Bell Biosystems (United States)

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:KEAP1MUT 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.

KRASG12C inhibitors, including MRTX849, are promising treatment options for KRAS-mutant non-small cell lung cancer (NSCLC). PD-1 inhibitors are approved in NSCLC; however, strategies to enhance checkpoint inhibitor therapy (CIT) are needed. KRASG12C mutations are smoking-associated transversion mutations associated with high tumor mutation burden, PD-L1 positivity, and an immunosuppressive tumor microenvironment. To evaluate the potential of MRTX849 to augment CIT, its impact on immune signaling and response to CIT was evaluated. In human tumor xenograft models, MRTX849 increased MHC class I protein expression and decreased RNA and/or plasma protein levels of immunosuppressive factors. In a KrasG12C -mutant CT26 syngeneic mouse model, MRTX849 decreased intratumoral myeloid-derived suppressor cells and increased M1-polarized macrophages, dendritic cells, CD4+, and CD8+ T cells. Similar results were observed in lung KrasG12C -mutant syngeneic and a genetically engineered mouse (GEM) model. In the CT26 KrasG12C model, MRTX849 demonstrated marked tumor regression when tumors were established in immune-competent BALB/c mice; however, the effect was diminished when tumors were grown in T-cell-deficient nu/nu mice. Tumors progressed following anti-PD-1 or MRTX849 single-agent treatment in immune-competent mice; however, combination treatment demonstrated durable, complete responses (CRs). Tumors did not reestablish in the same mice that exhibited durable CRs when rechallenged with tumor cell inoculum, demonstrating these mice developed adaptive antitumor immunity. In a GEM model, treatment with MRTX849 plus anti-PD-1 led to increased progression-free survival compared with either single agent alone. These data demonstrate KRAS inhibition reverses an immunosuppressive tumor microenvironment and sensitizes tumors to CIT through multiple mechanisms.