Impact of Co-mutations and Transcriptional Signatures in Non-Small Cell Lung Cancer Patients Treated with Adagrasib in the KRYSTAL-1 Trial

Authors

Marcelo V Negrao
Alvaro G Paula
David Molkentine
Laura Hover
Monique Nilsson
Natalie Vokes
Lars Engstrom
Andrew Calinisan
David M Briere
Laura Waters
Jill Hallin
Lixia Diao
Mehmet Altan
George R Blumenschein
Ferdinandos Skoulidis
Jing Wang
Scott E Kopetz
David S Hong
Don L Gibbons
Peter Olson
James G Christensen
John V Heymach

Publication Date

3-17-2025

Journal

Clinical Cancer Research

Abstract

Purpose: KRAS inhibitors are revolutionizing the treatment of non-small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration.

Experimental design: Patients with advanced KRASG12C-mutant NSCLC treated with adagrasib [KRYSTAL-1 (NCT03785249)] were included in the analysis. Pretreatment next-generation sequencing data were collected per protocol. HTG EdgeSeq Transcriptome Panel was used for gene expression profiling. Clinical endpoints included objective response, progression-free survival (PFS), and overall survival (OS). KRASG12C-mutant NSCLC cell lines and xenograft models were used for sensitivity analyses and combination drug screens.

Results: KEAP1 MUT and STK11MUT were associated with shorter survival to adagrasib [KEAP1: PFS 4.1 vs. 9.9 months, HR 2.7, P < 0.01; OS 5.4 vs. 19.0 months, HR 3.6, P < 0.01; STK11: PFS 4.2 vs. 11.0 months, HR 2.2, P < 0.01; OS 9.8 months vs. not reached (NR), HR 2.6, P < 0.01]. KEAP1WT/STK11WT status identified adagrasib-treated patients with significantly longer PFS (16.9 months) and OS (NR). Preclinical analyses further validate the association between KEAP1 loss of function and adagrasib resistance. Adagrasib and mTOR inhibitor combinations produced higher treatment efficacy in NSCLC models harboring STK11 and KEAP1 co-mutations. NRF2HIGH signaling was associated with shorter survival to adagrasib (PFS: 4.2 vs. 8.4 months, HR 2.0, P = 0.02; OS: 6.5 vs. 19.0 months, HR 2.8, P < 0.01) even in patients with KEAP1WT NSCLC. KEAP1WT/STK11WT/NRF2LOW status identified patients-32%-with longer survival to adagrasib (PFS 12.0 vs. 4.2 months, HR 0.2, P < 0.01; OS NR vs. 8.0 months, HR 0.1, P < 0.01).

Conclusions: KEAP1, STK11, and NRF2 status define patients with KRASG12C-mutant NSCLC with markedly distinct outcomes to adagrasib. These results further support the use of genomic features-mutational and nonmutational-for the treatment selection of patients with KRASG12C-mutant NSCLC.

Keywords

Humans, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Mutation, Mice, AMP-Activated Protein Kinase Kinases, Kelch-Like ECH-Associated Protein 1, Proto-Oncogene Proteins p21(ras), Animals, Female, Male, Protein Serine-Threonine Kinases, Xenograft Model Antitumor Assays, Aged, Middle Aged, Cell Line, Tumor, Transcriptome, Gene Expression Regulation, Neoplastic, NF-E2-Related Factor 2, Gene Expression Profiling

DOI

10.1158/1078-0432.CCR-24-2310

PMID

39804166

PMCID

PMC11911804

PubMedCentral® Posted Date

1-13-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes