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

<div>AbstractPurpose:<p>KRAS inhibitors are revolutionizing the treatment of non–small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration.</p>Experimental Design:<p>Patients with advanced <i>KRAS</i>^<i>G12C</i>-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). <i>KRAS</i>^<i>G12C</i>-mutant NSCLC cell lines and xenograft models were used for sensitivity analyses and combination drug screens.</p>Results:<p><i>KEAP1</i>^<i>MUT</i> and <i>STK11</i>^<i>MUT</i> were associated with shorter survival to adagrasib [<i>KEAP1</i>: PFS 4.1 vs. 9.9 months, HR 2.7, <i>P</i> < 0.01; OS 5.4 vs. 19.0 months, HR 3.6, <i>P</i> < 0.01; <i>STK11</i>: PFS 4.2 vs. 11.0 months, HR 2.2, <i>P</i> < 0.01; OS 9.8 months vs. not reached (NR), HR 2.6, <i>P</i> < 0.01]. <i>KEAP1</i>^<i>WT</i>/<i>STK11</i>^<i>WT</i> status identified adagrasib-treated patients with significantly longer PFS (16.9 months) and OS (NR). Preclinical analyses further validate the association between <i>KEAP1</i> loss of function and adagrasib resistance. Adagrasib and mTOR inhibitor combinations produced higher treatment efficacy in NSCLC models harboring <i>STK11</i> and <i>KEAP1</i> co-mutations. NRF2^HIGH signaling was associated with shorter survival to adagrasib (PFS: 4.2 vs. 8.4 months, HR 2.0, <i>P</i> = 0.02; OS: 6.5 vs. 19.0 months, HR 2.8, <i>P</i> < 0.01) even in patients with <i>KEAP1</i>^<i>WT</i> NSCLC. <i>KEAP1</i>^<i>WT</i>/<i>STK11</i>^<i>WT</i>/NRF2^LOW status identified patients—32%—with longer survival to adagrasib (PFS 12.0 vs. 4.2 months, HR 0.2, <i>P</i> < 0.01; OS NR vs. 8.0 months, HR 0.1, <i>P</i> < 0.01).</p>Conclusions:<p><i>KEAP1</i>, <i>STK11</i>, and NRF2 status define patients with <i>KRAS</i>^<i>G12C</i>-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 <i>KRAS</i>^<i>G12C</i>-mutant NSCLC.</p></div>