2025
KRAS G12C-associated immunotherapy benefit in NSCLC is substantially mediated by tobacco-induced tumor mutation burden, not allele-specific effects
Liu M, Townsend J. KRAS G12C-associated immunotherapy benefit in NSCLC is substantially mediated by tobacco-induced tumor mutation burden, not allele-specific effects. Lung Cancer 2025, 108749. DOI: 10.1016/j.lungcan.2025.108749.Peer-Reviewed Original ResearchNon-small cell lung cancerImmune-checkpoint inhibitionTumor mutational burdenMutational burdenG12C mutationLung adenocarcinomaElevated tumor mutation burdenHigh tumor mutational burdenOncogenic potentialCell lung cancerKRAS G12C mutationImmunotherapy benefitICI outcomesSmoking historyLung cancerG12D mutationHazard ratioAllele-specific effectsKRASClinical trendsKRAS G12CResponse rateTumorG12CMutations
2024
Clinical utility of upfront liquid biopsy in non-small cell lung cancer in the community setting.
Doro L, Ozcan G, Vredenburgh J, Collier E. Clinical utility of upfront liquid biopsy in non-small cell lung cancer in the community setting. Journal Of Clinical Oncology 2024, 20: 316-316. DOI: 10.1200/op.2024.20.10_suppl.316.Peer-Reviewed Original ResearchNon-small cell lung cancerNon-small cell lung cancer patientsCell lung cancerLiquid biopsyAdvanced non-small cell lung cancerLung cancerDiagnosis of advanced non-small cell lung cancerDiagnosed NSCLCNext generation sequencingMolecular profilingClinical utilityLiquid biopsy resultsComprehensive molecular profilingTarget genetic abnormalitiesKRAS G12C mutationProportion of patientsProgression of eGFRPartial responsePlasma genotypingBiopsy resultsBRCA carriersTreatment failureOncoKB databaseSystemic treatmentActionable mutationsCirculating Tumor DNA Dynamics Reveal KRAS G12C Mutation Heterogeneity and Response to Treatment with the KRAS G12C Inhibitor Divarasib in Solid Tumors
Choi Y, Dharia N, Jun T, Chang J, Royer-Joo S, Yau K, Assaf Z, Aimi J, Sivakumar S, Montesion M, Sacher A, LoRusso P, Desai J, Schutzman J, Shi Z, group A. Circulating Tumor DNA Dynamics Reveal KRAS G12C Mutation Heterogeneity and Response to Treatment with the KRAS G12C Inhibitor Divarasib in Solid Tumors. Clinical Cancer Research 2024, 30: of1-of10. PMID: 38995268, PMCID: PMC11369623, DOI: 10.1158/1078-0432.ccr-24-0255.Peer-Reviewed Original ResearchConceptsKRAS G12C mutationTumor fractionSolid tumorsTumor typesG12C mutationOn-treatment time pointsNon-small cell lung cancerMutational heterogeneityAssociated with tumor typeProgression-free survivalPlasma samplesPhase 1 studyCell lung cancerCycle 1 dayAssociated with patient outcomesVariant allele frequencyAssociated with responseCtDNA levelsCtDNA profilingMetastatic sitesTruncal mutationsTumor DNATreatment responseLung cancerTumor tissuesKROCUS: A phase II study investigating the efficacy and safety of fulzerasib (GFH925) in combination with cetuximab in patients with previously untreated advanced KRAS G12C mutated NSCLC.
Gregorc V, González-Cao M, Salvagni S, Koumarianou A, Gil-Bazo I, Maio M, Viteri S, Majem M, Gutiérrez V, Bernabe Caro R, Sanmamed M, Zhu H, Shen H, Wang Y, Rosell R. KROCUS: A phase II study investigating the efficacy and safety of fulzerasib (GFH925) in combination with cetuximab in patients with previously untreated advanced KRAS G12C mutated NSCLC. Journal Of Clinical Oncology 2024, 42: lba8511-lba8511. DOI: 10.1200/jco.2024.42.17_suppl.lba8511.Peer-Reviewed Original ResearchTreatment-related adverse eventsDisease control ratePhase II studyEpidermal growth factor receptorKRAS G12C inhibitorsDose reduction/interruptionBrain metastasesII studySafety profileG12C inhibitorsBaseline PD-L1 expressionBaseline brain metastasesActivation of epidermal growth factor receptorPD-L1 expressionTreating NSCLC patientsAnti-EGFR antibodiesFront-line treatmentKRAS G12C mutationGrowth factor receptorNSCLC ptsNSCLC modelsTumor shrinkageFrontline therapyNSCLC patientsOpen-label
2023
Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial
Desai J, Alonso G, Kim S, Cervantes A, Karasic T, Medina L, Shacham-Shmueli E, Cosman R, Falcon A, Gort E, Guren T, Massarelli E, Miller W, Paz-Ares L, Prenen H, Amatu A, Cremolini C, Kim T, Moreno V, Ou S, Passardi A, Sacher A, Santoro A, Stec R, Ulahannan S, Arbour K, Lorusso P, Luo J, Patel M, Choi Y, Shi Z, Mandlekar S, Lin M, Royer-Joo S, Chang J, Jun T, Dharia N, Schutzman J, Han S. Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. Nature Medicine 2023, 30: 271-278. PMID: 38052910, PMCID: PMC10803265, DOI: 10.1038/s41591-023-02696-8.Peer-Reviewed Original ResearchPhase 1b trialColorectal cancerSafety profileMedian progression-free survivalTreatment-related adverse eventsInhibitor-naive patientsKRAS G12C inhibitionAntitumor activityManageable safety profileObjective response rateProgression-free survivalPreliminary antitumor activityKRAS G12C mutationKRAS G12C inhibitorsEpidermal growth factor receptorVariant allele frequencyGrowth factor receptorAdverse eventsMedian durationTreatment withdrawalPoor prognosisDisease progressionArm CDose reductionG12C inhibitorsSingle-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation
Sacher A, LoRusso P, Patel M, Miller W, Garralda E, Forster M, Santoro A, Falcon A, Kim T, Paz-Ares L, Bowyer S, de Miguel M, Han S, Krebs M, Lee J, Cheng M, Arbour K, Massarelli E, Choi Y, Shi Z, Mandlekar S, Lin M, Royer-Joo S, Chang J, Dharia N, Schutzman J, Desai J. Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation. New England Journal Of Medicine 2023, 389: 710-721. PMID: 37611121, DOI: 10.1056/nejmoa2303810.Peer-Reviewed Original ResearchConceptsMedian progression-free survivalTreatment-related adverse eventsProgression-free survivalAdverse eventsSolid tumorsG12C mutationLow-grade adverse eventsGrade 3 eventsGrade 4 eventsTreatment-related deathsDiscontinuation of treatmentMetastatic solid tumorsPhase 1 studyDurable clinical responsesBiomarkers of responseKRAS G12C mutationAssessment of safetyVariant allele frequencyClinical responseColorectal cancerSerial assessmentDose reductionG12C inhibitorsPatientsTumor DNA
2022
OA03.04 Phase I A Study to Evaluate GDC-6036 Monotherapy in Patients with Non-small Cell Lung Cancer (NSCLC) with KRAS G12C Mutation
Sacher A, Patel M, Miller W, Desai J, Garralda E, Bowyer S, Kim T, De Miguel M, Falcon A, Krebs M, Lee J, Cheng M, Han S, Shacham-Shmueli E, Forster M, Jerusalem G, Massarelli E, Rodriguez L, Prenen H, Walpole I, Arbour K, Choi Y, Dharia N, Lin M, Mandlekar S, Joo S, Shi Z, Schutzman J, LoRusso P. OA03.04 Phase I A Study to Evaluate GDC-6036 Monotherapy in Patients with Non-small Cell Lung Cancer (NSCLC) with KRAS G12C Mutation. Journal Of Thoracic Oncology 2022, 17: s8-s9. DOI: 10.1016/j.jtho.2022.07.023.Peer-Reviewed Original Research362P Phase Ia study to evaluate GDC-6036 monotherapy in patients with colorectal cancer (CRC) with KRAS G12C mutation
Desai J, Han S, Forster M, Kim T, Casal G, Shmueli E, Bowyer S, De Miguel M, Gonzalez A, Jones R, Krebs M, Miller W, Paz-Ares L, Lorusso P, Sacher A, Dharia N, Lin M, Schutzman J, Shi Z, Patel M. 362P Phase Ia study to evaluate GDC-6036 monotherapy in patients with colorectal cancer (CRC) with KRAS G12C mutation. Annals Of Oncology 2022, 33: s701-s702. DOI: 10.1016/j.annonc.2022.07.500.Peer-Reviewed Original Research459MO Phase Ia study to evaluate GDC-6036 monotherapy in patients with solid tumors with a KRAS G12C mutation
Patel M, Lee J, De Miguel M, Burns T, Gonzalez A, Kim T, Krebs M, Prenen H, Shmueli E, Desai J, Lorusso P, Sacher A, Choi Y, Dharia N, Lin M, Mandlekar S, Royer-Joo S, Schutzman J, Garralda E. 459MO Phase Ia study to evaluate GDC-6036 monotherapy in patients with solid tumors with a KRAS G12C mutation. Annals Of Oncology 2022, 33: s749. DOI: 10.1016/j.annonc.2022.07.588.Peer-Reviewed Original ResearchKRYSTAL-1: Updated activity and safety of adagrasib (MRTX849) in patients (Pts) with unresectable or metastatic pancreatic cancer (PDAC) and other gastrointestinal (GI) tumors harboring a KRASG12C mutation.
Bekaii-Saab T, Spira A, Yaeger R, Buchschacher G, McRee A, Sabari J, Johnson M, Barve M, Hafez N, Velastegui K, Christensen J, Kheoh T, Der-Torossian H, Rybkin I. KRYSTAL-1: Updated activity and safety of adagrasib (MRTX849) in patients (Pts) with unresectable or metastatic pancreatic cancer (PDAC) and other gastrointestinal (GI) tumors harboring a KRASG12C mutation. Journal Of Clinical Oncology 2022, 40: 519-519. DOI: 10.1200/jco.2022.40.4_suppl.519.Peer-Reviewed Original ResearchDisease control rateKRAS G12C mutationProgression-free survivalPartial responseGI tumorsClinical activityG12C mutationPancreatic cancerSolid tumorsMedian progression-free survivalTreatment-related adverse eventsGrade 3/4 eventsGrade 5 eventsPhase 1/2 studyAdvanced solid tumorsMetastatic pancreatic cancerMetastatic solid tumorsEncouraging clinical activityPhase 2 cohortExtensive tissue distributionKRAS G12C inhibitorsFavorable pharmacokinetic propertiesEvaluable ptsKRASG12C mutationData cutoff
2021
364 KRAS mutations in patients with nonsquamous non–small-cell lung cancer: prevalence and relationship with PD-L1 expression, tumor mutation burden and smoking status
Garassino M, Rodriguez-Abreu D, Gadgeel S, Kowalski D, Kasahara K, Felip E, Wu Y, de Castro G, Cho B, Turna H, Horinouchi H, Reck M, Hui R, Garon E, Boyer M, Mok T, Lopes G, Kobie J, Li Y, Ayers M, Cristescu R, Zhao B, Pietanza M, Herbst R. 364 KRAS mutations in patients with nonsquamous non–small-cell lung cancer: prevalence and relationship with PD-L1 expression, tumor mutation burden and smoking status. Journal For ImmunoTherapy Of Cancer 2021, 9: a391-a391. DOI: 10.1136/jitc-2021-sitc2021.364.Peer-Reviewed Original ResearchPD-L1 TPSKRAS G12C mutationPD-L1 expressionPlatinum-based chemotherapyTumor PD-L1 expressionEGFR/ALK alterationsFirst-line therapyNon-squamous NSCLCNonsquamous NSCLCTumor mutation burdenPembrolizumab monotherapyKRAS mutational statusKEYNOTE-042KEYNOTE-189KRAS mutationsFormer smokersG12C mutationPatient characteristicsALK alterationsPD-L1Smoking statusMutation burdenKRAS G12CHigh tumor PD-L1 expressionMutational status
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