Targeting KRAS in non-small-cell lung cancer: recent progress and new approaches
Authors: M. Reck, D.P. Carbone, M. Garassino, F. Barlesi
Journal: Annals of Oncology (2021)

•Better understanding of RAS signaling has led to the development of promising directly blocking compounds in KRAS-mutant tumors.•New drug candidates take advantage of the increased knowledge of the KRAS mutation complex and relevant protein structures.•Increasing evidence continues to demonstrate the genomic heterogeneity in KRAS-mutated NSCLC.•Current efforts include understanding and overcoming resistance after treatment with KRASG12C inhibitors. Rat sarcoma (RAS) is the most frequently mutated oncogene in human cancer, with Kirsten rat sarcoma (KRAS) being the most commonly mutated RAS isoform. Overall, KRAS accounts for 85% of RAS mutations observed in human cancers and is present in 35% of lung adenocarcinomas (LUADs). While the use of targeted therapies and immune checkpoint inhibitors (CPIs) has drastically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC) in recent years, historic attempts to target KRAS (both direct and indirect approaches) have had little success, and no KRAS-specific targeted therapies have been approved to date for patients in this molecular subset of NSCLC. With the discovery by Ostrem, Shokat, and colleagues of the switch II pocket on the surface of the active and inactive forms of KRAS, we now have an improved understanding of the complex interactions involved in the RAS family of signaling proteins which has led to the development of a number of promising direct KRASG12C inhibitors, such as sotorasib and adagrasib. In previously treated patients with KRASG12C-mutant NSCLC, clinical activity has been shown for both sotorasib and adagrasib monotherapy; these data suggest promising new treatment options are on the horizon. With the stage now set for a new era in the treatment of KRASG12C-mutated NSCLC, many questions remain to be answered in order to further elucidate the mechanisms of resistance, how best to use combination strategies, and if KRASG12C inhibitors will have suitable activity in earlier lines of therapy for patients with advanced/metastatic NSCLC. Rat sarcoma (RAS) is the most frequently mutated oncogene in human cancer, with Kirsten rat sarcoma (KRAS) being the most commonly mutated RAS isoform. Overall, KRAS accounts for 85% of RAS mutations observed in human cancers and is present in 35% of lung adenocarcinomas (LUADs). While the use of targeted therapies and immune checkpoint inhibitors (CPIs) has drastically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC) in recent years, historic attempts to target KRAS (both direct and indirect approaches) have had little success, and no KRAS-specific targeted therapies have been approved to date for patients in this molecular subset of NSCLC. With the discovery by Ostrem, Shokat, and colleagues of the switch II pocket on the surface of the active and inactive forms of KRAS, we now have an improved understanding of the complex interactions involved in the RAS family of signaling proteins which has led to the development of a number of promising direct KRASG12C inhibitors, such as sotorasib and adagrasib. In previously treated patients with KRASG12C-mutant NSCLC, clinical activity has been shown for both sotorasib and adagrasib monotherapy; these data suggest promising new treatment options are on the horizon. With the stage now set for a new era in the treatment of KRASG12C-mutated NSCLC, many questions remain to be answered in order to further elucidate the mechanisms of resistance, how best to use combination strategies, and if KRASG12C inhibitors will have suitable activity in earlier lines of therapy for patients with advanced/metastatic NSCLC. Rat sarcoma (RAS) is the most frequently mutated oncogene in human cancer,1Soh J. Okumura N. Lockwood W.W. et al.Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells.PLoS One. 2009; 4: e7464Crossref PubMed Scopus (193) Google Scholar,2Bos J.L. Ras Oncogenes in human cancer: a review.Cancer Res. 1989; 49: 4682-4689PubMed Google Scholar with Kirsten rat sarcoma (KRAS) being the most commonly mutated RAS isoform3Prior I.A. Lewis P.D. Mattos C. A comprehensive survey of Ras mutations in cancer.Cancer Res. 2012; 72: 2457-2467Crossref PubMed Scopus (1378) Google Scholar and a key clonal oncogenic driver. Overall, KRAS accounts for 85% of RAS mutations observed in human cancers.4Simanshu D.K. Nissley D.V. McCormick F. RAS proteins and their regulators in human disease.Cell. 2017; 170: 17-33Abstract Full Text Full Text PDF PubMed Scopus (1024) Google Scholar The three human cancer types with the highest rate of KRAS mutations are pancreatic (88%), colorectal (45%-50%), and lung cancers (31%-35%).5Prior I.A. Hood F.E. Hartley J.L. The frequency of Ras mutations in cancer.Cancer Res. 2020; 80: 2969-2974Crossref PubMed Scopus (393) Google Scholar Despite decades of preclinical and clinical research aimed at identifying inhibitors of RAS, to date there are no approved therapies specifically inhibiting mutated forms of KRAS or its downstream signaling. A better understanding of the complex interactions involved in the RAS family of signaling proteins, however, has led to the development of a number of promising compounds that directly block KRAS activity in patients with KRAS-mutant NSCLC and to the exploration of new combination approaches to inhibit KRAS. These new KRAS inhibitors, which are being investigated as monotherapies and also in combination with other therapies, have the potential to represent an important advance in the treatment of KRAS-mutated NSCLC. In this article, we discuss the biology and history of targeting KRAS in lung cancer and provide an update on these emerging therapies. KRAS encodes a membrane-bound guanosine triphosphatase (GTPase), which is inactive when bound to guanosine diphosphate (GDP) and active when bound to guanosine triphosphate (GTP).6Hallin J. Engstrom L.D. Hargis L. et al.The KRAS(G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients.Cancer Discov. 2020; 10: 54-71Crossref PubMed Scopus (682) Google Scholar The cycling of RAS proteins to their active GTP-bound state is promoted by a guanine nucleotide exchange factor (GEF), such as son of sevenless isoform 1 (SOS1) protein.7Vigil D. Cherfils J. Rossman K.L. Der C.J. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?.Nat Rev Cancer. 2010; 10: 842-857Crossref PubMed Scopus (603) Google Scholar,8Hillig R.C. Sautier B. Schroeder J. et al.Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction.Proc Natl Acad Sci U S A. 2019; 116: 2551-2560Crossref PubMed Scopus (218) Google Scholar This active form of KRAS acts like a cellular switch that, when turned on by extracellular stimuli, can activate downstream signaling pathways responsible for fundamental cell processes9Malumbres M. Barbacid M. RAS oncogenes: the first 30 years.Nat Rev Cancer. 2003; 3: 459-465Crossref PubMed Scopus (1478) Google Scholar (Figure 1). Key effector pathways downstream of oncogenic KRAS include mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3K), and Ras-like (Ral) GEF (RalGEF); all of these effectors are responsible for cell proliferation, cell cycle regulation, metabolic changes, cell survival, and cell differentiation.10Stokoe D. Macdonald S.G. Cadwallader K. Symons M. Hancock J.F. Activation of Raf as a result of recruitment to the plasma membrane.Science. 1994; 264: 1463-1467Crossref PubMed Scopus (903) Google Scholar The KRAS protein cycles between GTP- and GDP-bound states and has a resynthesis half-life of ∼24 h.11Shukla S. Allam U.S. Ahsan A. et al.KRAS protein stability is regulated through SMURF2: UBCH5 complex-mediated beta-TrCP1 degradation.Neoplasia. 2014; 16: 115-128Crossref PubMed Scopus (69) Google Scholar,12Canon J. Rex K. Saiki A.Y. et al.The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.Nature. 2019; 575: 217-223Crossref PubMed Scopus (1139) Google Scholar KRAS can be dysregulated and lead to tumor growth, playing a key role in controlling interactions between cancer cells and the microenvironment, which ultimately affects therapeutic response.13Carvalho P.D. Machado A.L. Martins F. Seruca R. Velho S. Targeting the tumor microenvironment: an unexplored strategy for mutant KRAS tumors.Cancers (Basel). 2019; 11: 2010Crossref Scopus (31) Google Scholar Mutant KRAS cells have also been associated with decreased major histocompatibility class I (MHC I) expression, upregulation of programmed cell death–ligand 1 (PD-L1), and promotion of an immunosuppressive immune cell population in the tumor microenvironment (TME)13Carvalho P.D. Machado A.L. Martins F. Seruca R. Velho S. Targeting the tumor microenvironment: an unexplored strategy for mutant KRAS tumors.Cancers (Basel). 2019; 11: 2010Crossref Scopus (31) Google Scholar via the recruitment, accumulation, and maintenance of myeloid-derived suppressor cells (MDSCs) to the TME.14Liao W. Overman M.J. Boutin A.T. et al.KRAS-IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer.Cancer Cell. 2019; 35: 559-572.e7Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar Preclinical studies conducted on KRAS mutations in lung adenocarcinoma (LUAD), pancreatic, and colorectal cancer suggest that these alterations occur early in the carcinogenesis process and promote cancer cell survival, invasion, and migration.15Johnson L. Mercer K. Greenbaum D. et al.Somatic activation of the K-ras oncogene causes early onset lung cancer in mice.Nature. 2001; 410: 1111-1116Crossref PubMed Scopus (978) Google Scholar Point mutations represent a common dysregulation in the KRAS gene that leads to a constitutively active GTP-bound state, thereby triggering downstream oncogenic pathways.16Bourne H.R. Sanders D.A. McCormick F. The GTPase superfamily: a conserved switch for diverse cell functions.Nature. 1990; 348: 125-132Crossref PubMed Scopus (2068) Google Scholar, 17Bourne H.R. Sanders D.A. McCormick F. The GTPase superfamily: conserved structure and molecular mechanism.Nature. 1991; 349: 117-127Crossref PubMed Scopus (2952) Google Scholar, 18Scheffzek K. Ahmadian M.R. Kabsch W. et al.The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants.Science. 1997; 277: 333-338Crossref PubMed Scopus (1223) Google Scholar Smoking has been strongly associated with KRAS mutations in lung cancer. KRAS mutations are more common in LUADs (20%-40%) and less common (∼5%) in squamous NSCLC.19Martin P. Leighl N.B. Tsao M.-S. Shepherd F.A. KRAS mutations as prognostic and predictive markers in non-small cell lung cancer.J Thorac Oncol. 2013; 8: 530-542Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar Such mutations are also more common in cigarette smokers versus nonsmokers (30% versus 11%) and in Western versus Asian populations (26% versus 11%).20Adderley H. Blackhall F.H. Lindsay C.R. KRAS-mutant non-small cell lung cancer: converging small molecules and immune checkpoint inhibition.EBioMedicine. 2019; 41: 711-716Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar KRAS mutations have been observed in up to 30% of patients with NSCLC21Skoulidis F. Heymach J.V. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.Nat Rev Cancer. 2019; 19: 495-509Crossref PubMed Scopus (490) Google Scholar and occur primarily (>95%) at codons 12 and 13. A large study found that the most common codon variants in the protein were mutations from amino acid glycine (Gly) to cysteine (Cys) (or G12C variants), which accounted for 39% of KRAS mutations, followed by mutations from amino acid Gly to valine (Val) G12V (21%) and mutations from amino acid G to aspartic acid (Asp) G12D (17%).22Dogan S. Shen R. Ang D.C. et al.Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers.Clin Cancer Res. 2012; 18: 6169-6177Crossref PubMed Scopus (472) Google Scholar Compared with other KRAS mutations, G12C is more common in women (P = 0.007).22Dogan S. Shen R. Ang D.C. et al.Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers.Clin Cancer Res. 2012; 18: 6169-6177Crossref PubMed Scopus (472) Google Scholar In addition, the distribution of mutations and codon variants in KRAS differs by smoking status. Smoking-associated KRASG12C (41% of former smokers [those who have quit smoking 1 year before diagnosis] and current smokers [those still smoking or who have quite <1 year before diagnosis]) or KRASG12V mutations are associated with transversion mutations in the DNA, involving nucleotide changes from guanine (G) to thymine (T) or guanine (Gua) to cytosine (Cyt). On the other hand, among never-smokers (<100 lifetime cigarettes), the most common KRAS mutation was KRASG12D (56%), a transition mutation involving nucleotide changes from Gua to adenine (Ade).22Dogan S. Shen R. Ang D.C. et al.Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers.Clin Cancer Res. 2012; 18: 6169-6177Crossref PubMed Scopus (472) Google Scholar Data on the prognostic value of KRAS mutations in NSCLC are conflicting. Some reports suggest that patients with KRAS mutations have a poor prognosis, while other studies demonstrate that patients with wild-type (WT) KRAS and mutant KRAS have similar outcomes.23Rodenhuis S. van de Wetering M.L. Mooi W.J. Evers S.G. van Zandwijk N. Bos J.L. Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung.N Engl J Med. 1987; 317: 929-935Crossref PubMed Scopus (495) Google Scholar, 24Mascaux C. Iannino N. Martin B. et al.The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis.Br J Cancer. 2005; 92: 131-139Crossref PubMed Scopus (526) Google Scholar, 25Villaruz L.C. Socinski M.A. Cunningham D.E. et al.The prognostic and predictive value of KRAS oncogene substitutions in lung adenocarcinoma.Cancer. 2013; 119: 2268-2274Crossref PubMed Scopus (46) Google Scholar, 26Goulding R.E. Chenoweth M. Carter G.C. et al.KRAS mutation as a prognostic factor and predictive factor in advanced/metastatic non-small cell lung cancer: a systematic literature review and meta-analysis.Cancer Treat Res Commun. 2020; 24: 100200Crossref PubMed Scopus (26) Google Scholar Although great progress in discovering and developing targeted therapies for molecular subsets of LUAD has been made, no currently approved drugs specifically target any KRAS mutation, which occurs in about one-third of patients with LUAD (see Figure 2).21Skoulidis F. Heymach J.V. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.Nat Rev Cancer. 2019; 19: 495-509Crossref PubMed Scopus (490) Google Scholar KRAS has been the subject of extensive drug development efforts for nearly 40 years. These efforts have included targeting the KRAS protein itself as well as its post-translational modifications, membrane localization, protein-protein interactions, and downstream signaling pathways. Most of these approaches have not proved successful in clinical studies27Christensen J.G. Olson P. Briere T. Wiel C. Bergo M.O. Targeting Kras G12C-mutant cancer with a mutation-specific inhibitor.J Intern Med. 2020; 288: 183-191Crossref PubMed Scopus (56) Google Scholar (see Table 1), because, as the discovery by Ostrem, Shokat and colleagues has demonstrated, the KRAS protein has a relatively shallow, smooth surface, with the exception of the GTP/GDP-binding pocket.6Hallin J. Engstrom L.D. Hargis L. et al.The KRAS(G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients.Cancer Discov. 2020; 10: 54-71Crossref PubMed Scopus (682) Google Scholar,28Jarvis L.M. Have drug hunters finally cracked KRas?.Chem Eng News. 2016; 94: 28-33Google Scholar,29Ostrem J.M.L. Shokat K.M. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design.Nat Rev Drug Discov. 2016; 15: 771-785Crossref PubMed Scopus (383) Google ScholarTable 1Historical attempts to target KRAS in NSCLCTarget/pathwayDrug/assetRAF-MEK-ERKSalirasib, trametinib, sorafenibFarnesyl transferaseTipifarnib, ionafarnib, salirasibNF-κBBortezomibRhoA-FAKDefactinibPI3K-AKT-mTORRidaforolimus, sorafenib, copanlisibHSP90 and MEKAUY-922, selumetinibMETPimasertib, ganetespib, onartuzumabHDAC inhibitionBelinastatDNA alkylationKR-12PDEδDeltasonamide 1 and 2GeranylgeranyltransferaseGGTI-2418KRAS siRNASGS6 siRNA, KRAS-siRNA NPKRAS (vaccine)mRNA-5671SOS1BI 1701963KRAS degradationPTD-RBD-VIFRAS-mimeticRigosertibGlutaminaseCB-839BCL2 and MEK (synthetic lethality)Navitoclax, trametinibTBK1 and MEK (synthetic lethality)Momelotinib, trametinibCDK4 and MEK (synthetic lethality)Palbociclib, PD-0325901, abemaciclibSHP2 and MEKSHP099, AZD6244AKT, protein kinase B; BCL-2, B-cell lymphoma 2; CDK4, cyclin-dependent kinase 4; ERK, extracellular receptor kinase; FAK, focal adhesion kinase; HDAC, histone deacetylase; Hsp90, heat shock protein 90; KRAS, Kirsten rat sarcoma; MEK, mitogen-activated protein kinase kinase; MET, mesenchymal-epithelial transition; mTOR: mammalian target of rapamycin; NF-kB: nuclear factor-kappa B; NSCLC, non-small-cell lung cancer; PDEδ, phosphodiesterase-δ; PI3K, phosphoinositide 3-kinase; RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma; RhoA, Ras homolog family member A; RTK, receptor tyrosine kinase; SHP2, Src homology 2; siRNA, small interfering ribonucleic acid; SOS1, son of sevenless isoform 1; TBK1, TANK-binding kinase 1. Open table in a new tab AKT, protein kinase B; BCL-2, B-cell lymphoma 2; CDK4, cyclin-dependent kinase 4; ERK, extracellular receptor kinase; FAK, focal adhesion kinase; HDAC, histone deacetylase; Hsp90, heat shock protein 90; KRAS, Kirsten rat sarcoma; MEK, mitogen-activated protein kinase kinase; MET, mesenchymal-epithelial transition; mTOR: mammalian target of rapamycin; NF-kB: nuclear factor-kappa B; NSCLC, non-small-cell lung cancer; PDEδ, phosphodiesterase-δ; PI3K, phosphoinositide 3-kinase; RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma; RhoA, Ras homolog family member A; RTK, receptor tyrosine kinase; SHP2, Src homology 2; siRNA, small interfering ribonucleic acid; SOS1, son of sevenless isoform 1; TBK1, TANK-binding kinase 1. Until about 5 years ago, direct targeting of KRAS was seen as highly challenging due to the complexity of its biochemistry,30Tomasini P. Walia P. Labbe C. Jao K. Leighl N.B. Targeting the KRAS pathway in non-small cell lung cancer.Oncologist. 2016; 21: 1450-1460Crossref PubMed Scopus (91) Google Scholar the high affinity of GTP for KRAS,31Gysin S. Salt M. Young A. McCormick F. Therapeutic strategies for targeting ras proteins.Genes Cancer. 2011; 2: 359-372Crossref PubMed Scopus (264) Google Scholar and its limited number of active binding sites.32Spoerner M. Herrmann C. Vetter I.R. Kalbitzer H.R. Wittinghofer A. Dynamic properties of the Ras switch I region and its importance for binding to effectors.Proc Natl Acad Sci U S A. 2001; 98: 4944-4949Crossref PubMed Scopus (254) Google Scholar Recent advances in computational modeling33Buhrman G. O'Connor C. Zerbe B. et al.Analysis of binding site hot spots on the surface of Ras GTPase.J Mol Biol. 2011; 413: 773-789Crossref PubMed Scopus (120) Google Scholar and crystallography have led to the discovery of small molecules that bind directly to specific RAS conformations.34Ostrem J.M. Peters U. Sos M.L. Wells J.A. Shokat K.M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions.Nature. 2013; 503: 548-551Crossref PubMed Scopus (1469) Google Scholar The binding affinity of these early-stage compounds needed to be substantially improved, however, for them to work effectively as therapies. Although these compounds proved that RAS is a druggable target, they lacked potency and some lacked specificity for the mutated forms of RAS.35Shima F. Matsumoto S. Yoshikawa Y. Kawamura T. Isa M. Kataoka T. Current status of the development of Ras inhibitors.J Biochem. 2015; 158: 91-99Crossref PubMed Scopus (25) Google Scholar Numerous other strategies for indirectly targeting KRAS were explored as well, including post-translational modifications, membrane localization, protein-protein interactions, and inhibition of downstream signaling pathways. The farnesylation of RAS protein is required both for its normal physiologic function and for the transforming capacity of its oncogenic mutants. Over the last several decades, farnesyl transferase inhibitors (FTIs) were developed as anticancer agents to disrupt the farnesylation of oncogenic RAS. Some of these FTIs (e.g., tipifarnib and salirasib) have undergone clinical investigation but have not shown clinical efficacy in KRAS-mutant NSCLC.36Adjei A.A. Mauer A. Bruzek L. et al.Phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced non-small-cell lung cancer.J Clin Oncol. 2003; 21: 1760-1766Crossref PubMed Scopus (186) Google Scholar,37Riely G.J. Johnson M.L. Medina C. et al.A phase II trial of salirasib in patients with lung adenocarcinomas with KRAS mutations.J Thorac Oncol. 2011; 6: 1435-1437Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar Mechanisms by mutant KRAS to combat farnesylation and activate oncogenesis, such as alternative prenylation by geranylgeranyl transferases, have led to the failure of these studies.38Heymach J.V. Johnson D.H. Khuri F.R. et al.Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer.Ann Oncol. 2004; 15: 1187-1193Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar Small molecules were also developed that inhibited the rapidly accelerated fibrosarcoma (RAF) association in cells and reduced the phosphorylation of downstream molecules, such as mitogen-activated protein kinase kinase (MEK) and extracellular regulated kinase (ERK).35Shima F. Matsumoto S. Yoshikawa Y. Kawamura T. Isa M. Kataoka T. Current status of the development of Ras inhibitors.J Biochem. 2015; 158: 91-99Crossref PubMed Scopus (25) Google Scholar,39Shima F. Yoshikawa Y. Ye M. et al.In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction.Proc Natl Acad Sci U S A. 2013; 110: 8182-8187Crossref PubMed Scopus (242) Google Scholar While MEK has been hypothesized as a suitable target for downstream KRAS inhibition, the efficacy of MEK inhibitors as monotherapy in clinical trials has been modest. Selumetinib, an allosteric, selective inhibitor of MEK1/2, demonstrated preclinical activity in KRAS-mutated cancers.40Garon E.B. Finn R.S. Hosmer W. et al.Identification of common predictive markers of in vitro response to the MEK inhibitor selumetinib (AZD6244; ARRY-142886) in human breast cancer and non-small cell lung cancer cell lines.Mol Cancer Ther. 2010; 9: 1985-1994Crossref PubMed Scopus (56) Google Scholar In a randomized phase II trial in 87 pretreated patients with KRAS-mutated advanced NSCLC, which compared selumetinib + docetaxel with docetaxel + placebo, however, differences in overall survival (OS) were not statistically significant (9.4 versus 5.2 months; P = 0.21). Differences in other measures did reach statistical significance: objective response rate (ORR) in the selumetinib/docetaxel group was 37% versus 0% in the docetaxel/placebo group (P < 0.0001) and progression-free survival (PFS) was 5.3 versus 2.1 months (P = 0.014).41Janne P.A. Shaw A.T. Pereira J.R. et al.Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomized, multicentre, placebo-controlled, phase 2 study.Lancet Oncol. 2013; 14: 38-47Abstract Full Text Full Text PDF PubMed Scopus (570) Google Scholar In another study, 510 patients with KRAS-mutant advanced NSCLC were randomized to receive selumetinib + docetaxel or placebo + docetaxel as second-line therapy. This study failed to show an improvement in PFS (HR, 0.93)].42Janne P.A. van den Heuvel M.M. Barlesi F. et al.Selumetinib plus docetoxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer. The SELECT-1 randomized clinical trial.JAMA. 2017; 317: 1844-1853Crossref PubMed Scopus (264) Google Scholar Preclinical studies have demonstrated that KRAS-mutant NSCLC cell lines and xenografts with additional alterations in either the tumor protein p53 (TP53) or cyclin-dependent kinase inhibitor 2A (CDKN2A; INK4A/ARF) loci are sensitive to focal adhesion kinase (FAK) inhibition.43Gerber D.E. Camidge D.R. Morgensztern D. et al.Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previouslly treated advanced KRAS mutant non-small cell lung cancer.Lung Cancer. 2020; 139: 60-67Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar In a phase II study that investigated FAK inhibition in heavily pretreated patients with KRAS-mutant NSCLC, defactinib monotherapy demonstrated modest clinical activity (median PFS, 45 days) and efficacy was not associated with TP53 and CDKN2A status.43Gerber D.E. Camidge D.R. Morgensztern D. et al.Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previouslly treated advanced KRAS mutant non-small cell lung cancer.Lung Cancer. 2020; 139: 60-67Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar Seminal work conducted by Ostrem, Shokat and colleagues has paved the way for the discovery of a new generation of direct inhibitors of KRASG12C. Their investigation of the crystal structure of the mutant protein bound to GDP revealed a new pocket beneath the effector binding switch II region, not apparent in previous models of RAS; the discovery of this new pocket allowed for the direct targeting of KRAS.34Ostrem J.M. Peters U. Sos M.L. Wells J.A. Shokat K.M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions.Nature. 2013; 503: 548-551Crossref PubMed Scopus (1469) Google Scholar Numerous drug candidates have since been synthesized that take advantage of the increased understanding of mutant KRASG12C protein structure and rely on covalent binding to cysteine (C). Sotorasib (AMG510) is a covalent KRASG12C inhibitor that irreversibly and selectively binds to the switch II pocket within mutant KRAS, locking it in the inactive GDP-bound state. Pharmacokinetic (PK) analyses of phase I data demonstrated that the half-life of sotorasib is ∼5.5 h.44Govindan R. Phase 1 study of AMG 510, a novel KRASG12C inhibitor, in advanced solid tumors with KRAS P. G12C mutation.in: Poster presented at the European Society for Medical Oncology Congress. 2019Google Scholar Sotorasib monotherapy was evaluated in a phase I/II study (CodeBreak 100: NCT03600883; Table 2) in patients with previously treated, locally advanced or metastatic malignancies harboring a KRASG12C mutation, with a primary endpoint of ORR. At the 960-mg once daily dose continued until disease progression that was selected for phase II in patients with metastatic NSCLC (N = 124), ORR was 37.1% and disease control rate (DCR) was 80.6% (Figure 3). In these patients with NSCLC, median duration of response was 10.0 months, median time to objective response was 1.4 months, and median PFS was 6.8 months for sotorasib. Grade 3 or 4 (This is based on standing tumor staging criteria in NSCLC) treatment-related adverse events (TRAEs) occurred in 19.8% of patients (N = 126).45Hong D.S. Fakih M.G. Strickler J.H. et al.KRAS(G12C) inhibition with sotorasib in advanced solid tumors.N Engl J Med. 2020; 383: 1207-1217Crossref PubMed Scopus (852) Google Scholar,46Li L.T. CodeBreaK 100: registrational phase 2 trial of sotorasib in KRAS p.G12C mutated non small cell lung cancer.in: Abstract presented at the 2020 Virtual World Conference on Lung Cancer. 2021Google Scholar TRAEs with sotorasib occurring in >5% of patients include gastrointestinal toxicities such as diarrhea (4% grade 3), nausea, and vomiting, as well as hepatotoxicities such as alanine aminotransferase (ALT) increase (6.3% grade 3) and aspartate aminotransferase (AST) increase (5.6% grade 3). TRAEs led to treatment discontinuation in 7.1% of patients and to dose modification in 22.2% of patients. Sotorasib was granted breakthrough designation by the U.S. Food and Drug Administration (FDA) and a new drug application (NDA) was filed in December 2020. Furthermore, the global phase III trial, CodeBreak 200 (NCT04303780), comparing sotorasib with docetaxel in patients with KRASG12C-mutated NSCLC is ongoing.Table 2KRAS-targeting agents in clinical or preclinical development in NSCLCTargetManufacturerAgentStatusClinicalTrials.gov identifierKRASG12CMirati Therapeutics, Inc.AdagrasibPhase I/IIPhase I/IIPhase IIPhase IIINCT03785249NCT04330664NCT04613596NCT04685135KRASG12CAmgenSotorasibPhase IbPhase I/IIPhase IIINCT04185883NCT03600883NCT04303780KRASG12CInventisBioD-1553Phase I/IINCT04585035KRASG12CGenentechGDC-6036/RG6330Phase INCT04449874KRASG12CAstraZenecaAZD4625Phase IPendingKRASG12CNovartisJDQ443Phase INCT04699188KRASG12CJacobioJAB-21000PreclinicalN/AKRASG12DJacobioJAB-22000PreclinicalN/AKRASG12VJacobioJAB-23000PreclinicalN/AKRASBridgeBioBBP-454PreclinicalN/AKRASG12CLillyLY3537982PreclinicalN/AKRASG12CLillyLY3499446DiscontinuedNCT04165031KRASG12CJanssenJNJ-74699157DiscontinuedNCT04006301KRAS, Kirsten rat sarcoma viral oncogene homolog; N/A, not appli