Co-mutations and KRAS G12C inhibitor efficacy in advanced NSCLC.
Marcelo Vailati NegrãoHaniel A AraujoGiuseppe LambertiAlissa J CooperNeal S AkhaveTeng ZhouLukas DelasosJ Kevin HicksMihaela AldeaGabriele MinutiJacobi HinesJacqueline V AredoMichael J DennisTurja ChakrabartiSusan C ScottPaolo BironzoMatthias SchefflerPetros ChristopoulosAlbrecht StenzingerJonathan W RiessSo Yeon KimSarah B GoldbergMingjia LiQi WangYun QingYing NiMinh Truong DoRichard LeeBiagio RicciutiJoao M Victor AlessiJing WangBlerina ResuliLorenza LandiShu-Chi TsengMizuki NishinoSubba R DigumarthyWaree RinsurongkawongVadeerat RinsurongkawongAra A VaporciyanGeorge R BlumenscheinJianjun ZhangDwight H OwenCollin M BlakelyGiannis S MountziosCatherine A ShuChristine M BestvinaMarina-Chiara GarassinoKristen A MarroneJhanelle E GraySandip Pravin PatelAmy L CummingsHeather A WakeleeJuergen WolfGiorgio Vittorio ScagliottiFederico CappuzzoFabrice BarlesiPradnya D PatilLeylah DrusboskyDon L GibbonsFunda Meric-BernstamJiun-Kae Jack LeeJohn Victor HeymachDavid S HongRebecca S HeistMark M AwadFerdinandos SkoulidisPublished in: Cancer discovery (2023)
Molecular modifiers of KRAS G12C inhibitor (KRAS G12Ci) efficacy in advanced KRAS G12C-mutant NSCLC are poorly defined. In a large unbiased clinico-genomic analysis of 424 NSCLC patients, we identified and validated co-alterations in KEAP1, SMARCA4 and CDKN2A as major independent determinants of inferior clinical outcomes with KRAS G12Ci monotherapy. Collectively, co-mutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ~50% of those with early disease progression (PFS≤3 months) with KRAS G12Ci. Pathway-level integration of less prevalent co-alterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRAS G12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRAS G12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRAS G12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies.
Keyphrases
- wild type
- small cell lung cancer
- end stage renal disease
- dna damage response
- newly diagnosed
- advanced non small cell lung cancer
- chronic kidney disease
- brain metastases
- type diabetes
- randomized controlled trial
- clinical trial
- case report
- patient reported outcomes
- gene expression
- adipose tissue
- open label
- insulin resistance
- skeletal muscle
- epidermal growth factor receptor
- study protocol
- genome wide analysis