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Cited by 619Lung Cancer Treatments and MutationsLung Cancer Diagnosis and TreatmentLung Cancer Research Studies

The DOI matches its Crossref record; 29 of the 29 references it cites were found in a registry or an index.

Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial

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de Langen, Adrianus Johannes, Johnson, Melissa L, Mazieres, Julien, Dingemans, Anne-Marie C, Mountzios, Giannis, Pless, Miklos, Wolf, Jürgen, Schuler, Martin, Lena, Hervé, Skoulidis, Ferdinandos, Yoneshima, Yasuto, Kim, Sang-We, Linardou, Helena, Novello, Silvia, van der Wekken, Anthonie J, Chen, Yuanbin, Peters, Solange, Felip, Enriqueta, Solomon, Benjamin J, Ramalingam, Suresh S., Dooms, Christophe, Lindsay, Colin R, Ferreira, Carlos Gil, Blais, Normand, Obiozor, Cynthia C, Wang, Yang, Mehta, Bhakti, Varrieur, Tracy, Ngarmchamnanrith, Gataree, Stollenwerk, Björn, Waterhouse, David, Paz-Ares, Luis·2023·The Lancet
DOI 10.1016/s0140-6736(23)00221-0
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Abstract

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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  1. Awad, 2022, Sotorasib in advanced KRAS p.G12C-mutated non-small cell lung cancer (NSCLC): safety and efficacy data from the global expanded access program (EAP), Ann Oncol, 33, S448

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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
Venue
The Lancet
Publisher
Elsevier BV
Published
2023-03
Volume
401
Issue
10378
Pages
733-746
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
DOI
10.1016/s0140-6736(23)00221-0
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
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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