Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jun 21.
doi: 10.1007/s12325-025-03259-8. Online ahead of print.

Matching-Adjusted Indirect Comparison of Sotorasib Versus Adagrasib in Previously Treated Advanced/Metastatic Non-Small Cell Lung Cancer Harboring KRAS G12C Mutation

Divyan Chopra  1 , Zhiyi Lan  2 , David M Waterhouse  3 , Jürgen Wolf  4 , Enriqueta Felip  5 , Hoora Moradian  2 , Nadia Karim  6 , Cynthia Obiozor  1 , Björn Stollenwerk  7
Affiliations

Matching-Adjusted Indirect Comparison of Sotorasib Versus Adagrasib in Previously Treated Advanced/Metastatic Non-Small Cell Lung Cancer Harboring KRAS G12C Mutation

Divyan Chopra et al. Adv Ther. .

Abstract

Introduction: Sotorasib and adagrasib are the only treatments approved in the USA and Europe for advanced/metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC). In the absence of head-to-head trials, a matching-adjusted indirect comparison (MAIC) was conducted to assess the relative efficacy and safety of sotorasib versus adagrasib using phase 3 trials.

Methods: Patient-level data from CodeBreaK 200 were reweighted to match the baseline characteristics reported in KRYSTAL-12. The analysis evaluated progression free-survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAE). Age, sex, region, prior treatment, brain metastases, and liver metastases were selected for adjustment in the primary analysis per clinical guidance, using an unanchored approach (no common comparator). We conducted sensitivity analyses including additional covariates or anchoring the analysis via common comparator (docetaxel). Additional subgroup analysis was performed in patients with baseline brain metastases, assessing systemic PFS.

Results: Following adjustment, the reweighted patient characteristics from CodeBreaK 200 and KRYSTAL-12 were well balanced. In the primary analysis, sotorasib and adagrasib showed similar efficacy: PFS (HR [hazard ratio] 0.93; 95% confidence interval [CI] 0.70-1.22; p = 0.589) and ORR (odds ratio 0.86; 95% CI 0.53-1.38; p = 0.524). Among patients with brain metastases, sotorasib demonstrated a 39% reduced risk of progression compared with adagrasib (HR 0.61; 95% CI 0.38-0.98; p = 0.040). Sotorasib also demonstrated a more favorable safety profile than adagrasib, with lower odds of TRAEs, TRAEs leading to dose reduction or dose interruption, and all eight individual TRAEs evaluated. Sensitivity analyses supported the robustness of base-case results.

Conclusion: In this MAIC, sotorasib and adagrasib showed comparable efficacy in previously treated advanced KRAS G12C-mutated NSCLC. Among patients with baseline brain metastases, PFS point estimates favored sotorasib. Sotorasib also demonstrated a favorable overall safety profile. These findings may help inform payer decisions and clinical practice in the treatment of KRAS G12C-mutated NSCLC.

Keywords: KRAS G12C mutation; Adagrasib; Matching-adjusted indirect comparison; Non-small cell lung cancer; Objective response rate; Progression-free survival; Sotorasib; Treatment-related adverse event.

Plain language summary

Two drugs, sotorasib and adagrasib, are approved in the USA and Europe for patients with advanced or metastatic non-small cell lung cancer who have a KRAS G12C gene mutation. However, there are no clinical trials that directly compare these two treatments. To address this, a method called matching-adjusted indirect comparison can help compare results from different clinical trials by reducing differences in patient characteristics between the trials and minimizing bias. This study conducted a matching-adjusted indirect comparison to compare how well sotorasib and adagrasib perform and how safe they are, based on data from pivotal clinical trials. The findings show that both drugs were similarly effective at slowing down cancer progression and shrinking tumors. Additionally, sotorasib had fewer side effects compared with adagrasib. These findings provide important insights to help patients, doctors, and healthcare decision-makers choose the most suitable treatment option for non-small cell lung cancer with a KRAS G12C mutation.

PubMed Disclaimer

Conflict of interest statement

Declarations. Conflicts of Interest: Divyan Chopra, Nadia Karim, Cynthia Obiozor, and Björn Stollenwerk are employees of and stockholders in Amgen. Hoora Moradian is an employee of Cytel that received consultancy fees from Amgen. Zhiyi Lan was employed by Cytel, Inc., at the time of study conduct. Jürgen Wolf received advisory board and lecture fees from AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint, Bristol Myers Squibb (BMS), Boehringer Ingelheim, Chugai, Daiichi Sankyo, Ellipses Pharma, Genmab, Janssen, Lilly, Loxo, Merck, Murati, Merck Sharp & Dohme (MSD), Novartis, Novalent, Pfizer, Pierre-Fabre, Regeneron, Roche, Seattle Genetics, Takeda, and Turning Point as well as research support from AstraZeneca, BMS, Janssen Pharmaceutica, Novartis, and Pfizer. David M. Waterhouse has served in a consulting or advisory role for BMS, AZTherapies, AbbVie, Amgen, McGivenny Global, Janssen Oncology, Seattle Genetics, Exelixis, Eisai, EMD Serono, Merck, Pfizer, Mirati Therapeutics, Regeneron/Sanofi, Fresenius KBI, Lilly, Sanofi, Astellas Pharma, Gilead Sciences, Takeda, Daiichi Sankyo, Novartis, Bayer, AVEO; has participated in speakers’ bureaus for BMS, Janssen Oncology, Merck, AstraZeneca, Amgen, and EMD Serono; has received travel, accommodations, expenses from BMS. Enriqueta Felip has received consulting fees from AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, F. Hoffmann-La Roche, Gilead, GlaxoSmithKline, Iteos Therapeutics, Janssen, Johnson & Johnson, MSD, Novartis, Pierre-Fabre, Pfizer, Regeneron, and Turning Point; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, AstraZeneca, BMS, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, Gilead, Janssen, Johnson & Johnson, Medical Trends, Medscape, Merck Serono, MSD, Novartis, Peervoice, Pfizer, and Regeneron; has received support for attending meetings and/or travel from AstraZeneca, Janssen, and Roche; is an independent member of the board of Grifols. Disclosure: Zhiyi Lan was employed by Cytel, Inc. at the time of study conduct. Zhiyi’s current affiliation is IQVIA Inc., CA, USA. Ethical Approval: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. The CodeBreak 200 trial used in the study was conducted in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The protocol and amendments were approved by the institutional review board at each participating site and regulatory authorities of participating countries. The protocol for the KRYSTAL-12 trial states that the study will be conducted in accordance with International Ethical Guidelines for Biomedical Research Involving Human Patients (Council for International Organizations of Medical Sciences 2002), Guidelines for Good Clinical Practice (GCP) (International Council for Harmonisation [ICH] 1996), ICH E6 (R2) and concepts that have their origin in the Declaration of Helsinki (World Medical Association 1996, 2008 & 2013), the study will be conducted under a protocol reviewed and approved by an institutional review board/ethics committee.

Similar articles

See all similar articles

References

    1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer J Clin. 2024;74(3):229–63. - DOI
    1. Wéber A, Morgan E, Vignat J, et al. Lung cancer mortality in the wake of the changing smoking epidemic: a descriptive study of the global burden in 2020 and 2040. BMJ Open. 2023;13(5):e065303. - DOI - PubMed - PMC
    1. Zhou J, Xu Y, Liu J, Feng L, Yu J, Chen D. Global burden of lung cancer in 2022 and projections to 2050: incidence and mortality estimates from GLOBOCAN. Cancer Epidemiol. 2024;93:102693. - DOI - PubMed
    1. American Cancer Society. What is lung cancer? 2019. https://www.cancer.org/cancer/lung-cancer/about/what-is.html . Accessed Feb 11, 2021.
    1. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446–54. - DOI - PubMed

LinkOut - more resources