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. 2025 Aug;31(8):2755-2767.
doi: 10.1038/s41591-025-03732-5. Epub 2025 May 28.

Molecular determinants of sotorasib clinical efficacy in KRASG12C-mutated non-small-cell lung cancer

Ferdinandos Skoulidis  1 , Bob T Li  2   3 , Adrianus Johannes de Langen  4 , David S Hong  5 , Herve Lena  6 , Juergen Wolf  7 , Grace K Dy  8 , Alessandra Curioni Fontecedro  9   10 , Pascale Tomasini  11 , Vamsidhar Velcheti  12 , Anthonie J van der Wekken  13 , Christophe Dooms  14 , Luis Paz-Ares Rodriguez  15 , Giannis Mountzios  16 , Adrian Sacher  17 , Ernest Nadal  18 , Sebastien Couraud  19 , Sang-We Kim  20 , Kenneth O'Byrne  21 , Danilo Rocco  22 , Ryo Toyozawa  23 , Izabela Chmielewska  24 , Colin R Lindsay  25   26 , Antreas Hindoyan  27 , Lata Mukundan  27 , Tomasz Wilmanski  27 , Abraham Anderson  27 , Christine Ardito-Abraham  27 , Amrita Pati  27 , Anita Reddy  27 , Bhakti Mehta  27 , Martin Schuler  28
Affiliations

Molecular determinants of sotorasib clinical efficacy in KRASG12C-mutated non-small-cell lung cancer

Ferdinandos Skoulidis et al. Nat Med. 2025 Aug.

Abstract

Molecular determinants of KRAS(G12C)inhibitor efficacy in KRASG12C-mutated non-small-cell lung cancer (NSCLC) remain poorly characterized. Here we report one of the largest integrated analyses to date of sotorasib clinical efficacy biomarkers from the phase 2 CodeBreaK 100 and phase 3 CodeBreaK 200 studies. We reveal differential sotorasib activity and relative benefit compared to docetaxel across KRASG12C-mutated NSCLC co-mutational subsets and transcriptional subtypes. We also identify low expression of TTF1 and KEAP1 co-mutations/NRF2 activation as major determinants of sotorasib anti-tumor efficacy and adverse prognostic features. Exploratory analyses highlight potential tumor cell-extrinsic contributors to sotorasib anti-tumor activity and suggest that early on-treatment clearance of KRASG12C- circulating tumor DNA may refine clinical response prediction algorithms. Our findings advance precision medicine for patients with KRASG12C-mutated NSCLC and establish a framework for patient stratification and selection for treatment intensification with rationally applied therapeutic combinations.

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Conflict of interest statement

Competing interests: F.S. reports consulting/advisory board fees from Amgen, AstraZeneca, AImmune (spouse), BeiGene, BergenBio, BridgeBio, Bristol Myers Squibb, Calithera Biosciences, Guardant Health, Hookipa Pharma, Merck Sharp & Dohme, Novartis, Novocure, Regeneron, Revolution Medicines, Roche and Tango Therapeutics; grant or research support (to institution) from Amgen, Mirati Therapeutics, Revolution Medicines, Pfizer, Novartis and Merck & Co; stock ownership in BioNTech (ended in 2021) and Moderna (ended in 2021); honoraria/lecture fees from the European Society for Medical Oncology (ESMO), the Japanese Lung Cancer Society, Medscape, Intellisphere, VSPO McGill University, RV Mais Promocao Eventos, MJH Life Sciences, IDEOlogy Health, MI&T, Physiciansʼ Education Resource (PER), Curio, DAVA Oncology, the American Association for Cancer Research (AACR) and the International Association for the Study of Lung Cancer (IASLC); and travel support from DAVA Oncology, Tango Therapeutics, AstraZeneca, Amgen, Inc., Bristol Myers Squibb, Revolution Medicines, AACR, IASLC, MJH Life Sciences, IDEOlogy Health, MI&T, PER and Curio. B.T.L. has received research funding from Roche/Genentech (to institution), AstraZeneca (to institution), Daiichi Sankyo (to institution), Hengrui Therapeutics (to institution), Amgen (to institution), Eli Lilly (to institution), MORE Health (to institution), Bolt Biotherapeutics (to institution) and Ambrx (to institution); has patents, royalties and other intellectual property from US62/514,661 (to institution), US62/685,057 (to institution), Karger Publishers and Shanghai Jiao Tong University Press; has received travel, accommodations and expenses from MORE Health and Jiangsu Hengrui Medicine; and has uncompensated relationships with Amgen, AstraZeneca, Genentech, Eli Lilly, Boehringer Ingelheim and Daiichi Sankyo. A.J.d.L. has financial interests in and has received institutional and research grant funding from Bristol Myers Squibb, Merck Sharp & Dohme, Boehringer Ingelheim and AstraZeneca and has non-financial and other interests in Merck Serono and Roche. D.S.H. owns stock or has other ownership interests in OncoResponse, Telperian and MolecularMatch; has acted in a consulting or advisory role for Bayer, Guidepoint Global, Gerson Lehrman Group, Alphasights, Axiom Biotechnologies, Medscape, Numab, Pfizer, Takeda, Trieza Therapeutics, WebMD, Infinity Pharmaceuticals, Amgen, Adaptimmune, Boxer Capital, EcoR1 Capital, Tavistock Life Sciences, Baxter, COG, Genentech, GroupH, Janssen, Acuta, HCW Precision, Prime Oncology, ST Cube, Alkermes, AUM Biosciences, BridgeBio, Cor2Ed, Gilead Sciences, Immunogen, Liberum, Oncologia Brasil, Pharma Intelligence, Precision Oncology Experimental Therapeutics, Turning Point Therapeutics, ZIOPHARM Oncology, Cowen, Gennao Bio, MedaCorp, YingLing Pharma and RAIN; received research funding from Genentech (to institution), Amgen (to institution), Daiichi Sankyo (to institution), Adaptimmune (to institution), AbbVie (to institution), Bayer (to institution), Infinity Pharmaceuticals (to institution), Kite, a Gilead Company (to institution), MedImmune (to institution), the National Cancer Institute (to institution), Fate Therapeutics (to institution), Pfizer (to institution), Novartis (to institution), Numab (to institution), Turning Point Therapeutics (to institution), Kyowa (to institution), Loxo (to institution), Merck (to institution), Eisai (to institution), Genmab (to institution), Mirati Therapeutics (to institution), Mologen (to institution), Takeda (to institution), AstraZeneca (to institution), Navire (to institution), VM Pharma (to institution), Erasca, Inc. (to institution), Bristol Myers Squibb (to institution), Adlai Nortye (to institution), Seagen (to institution), Deciphera (to institution), Pyramid Biosciences (to institution), Eli Lilly (to institution), Endeavor BioMedicines (to institution), F. Hoffmann LaRoche (to institution), Ignyta (to institution), Teckro (to institution) and TCR2 Therapeutics (to institution); and received reimbursement for travel, accommodations, expenses from Genmab, the Society for Immunotherapy of Cancer, Bayer Schering Pharma, the American Society of Clinical Oncology, AACR and Telperian. H.L. has financial interests in or received personal and other fees from Daiichi Sankyo, AstraZeneca, Pfizer, Novartis, Amgen, Merck Sharp & Dohme, Roche, Bristol Myers Squibb, Eli Lilly and Boehringer Ingelheim. J.W. has financial interests in and/or received personal, advisory board or lectures fees or institutional/research grants from Amgen, AstraZeneca, Bayer, Blueprint, Bristol Myers Squibb, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Merck, Janssen, Eli Lilly, Loxo, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Seattle Genetics, Takeda, Turning Point and Nuvalent. G.K.D. has acted in a consulting or advisory role for AstraZeneca, Mirati Therapeutics, Eli Lilly and Amgen and received research funding from Amgen (to institution), AstraZeneca (to institution), Mirati Therapeutics (to institution), Eli Lilly (to institution), Sanofi (to institution), Bioatla (to institution), Regeneron (to institution), Iovance Biotherapeutics (to institution) and Revolution Medicines (to institution). A.C.F. has acted in a consulting or advisory role for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daichii Sankyo, Janssen, Medscape, Merck Sharp & Dohme, Roche/Genentech and Takeda; presented in a company-organized public event for Amgen, AstraZeneca, Bristol Myers Squibb, Foundation Medicine, Medscape, Merck Sharp & Dohme, Roche/Genentech and Takeda; and received grants or research support as a sub-investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme and Roche/Genentech. P.T. has acted in a consulting or advisory role for AstraZeneca, Roche, Bristol Myers Squibb Foundation, Takeda, Amgen and Janssen and has received reimbursement for travel, accommodations and expenses from Bristol Myers Squibb/Pfizer, AstraZeneca and Takeda. V.V. has received honoraria from ITeos Therapeutics; acted in a consulting or advisory role for Bristol Myers Squibb, Merck, AstraZeneca/MedImmune, GlaxoSmithKline, Amgen, Elevation Oncology, Merus and Taiho Oncology; and received research funding from Genentech (to institution), Trovagene (to institution), Eisai (to institution), OncoPlex Diagnostics (to institution), Alkermes (to institution), NantWorks (to institution), Genoptix (to institution), Altor BioScience (to institution), Merck (to institution), Bristol Myers Squibb (to institution), Atreca (to institution), Heat Biologics (to institution), Leap Therapeutics (to institution), RSIP Vision (to institution) and GlaxoSmithKline (to institution). A.J.v.d.W.: financial interests—institutional: research grants from AstraZeneca, Boehringer Ingelheim, Pfizer, Roche and Takeda; financial interests—fees to institution from AstraZeneca, Boehringer Ingelheim, Pfizer, Roche, Takeda, Janssen Cilag, Eli Lilly, Amgen and Merck. C.D. has no competing interests to disclose. L.P.-A.R. has financial interests in and/or has received research grants from and/or payment/honoraria for lectures, presentations and speakers bureau participation from Merck Sharp & Dohme, AstraZeneca, Pfizer, Bristol Myers Squibb, Eli Lilly, Roche, PharmaMar, Merck, Novartis, Servier, Amgen, Sanofi, Bayer, Mirati Therapeutics, GlaxoSmithKline, Janssen, Takeda and Daiichi Sankyo. G.M. has financial interests in and/or received personal, consulting, honoraria, lecture/presentation, speakers bureaus, writing, traveling or other fees from Roche Hellas, Novartis Greece, BMS Greece, MSD Greece, AstraZeneca Greece, Takeda Hellas, Janssen Greece, GSK Greece, Amgen Hellas, Sanofi Greece, Boehringer Greece and Pierre Fabre Greece; had a leadership or fiduciary role, unpaid, for ESMO working groups (Educational Publication Working Group and Adolescents and Young Adults Working Group); and has acted as institutional/principal investigator for Roche Hellas, Novartis Greece, BMS Greece, MSD Greece, AstraZeneca Greece, Gilead Greece, GSK Greece, Amgen Hellas and Sanofi Greece. A.S. has received research funding from AstraZeneca, Genentech/Roche and Bristol Myers Squibb and has uncompensated relationships with Genentech/Roche and AstraZeneca. E.N. has received honoraria from Apollomics, Roche/Genentech and Transgene; acted in a consulting or advisory role for Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo Europe GmbH, Genmab, Janssen Oncology, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Pfizer, Pierre Fabre, Qiagen, Roche, Sanofi and Takeda; received research funding (to institution) from Bristol Myers Squibb, Merck Serono, Pfizer and Roche; and received travel, accommodations and expenses from Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche and Takeda. S.C. has received grants and contracts from Adene, AstraZeneca, BD Biosciences, Bristol Myers Squibb, Canon, Chugai, I-Medica, Janssen, Eli Lilly, Merck Sharp & Dohme, Pfizer, PharmaMar, Pierre Fabre, Regeneron, Roche, Sanofi, Takeda, Transdiag and Volition; received payment for expert testimony from Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Chugai, Fabentech, Health Event, Janssen, MaaT Pharma, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Sanofi and Takeda; received support for attending meetings and/or travel from Amgen, AstraZeneca, Bristol Myers Squibb, Chiesi, Janssen, Laidet, Pfizer, Roche and Takeda; had a leadership or fiduciary role in other board, society, committee or advocacy groups, unpaid, from Adene, Association de Recherche et d’Information Scientifique en Oncologie Thoracique (ARISTOT), Ensemble Nous Poumons, the Lung Cancer Policy Network and the Société de Pneumologie de Langue Française; and has other financial or non-financial interests from the Société Nationale des Chemins de fer Français (SNCF) (consulting physician, paid). S.-W.K. has no competing interests to disclose. K.O. owns stock or has other ownership interests in Carpe Vitae Pharmaceuticals, DGC Diagnostics and RepLuca Pharmaceuticals; has received honoraria from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Diacchi, Merck Group, Merck Sharp & Dohme, Pfizer/EMD Serono, Roche, Seagen, Takeda and TriStar Technology Group; has acted in a consulting or advisory role for Amgen, AstraZeneca/MedImmune, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Diacchi, Ipsen, Merck Sharp & Dohme, Pfizer, Roche/Genentech, Sanofi and Seagen; has participated in speakers bureaus for BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Janssen-Cilag, Merck Group, Merck Sharp & Dohme, Pfizer, Roche and Seagen; has received travel, accommodations and expenses from Bayer Holding and Sanofi; and is named on four active patents (institution)—two published and two provisional. D.R. has no competing interests to disclose. R.T. has received honoraria from AstraZeneca, Bristol Myers Squibb Japan, Chugai Pharma, Eli Lilly Japan, Merck Sharp & Dohme, Nippon Kayaku, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda and Thermo Fisher Scientific and has received research funding from AbbVie (to institution), Amgen (to institution), AnHeart Therapeutics (to institution), Daiichi Sankyo (to institution), Eli Lilly Japan (to institution), Novartis (to institution), Pfizer (to institution) and Takeda (to institution). I.C. has no competing interests to disclose. C.R.L. has financial interests in and has received personal, institutional, advisory board, research grant and other fees from Amgen, Qiagen and Revolution Medicines and has non-financial relationships with Amgen, BI, Mirati Therapeutics, Revolution Medicines, Roche and Apollomics. A.H. is an employee and stockholder/shareholder in Amgen. L.M. is an employee and stockholder/shareholder in Amgen. T.W. is an employee and stockholder/shareholder in Amgen. A.A. is an employee and stockholder/shareholder in Amgen and is listed as an inventor on several Amgen patents (does not receive royalties on these patents). C.A.-A. is an employee and stockholder/shareholder in Amgen. A.P. is an employee and stockholder/shareholder in Amgen. A.R. is an employee and stockholder/shareholder in Amgen. B.M. is an employee and stockholder/shareholder in Amgen. M.S. has received institutional research grants from AstraZeneca, Bristol Myers Squibb and Johnson & Johnson as well as consulting fees and fees of CME presentations and has participated on advisory boards for Amgen, AstraZeneca, Bristol Myers Squibb, Gilead, GlaxoSmithKline, Immunocore, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Regeneron, Roche and Sanofi.

Figures

Fig. 1
Fig. 1. Biomarker analysis methodology.
Baseline tissue samples (fresh/archival) were analyzed using the Tempus xT assay, which combined a 648-gene targeted DNA sequencing panel and whole-transcriptome RNA. PD-L1 protein level was assessed by local standard-of-care testing. Pre-treatment and post-treatment samples were assessed using plasma NGS: Resolution ctDx Lung assay (23 genes).
Fig. 2
Fig. 2. Analyses of tumor-intrinsic genomic determinants of sotorasib response and resistance.
a, Oncoprint of alterations (pathogenic or potentially pathogenic based on OncoKB, SnpEff and FATHMM designation) in patients with available tissue NGS data at baseline (CB100 + CB200 sotorasib and docetaxel arms). The rows indicate genes with reported alterations (short variants, copy number variants (gain or loss), insertions, deletions or fusions) sorted based on prevalence. Of note, 10 patients from CB200 (3.2% of patients across both CodeBreaK studies) were negative for KRASG12C by retrospective tissue NGS. However, 8 of 10 patients were still reported to be KRASG12C positive by the plasma ctDNA assay. Tissue heterogeneity and sample quality likely account for this discordance. All patients, including those with lack of KRASG12C detection by retrospectively performed tissue NGS, had prospective central laboratory confirmation of KRASG12C in tissues using the pre-defined diagnostic companion assay (KRAS RGQ PCR Kit (Qiagen)). Hence, these patients were included in the analyses. b, Forest plot showing hazard of progression (HR (95% CI)) with sotorasib compared to docetaxel treatment in CB200 patients grouped based on specified genomic alterations. FDR-adjusted, two-sided P values for the interaction between arm and gene alteration in Cox proportional hazards models are noted. c,d, Kaplan–Meier curves of PFS according to ATM mutation status in patients treated with sotorasib or docetaxel (CB200). e, Kaplan–Meier curve of PFS according to ATM mutation status in patients treated with sotorasib from the combined dataset. f,g, Kaplan–Meier curves of PFS (f) or OS (g) according to KEAP1 mutation status in patients treated with sotorasib in the combined dataset. CNV, copy number variation; MUT, mutant; NE, not estimable.
Fig. 3
Fig. 3. Transcriptomic determinants of sotorasib clinical efficacy.
a, Prevalence of transcriptional subtypes (KC, KL and KP) and TTF1 expression status (within KC/KL/KP) for patients with available RNA-seq data (CB100 + CB200 sotorasib and docetaxel arms). Box plot defines maxima (top of the box at the third quartile), minima (bottom of the box at the first quartile), center, whiskers (upper whisker extends to the lowest and highest values within 1.5× interquartile range of the first and third quartile) and percentile. b, Kaplan–Meier curves of PFS in patients with KC, KL and KP tumor types treated with sotorasib or docetaxel (CB200). The FDR-adjusted P values for the post hoc log-rank tests of PFS difference between sotorasib and docetaxel in the KC/KL/KP subtypes were 0.56, 0.03 and 0.50, respectively. c,d, Kaplan–Meier curves of PFS (c) or OS (d) across KC, KL and KP tumor types for patients treated with sotorasib in the combined dataset. e,f, Kaplan–Meier curves of PFS (e) or OS (f) according to TTF1 (high versus low) mRNA expression in patients treated with sotorasib in the combined dataset. g, ORR (% (95% CI)) according to TTF1 (high versus low) mRNA expression in patients treated with sotorasib in the combined dataset. OR and unadjusted, two-sided P value (Fisher’s exact test) are shown. FPKQ, fragments per kilobase per million reads, quantile normalized; NE, not estimable.
Fig. 4
Fig. 4. Impact of NRF2 activation status on clinical outcomes.
a, Prevalence of NRF2 activation status for patients with available RNA-seq data (CB100 + CB200 sotorasib and docetaxel arms). b,c, Kaplan–Meier curves for PFS (b) or OS (c) based on NRF2 (high versus low) activation status for patients treated with sotorasib in the combined dataset. d,e, Kaplan–Meier curves of PFS (d) or OS (e) based on TTF1 (high versus low) mRNA expression and NRF2 (high versus low) activation status for patients treated with sotorasib in the combined dataset. NE, not estimable.
Fig. 5
Fig. 5. Tumor immune contexture and sotorasib efficacy in KRASG12C-mutated NSCLC.
a, Forest plot showing hazard of progression with sotorasib versus docetaxel treatment in CB200 patients grouped based on tumor cell PD-L1 expression. Two-sided P values (Cox proportional hazards model) for PD-L1 level HRs were FDR adjusted. b, Pie chart indicating the prevalence of specific tumor immune subtypes (Thorsson immune phenotyping) in patients treated with sotorasib from the combined dataset. c,d, Kaplan–Meier curves of PFS (c) or OS (d) based on specific tumor immune subtypes for patients treated with sotorasib in the combined dataset. NE, not estimable.
Fig. 6
Fig. 6. Longitudinal monitoring of ctDNA to capture sotorasib response and resistance.
a, Longitudinal modeling to depict changes in KRASG12C VAF (LSM estimate (95% CI)) in patients treated with sotorasib versus patients treated with docetaxel at various timepoints indicated on the x-axis. FDR-adjusted, two-sided P values are shown for the difference between sotorasib and docetaxel at each timepoint from linear mixed models. b, Longitudinal modeling to depict changes in KRASG12C detection status (% (95% CI)) in patients with detectable ctDNA treated with sotorasib versus patients treated with docetaxel at various timepoints. FDR-adjusted, two-sided P values (McNemar test) are shown for the difference between post-baseline visit and baseline visit for each treatment group. c, PFS dependence on KRASG12C detection status (HR for KRASG12C status (95% CI)) from Cox proportional hazards models stratified by treatment arm. Center of the error bar is the HR. Two-sided P values were FDR adjusted. d–g, Kaplan–Meier curves of PFS in patients with detectable versus undetectable KRASG12C at C1D8 (d), C2D1 (e and f) or TTF-1 high (+) sotorasib patients at C2D1 (g). h, Oncoprint depicting pathogenic acquired variants at progression from sotorasib-treated patients from the combined dataset and pie chart showing the variant distribution among pathways of interest. The oncoprint rows indicate genes with reported alterations (short variants, copy number variants (gain or loss), insertions, deletions or fusions), sorted based on prevalence. C, cycle; CNV, copy number variation; D, day; LSM, least squares mean; NE, not estimable; SFU, safety follow-up.
Extended Data Fig. 1
Extended Data Fig. 1. Impact of co-occurring genomic alterations on sotorasib efficacy.
(a) Prevalence of patients with fast progression or long-term benefit according to ATM mutation status in CB200 and in patients treated with sotorasib from the combined dataset. (b, c) Kaplan-Meier curves of (b) PFS (CB100) and (c) OS (combined dataset) according to ATM mutation status in patients treated with sotorasib. (d, e) Kaplan-Meier curves of (d) PFS (CB200, left panel; CB100, right panel) and (e) OS (CB200, left panel; CB100, right panel) according to KEAP1 mutation status in patients treated with sotorasib. (f) Prevalence of patients with fast progression or long-term benefit according to KEAP1 mutation status in patients treated with sotorasib or docetaxel. (g) Prevalence of patients with fast progression or long-term benefit (left panel), and Kaplan-Meier curves of PFS (middle panel) and OS (right panel) according to SMARCA4 mutation status in patients treated with sotorasib from the combined dataset. CB100, CodeBreaK 100; CB200, CodeBreaK 200; KRAS, Kirsten rat sarcoma virus; MUT, mutant; OS, overall survival; PFS, progression-free survival; WT, wild-type.
Extended Data Fig. 2
Extended Data Fig. 2. STK11 alterations and sotorasib efficacy.
(a) Kaplan-Meier curves of PFS according to STK11 mutation status in patients treated with sotorasib (left panel) or docetaxel (right panel) from CB200. (b) Kaplan-Meier curves of OS according to STK11 mutation status in patients treated with sotorasib (left panel) or docetaxel (right panel) from CB200. (c) Kaplan-Meier curves of PFS (left panel) and OS (right panel) according to STK11 mutation status in patients treated with sotorasib from CB100. (d) Kaplan-Meier curves of PFS (top panels) and OS (bottom panels) according to STK11 mutation status in KEAP1 WT patients treated only with sotorasib from CB200 (left) or CB100 (right). CB100, CodeBreaK 100; CB200, CodeBreaK 200; KRAS, Kirsten rat sarcoma virus; MUT, mutant; OS, overall survival; PFS, progression-free survival; WT, wild-type.
Extended Data Fig. 3
Extended Data Fig. 3. Transcriptomic modifiers of sotorasib efficacy.
(a) Prevalence of transcriptional subtypes across CB100 and CB200 studies as noted. (b) Pooled TTF1 expression distribution (TTF1low or TTF1high) using K-means in patients from the combined dataset (CB100 + CB200 sotorasib and docetaxel arms). (c) Prevalence of TTF1low and TTF1high tumors, across CB100 and CB200 studies. (d) Kaplan-Meier curve of OS across KC, KL, and KP tumor types for patients treated with sotorasib or docetaxel in CB200. (e) Prevalence of patients with fast progression or long-term benefit across KC, KL, and KP tumor types for patients treated with sotorasib from the combined dataset. (f, g) Kaplan-Meier curves of (f) PFS and (g) OS across KC and KL/KP tumor types based on TTF1 expression for patients treated with sotorasib in the combined dataset. (h, i) Kaplan-Meier curves of (h) PFS and (i) OS based on TTF1 expression for patients treated with sotorasib or docetaxel in CB200. CB100, CodeBreaK 100; CB200, CodeBreaK 200; KRAS, Kirsten rat sarcoma virus; OS, overall survival; PFS, progression-free survival; RNA-seq, RNA sequencing; TTF-1, thyroid transcription factor-1.
Extended Data Fig. 4
Extended Data Fig. 4. NRF2 transcriptional output is a molecular modifier of sotorasib efficacy in KRASG12C-mutated NSCLC.
(a) KEAP1/STK11 mutation status by NRF2 status for patients with available data (CB100 + CB200 sotorasib and docetaxel arms). (b) Prevalence of NRF2low and NRF2high tumors across KC, KL, and KP tumor types, and TTF1low or TTF1high tumors for patients with available data (CB100 + CB200 sotorasib and docetaxel arms). (c) Kaplan-Meier curve of PFS based on NRF2 activation status for patients treated with sotorasib in CB200 (left panel) or CB100 (right panel). (d) Kaplan-Meier curves of PFS (top panels) and OS (bottom panels) according to NRF2 activation status in patients treated with sotorasib or docetaxel from CB200. CB100, CodeBreaK 100; CB200, CodeBreaK 200; KRAS, Kirsten rat sarcoma virus; MUT, mutant; OS, overall survival; PFS, progression-free survival; TTF-1, thyroid transcription factor-1; WT, wild-type.
Extended Data Fig. 5
Extended Data Fig. 5. Exploratory analyses of immune mechanisms underlying sotorasib response and resistance.
(a) Prevalence of KC, KL, and KP tumor types (left panel) or TP53, STK11, and KEAP1 mutation status (right panels) based on PD-L1 expression among patients treated with sotorasib in the combined dataset. (b) Kaplan-Meier curve of PFS based on PD-L1 TPS for patients treated with sotorasib in the combined dataset. (c) Prevalence of immune subtypes based on PD-L1 TPS for patients with RNA-seq and PD-L1 expression data among patients treated with sotorasib from the combined dataset. (d) Kaplan-Meier curve of PFS based on immune subtypes for patients treated with sotorasib in CB100 (left panel) and CB200 (right panel). (e) Prevalence of patients with fast progression or long-term benefit across immune subtypes for patients treated with sotorasib from the combined dataset. (f) Kaplan-Meier curve of PFS for patients with inflammatory subtype treated with sotorasib in the combined dataset. CB100, CodeBreaK 100; CB200, CodeBreaK 200; IFN-ɣ, interferon gamma; KRAS, Kirsten rat sarcoma virus; MUT, mutant; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TGF-β, transforming growth factor beta; RNA-seq, RNA-sequencing; TP53, tumor protein p53; TPS, tumor proportion score; WT, wild-type.
Extended Data Fig. 6
Extended Data Fig. 6. Longitudinal ctDNA monitoring in KRASG12C-mutated NSCLC.
(a, b) Kaplan-Meier curve of PFS based on KRASG12C ctDNA detectability at C3D1 for patients treated with (a) sotorasib or (b) docetaxel in CB200. (c) Prevalence of plasma genes with emergent pathogenic alterations for patients treated with sotorasib or docetaxel in the combined dataset. C, cycle; CB, CodeBreaK; D, day; KRAS, Kirsten rat sarcoma virus; PFS, progression-free survival.
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