Obiozor, C. C., Wang, Y., Mehta, B., Varrieur, T., Ngarmchamnanrith, G., Stollenwerk, B., Waterhouse, D., & Paz-Ares, L.
- Affiliations
- Sarah Cannon (US)
- Erasmus MC (NL)
- Henry Dunant Hospital (GR)
- Kantonsspital Winterthur (CH)
- University Hospital Cologne (DE)
- The University of Texas MD Anderson Cancer Center (US)
- Kyushu University Hospital (JP)
- Asan Medical Center (KR)
- Metropolitan Hospital (GR)
- Ospedale San Luigi Gonzaga (IT)
- Centre Hospitalier Universitaire Vaudois (CH)
- Vall d'Hebron Hospital Universitari (ES)
- Peter MacCallum Cancer Centre (AU)
- Emory University (US)
- KU Leuven (BE)
- University of Manchester (GB)
- Centre Hospitalier de l’Université de Montréal (CA)
- Amgen (United States) (US)
- Amgen (Switzerland) (CH)
- Oncology Hematology Care (US)
- Universidad Complutense de Madrid (ES)
- Corresponding author
- Paz-Ares, Luis
- ORCID
- Johnson, Melissa L
- Dingemans, Anne-Marie C
- Mountzios, Giannis
- Pless, Miklos
- Wolf, Jürgen
- Skoulidis, Ferdinandos
- Yoneshima, Yasuto
- Kim, Sang-We
- Linardou, Helena
- Novello, Silvia
- Chen, Yuanbin
- Peters, Solange
- Felip, Enriqueta
- Solomon, Benjamin J
- Ramalingam, Suresh S.
- Dooms, Christophe
- Lindsay, Colin R
- Ferreira, Carlos Gil
- Blais, Normand
- Wang, Yang
- Stollenwerk, Björn
- Waterhouse, David
- Paz-Ares, Luis
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2023-03
- Volume
- 401
- Issue
- 10378
- Pages
- 733-746
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W4319337483
- Cited by
- 619
- References
- 29
- Citations by year
- 2026: 146 · 2025: 196 · 2024: 196 · 2023: 81
- FWCI
- 113.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- HAL (submittedVersion)
- IRIS (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- SERVAL (Université de Lausanne) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Amgen
- Amgen Inc San Francisco
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- sotorasib, docetaxel, KRAS G12C mutation, non-small cell lung cancer, KRAS inhibitors, progression-free survival, second-line therapy, previously treated advanced NSCLC, central nervous system metastasis, treatment safety, oral versus intravenous administration, head-to-head comparison
- MeSH terms
- Docetaxel, Adolescent, Adult, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Piperazines, Pyridines, Pyrimidines, Proto-Oncogene Proteins p21(ras), Disease-Free Survival
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