FDA Approval Summary: Sotorasib for KRAS G12C -Mutated Metastatic NSCLC
Open accessAbstract
On May 28, 2021, the FDA granted accelerated approval to sotorasib (Lumakras, Amgen) for the treatment of adults with advanced non–small cell lung cancer (NSCLC) with a Kirsten rat sarcoma proto-oncogene (KRAS) G12C mutation who have received at least one prior systemic therapy. The approval was based on CodeBreaK 100 (Study 20170543), a dose-escalation and dose-expansion trial in patients with an advanced, KRAS G12C-mutated, solid tumor. The overall response rate (ORR) observed in patients with KRAS G12C-mutated NSCLC treated with sotorasib (n = 124) was 36% [95% confidence interval (CI), 28–45]. The median duration of response was 10.0 months (95% CI, 6.9–not estimable). The most common adverse reactions (≥20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. This is the first approval of a targeted therapy for KRAS G12C-mutated NSCLC. Because of pharmacokinetic data and ORRs of patient cohorts who took sotorasib at lower doses in the dose-escalation portion of CodeBreaK 100, a dose comparison study is being conducted as a post-marketing requirement.
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In 2021, the FDA approved sotorasib for the treatment of adult patients with KRAS G12C-mutated NSCLC, while adagrasib received similar approval the following year.
“In 2021, the FDA approved sotorasib for the treatment of adult patients with KRAS G12C-mutated NSCLC, while adagrasib received similar approval the following year [48,50,51,52,53].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [52]
The Abstract (page unavailable) states that the FDA approved sotorasib on May 28, 2021, for adults with advanced KRAS G12C-mutated NSCLC who had received prior systemic therapy. The paper does not report an approval of adagrasib in 2022, so it supports only the sotorasib part of the sentence. (LLM, conf=0.88)
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“…(Lumakras) gained accelerated FDA approval in May 2021 as the first targeted agent for locally advanced or metastatic, KRAS G12C -mutated NSCLC. 19 In December 2022, the FDA granted accelerated approval to a second KRAS inhibitor, adagrasib (Krazati), for the second-line treatment of locally…”
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“Long-duration treatment with sotorasib was well appreciated, with mild and manageable toxicities (Inhibitor 2021; Nakajima et al. 2022).”
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“DISCUSSION There are still no FDA-approved drugs that effectively target the most commonly mutated genes (KRAS, CDKN2A, TP53, and SMAD4) in PDAC, although Sotorasib (a KRAS-G12C inhibitor) was recently approved for advanced non-small cell lung cancer [1, 51].”
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“Sotorasib was the first-in-class KRAS G12C inhibitor to receive accelerated approval for the treatment of adults with locally advanced or metastatic NSCLC with KRAS G12C mutation who have progressed after ≥ 1 prior line of systemic therapy [17].”
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Global profiling of AMG510 modified proteins identified tumor suppressor KEAP1 as an off-target
Wang, Y., Zhong, B., Xu, C., Zhan, D., Zhao, S., Wu, H., Liu, M., Lan, X., Cai, D., Ding, Q., et al. (2023) · iScience · doi:10.1016/j.isci.2023.106080 · Cited by 19 · see citing works
Advancements in Systemic Therapy for Pancreatic Cancer
Brown, T. J., Reiss, K. A., & O’Hara, M. H. (2023) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_397082 · Cited by 20 · see citing works
Vaclová, T., Chakraborty, A., Sherwood, J. L., Ross, S. J., Carroll, D. K., Barrett, J. C., Downward, J., & de Bruin, E. C. (2022) · Scientific Reports · doi:10.1038/s41598-022-06369-3 · Cited by 19 · see citing works
Hofmarcher, T., Malmberg, C., & Lindgren, P. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1119506 · Cited by 19 · see citing works
Wankhede, D., Bontoux, C., Grover, S., & Hofman, P. M. (2023) · Diagnostics · doi:10.3390/diagnostics13193043 · Cited by 19 · see citing works
“Food and Drug Administration (FDA) for previously treated advanced NSCLC patients with mKRAS G12C [24,25].”
BackgroundAdvancing non-small cell lung cancer treatment: the power of combination immunotherapies
Wu, Y., Yu, G., Jin, K., & Qian, J. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1349502 · Cited by 20 · see citing works
Qi, W.-L., Li, H.-Y., Wang, Y., Xu, L., Deng, J.-T., Zhang, X., Wang, Y.-X., & Meng, L.-H. (2023) · Acta Pharmacologica Sinica · doi:10.1038/s41401-022-01015-0 · Cited by 19 · see citing works
“Though AMG510 and other KRAS covalent inhibitors such as MRTX849 have shown promising efficacy, the objective response rate was 36% for AMG510 [19] or 53.”
BackgroundIntegration of proteomics in the molecular tumor board
Thiery, J., & Fahrner, M. (2023) · PROTEOMICS · doi:10.1002/pmic.202300002 · Cited by 18 · see citing works
“Mutated proteins can be direct targets of drugs such as the KRAS G12C variant or propose a therapeutic direction [167, 168].”
BackgroundA Potent SOS1 PROTAC Degrader with Synergistic Efficacy in Combination with KRASG12C Inhibitor
Lv, Y., Yang, Z., Chen, Y., Ma, X., Guo, M., Zhang, C., Jiang, X., Wang, C., Li, Z., Tai, Z., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c01598 · Cited by 18 · see citing works
Chemical Proteomics–Guided Discovery of Covalent Ligands for Cancer Proteins
Zhang, X., & Cravatt, B. F. (2024) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-061421-041946 · Cited by 19 · see citing works
Khan, S., Upadhyay, S., Kauser, S., Hasan, G. M., Lu, W., Waters, M., Hassan, M. I., & Sohal, S. S. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14228021 · Cited by 17 · see citing works
Shi, Y., & Shin, D. S. (2023) · Biomolecules · doi:10.3390/biom13060984 · Cited by 17 · see citing works
“Recently approved sotorasib and adagrasib are the first KRAS G12C mutation-targeting drugs for the treatment of NSCLC patients [7].”
BackgroundPark, W., Han, J. H., Wei, S., Yang, E.-S., Cheon, S.-Y., Bae, S., Ryu, D., Chung, H., & Ha, K. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25020807 · Cited by 18 · see citing works
“Sotorasib [42] has been approved for KRAS mutations, and dabrafenib [43] and trametinib [43] have been approved for BRAF mutations.”
BackgroundWong, P. S. H., Akrami, A., Houk, B. E., Vuu, I., & James, C. A. (2022) · Bioanalysis · doi:10.4155/bio-2022-0173 · Cited by 17 · see citing works
Immunotherapy in Non-Small-Cell Lung Cancer Patients with Driver Alterations: A New Strategy?
Krzyżanowska, N., Krawczyk, P. A., Wojas‐Krawczyk, K., Kucharczyk, T., & Milanowski, J. (2022) · Cells · doi:10.3390/cells11203280 · Cited by 16 · see citing works
Zhao, Z., Li, X., Wang, F., Xu, Y., Liu, S., Han, Q., Yang, Z., Huang, W., Yin, Z., Liu, Q., et al. (2023) · Cancer Medicine · doi:10.1002/cam4.5871 · Cited by 15 · see citing works
Self-citationManagement of Brain Metastases: A Review of Novel Therapies
Bellur, S. S., Khosla, A. A., Ozair, A., Kotecha, R. R., McDermott, M. W., & Ahluwalia, M. S. (2023) · Seminars in Neurology · doi:10.1055/s-0043-1776782 · Cited by 16 · see citing works
KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination
Rosell, R., Lewintre, E. J., Cao, P., Cai, X., Xing, B., Ito, M., Gomez-Vazquez, J. L., Marco-Jordán, M., Fariñas, S. C., Cardona, A. F., et al. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01667-x · Cited by 16 · see citing works
“The Food and Drug Administration (FDA) granted accelerated approval to sotorasib for the treatment of NSCLC patients with KRAS G12C mutations who had received at least one previous line of therapy [8].”
BackgroundIdentification of a Highly Cooperative PROTAC Degrader Targeting GTP-Loaded KRAS(On) Alleles
Vetma, V., Puoti, I., Karolak, N. K., Chakraborti, S., Diers, E., Girardi, E., Khan, S., Kidd, G., Kropatsch, K., McLennan, R., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c10354 · Cited by 16 · see citing works
Oyedele, A.-Q. K., Ogunlana, A. T., Boyenle, I. D., Ibrahim, N. O., Gbadebo, I. O., Owolabi, N., Ashiru, M. A., Francis, A. C., Eyinade, O., & Adelusi, T. I. (2022) · Molecular Diversity · doi:10.1007/s11030-022-10534-1 · Cited by 16 · see citing works
“Nonetheless, it is important to mention that one of the side effects noticed with sotorasib in clinical trials is hepatotoxicity [51], and despite that, the drug was still approved for the treatment of patients with KRAS G12C-driven cancers.”
BackgroundRas superfamily GTPase activating proteins in cancer: Potential therapeutic targets?
Xiao, H., Wang, G., Zhao, M., Wen, S., Ouyang, L., & Sun, Q. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115104 · Cited by 15 · see citing works
Yu, L., Xu, J., Qiao, R., Zhong, H., Brueckl, W. M., & Zhong, R. (2023) · Translational Lung Cancer Research · doi:10.21037/tlcr-23-260 · Cited by 15 · see citing works
“Sotorasib was evaluated for secondline use in patients with metastatic NSCLC and the KRAS G12C mutation (32), but the median PFS was only 6.”
Strategic Insight into the Combination Therapies for Metastatic Colorectal Cancer
Kano, Y., Suenaga, M., & Uetake, H. (2023) · Current Oncology · doi:10.3390/curroncol30070480 · Cited by 16 · see citing works
“The overall response rate (ORR) observed in patients with KRASG12C-mutated non-small cell lung cancer (NSCLC) treated with sotorasib was 36% and sotorasib was first approved for KRASG12C-NSCLC by FDA in 2021 [66].”
BackgroundEmerging Prognostic and Predictive Factors in Pancreatic Cancer
Karamitopoulou, E. (2023) · Modern Pathology · doi:10.1016/j.modpat.2023.100328 · Cited by 15 · see citing works
SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers
Lilja, J., Kaivola, J., Conway, J. R. W., Vuorio, J., Parkkola, H., Roivas, P., Dibus, M., Chastney, M. R., Varila, T., Jacquemet, G., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-52326-1 · Cited by 14 · see citing works
“Secondly, while the current efforts strive to develop KRAS inhibitors 12,15 – 17, 53 , We provide proof-of-concept evidence of the ability of inhibitors targeting the SHANK3 – KRAS interaction to trigger apoptosis and limit the growth of KRAS -mutant cancers.”
Therapeutic Targeting the Allosteric Cysteinome of RAS and Kinase Families
Li, L., Meyer, C., Zhou, Z.-W., Elmezayen, A., & Westover, K. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167626 · Cited by 14 · see citing works
Tian, T., Li, Y., Li, J., Xu, J., Fan, H., Zhu, J., Wang, Y., Peng, F., Gong, Y., Du, Y., et al. (2024) · Translational Lung Cancer Research · doi:10.21037/tlcr-24-116 · Cited by 14 · see citing works
“KRAS mutation is known to be a poor prognostic factor (42), development of targeted therapies has been challenging for this subset of NSCLC for years, but there are now approved targeted inhibitors in the second-line and beyond therapy only for KRAS G12C mutation (43).”
The Retrofit: Lessons From Sotorasib's Dosing Conundrum
Singh, H., Vellanki, P. J., & Pazdur, R. (2024) · Journal of Clinical Oncology · doi:10.1200/jco.24.00310 · Cited by 14 · see citing works
Self-citationTargeting the MAPK pathway for NRAS mutant melanoma: from mechanism to clinic
Wang, Y., Xu, G., & Xia, H. (2025) · British Journal of Dermatology · doi:10.1093/bjd/ljaf178 · Cited by 15 · see citing works
Liu, Z., Song, L., Xie, J., Simoneau, A. R., Uchio, E., & Zi, X. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14030496 · Cited by 14 · see citing works
“, sotorasib and salirasib) [23,24], FGFR-3 inhibitor (e.”
A Long Overdue Targeted Treatment for KRAS Mutations in NSCLC: Spotlight on Adagrasib
Brazel, D., Arter, Z., & Nagasaka, M. (2022) · Lung Cancer Targets and Therapy · doi:10.2147/lctt.s383662 · Cited by 15 · see citing works
“G12C mutant advanced metastatic lung cancer post one prior line of therapy.(25) Here, we discuss adagrasib (MRTX849), another selective and potent KRAS inhibitor with similar mechanism of action to sotorasib.”
BackgroundWu, L., Rao, W., Guo, L., Zhang, F., Li, W., & Ying, J. (2025) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-025-06118-9 · Cited by 13 · see citing works
“In recent years, targeted drugs for KRAS G12C mutations, such as Sotolasib, have achieved good efficacy in clinical trials (Nakajima et al. 2022).”
Cytotoxic agents for electrochemotherapy: Efficacy, mechanisms of action, potential candidates
Morozas, A., Malyško-Ptašinskė, V., Nemeikaitė-Čėnienė, A., Kulbacka, J., Rembiałkowska, N., Ivaška, J., & Novickij, V. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118451 · Cited by 13 · see citing works
Álvarez-Pérez, J. C., Sanjuán‐Hidalgo, J., Arenas, A. M., Hernández-Navas, I., Benitez‐Cantos, M. S., Andrades, Á., Fariñas, S. C., Lewintre, E. J., Paz-Ares, L. G., Ferrer, I., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-62350-4 · Cited by 13 · see citing works
“16,31,41,43 than those expected from targeted therapies (60% to 70”
Zhao, Y., Liu, R., & Takeda, K. (2022) · Pharmaceutical Statistics · doi:10.1002/pst.2281 · Cited by 13 · see citing works
“And sponsor may be required to have a post approval trial to reevaluate the appropriate dose levels which could have an impact on the drug label.(6) Moreover, FDA has been promoting the concept of dose optimization not only in safety but also in efficacy.”
BackgroundDe, B. S., Farooqi, A. S., Mitchell, K. G., Ludmir, E. B., Lewis, J., Rinsurongkawong, W., Rinsurongkawong, V., Lee, J. J., Swisher, S. G., Gibbons, D. L., et al. (2023) · JCO Precision Oncology · doi:10.1200/po.22.00540 · Cited by 13 · see citing works
“(%) 0 65 (34) 1 30 (15) 2 77 (40) 3 22 (11) Sites of metastatic disease at diagnosis, No.”
BackgroundLiu, J., & Gao, J. (2023) · European Journal of Cancer Prevention · doi:10.1097/cej.0000000000000799 · Cited by 13 · see citing works
“The US Food and Drug Administration (FDA) has approved sotorasib, the KRAS-G12C inhibitor, for the treatment of patients with advanced NSCLC (Nakajima et al., 2022); however, treatment options are limited in advanced NSCLC patients that show drug resistance and disease recurrence after undergoing chemotherapy and targ…”
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Targeting Ras with protein engineering
Tomazini, A., & Shifman, J. M. (2023) · Oncotarget · doi:10.18632/oncotarget.28469 · Cited by 13 · see citing works
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The current therapeutic cancer vaccines landscape in non‐small cell lung cancer
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Small Molecules against Metastatic Tumors: Concrete Perspectives and Shattered Dreams
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Precision nanomedicine to treat non-small cell lung cancer
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The complex journey of targeting RAS in oncology
Wasiak, K., Ciunowicz, D., Kierasińska, A., Węgierska, M., Pacholczyk, M., Rieske, P., & Stoczyńska-Fidelus, E. (2025) · BMC Cancer · doi:10.1186/s12885-025-14033-y · Cited by 13 · see citing works
“Sotorasib was the first FDA-approved drug for patients with non-small cell lung cancer (NSCLC) characterized by the presence of the KRAS G12C mutation, if they received or underwent prior systemic therapy (NCT03600883) [38].”
- Authors
- Nakajima, E. C., Drezner, N., Li, X., Mishra-Kalyani, P. S., Liu, Y., Zhao, H., Bi, Y., Liu, J., Rahman, A., Wearne, E., Ojofeitimi, I., Hotaki, L. T., Spillman, D., Pazdur, R., Beaver, J. A., & Singh, H.
- Affiliations
- United States Food and Drug Administration (US)
- Corresponding author
- Nakajima, Erica C.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2021-12-10
- Volume
- 28
- Issue
- 8
- Pages
- 1482-1486
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC9012672
- OpenAlex
- W4200034683
- Cited by
- 333
- References
- 22
- Citations by year
- 2026: 45 · 2025: 78 · 2024: 84 · 2023: 85 · 2022: 41
- FWCI
- 33.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- HHS | U.S. Food and Drug Administration
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- sotorasib, KRAS G12C mutation, metastatic non-small cell lung cancer, accelerated FDA approval, targeted therapy, overall response rate, adverse effects, hepatotoxicity, dose comparison
- MeSH terms
- Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Piperazines, Pyridines, Pyrimidines, Proto-Oncogene Proteins p21(ras), Clinical Trials, Phase I as Topic
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