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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
  1. Marina Chiara Garassino1,
  2. Delvys Rodriguez-Abreu2,
  3. Shirish M Gadgeel3,
  4. Dariusz M Kowalski4,
  5. Kazuo Kasahara5,
  6. Enriqueta Felip6,
  7. Yi-Long Wu7,
  8. Gilberto de Castro8,
  9. Byoung Chul Cho9,
  10. Hande Z Turna10,
  11. Hidehito Horinouchi11,
  12. Martin Reck12,
  13. Rina Hui13,
  14. Edward B Garon14,
  15. Michael Boyer15,
  16. Tony SK Mok16,
  17. Gilberto Lopes17,
  18. Julie Kobie18,
  19. Yongjin Li18,
  20. Mark A Ayers18,
  21. Razvan Cristescu18,
  22. Bin Zhao18,
  23. M Catherine Pietanza18 and
  24. Roy S Herbst19
  1. 1University of Chicago Medicine and Biological Sciences, Chicago, IL, USA
  2. 2Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
  3. 3Henry Ford Cancer Institute/Henry Ford Health System, Detroit, MI, USA
  4. 4Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
  5. 5Kanazawa University Hospital, Kanazawa, Japan
  6. 6Vall d’Hebron University, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
  7. 7Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangdong, China
  8. 8Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil
  9. 9Yonsei Cancer Center, Seoul, Korea, Republic of
  10. 10Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey
  11. 11National Cancer Center Hospital, Tokyo, Japan
  12. 12LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany
  13. 13Westmead Hospital and University of Sydney, Sydney, NSW, Australia
  14. 14David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
  15. 15Chris O’Brien Lifehouse, Camperdown, Australia
  16. 16State Key Laboratory of Translational Oncology, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
  17. 17Sylvester Comprehensive Cancer Center at the University of Miami and the Miller School of Medicine, Miami, FL, USA
  18. 18Merck and Co., Inc., Kenilworth, NJ, USA
  19. 19Yale University School of Medicine, Yale Comprehensive Cancer Center, New Haven, CT, USA


Background Pembrolizumab is a standard-of-care first-line treatment for advanced/metastatic NSCLC, either as monotherapy (for patients with PD-L1 tumor proportion score [TPS] ≥1%) or combined with platinum chemotherapy. An improved OS benefit has been demonstrated for both pembrolizumab monotherapy and pembrolizumab plus chemotherapy in patients with higher tumor PD-L1 expression, and for pembrolizumab monotherapy in patients with higher tissue tumor mutation burden (tTMB). Mutations in KRAS occur relatively frequently in patients with nonsquamous NSCLC but infrequently in those with squamous NSCLC; most mutations are in codon 12. Notably, the pembrolizumab OS treatment effect was not diminished in patients with KRAS G12C mutations in phase 3 studies evaluating pembrolizumab monotherapy and pembrolizumab in combination with chemotherapy.1 2 Herein we describe prevalence of KRAS mutations among patients with advanced nonsquamous NSCLC from two phase 3 clinical studies evaluating first-line pembrolizumab (KEYNOTE-042 and KEYNOTE-189) and the relationship of such mutations with select patient characteristics.

Methods KEYNOTE-042 (NCT02220894) evaluated pembrolizumab versus platinum-based chemotherapy for advanced PD-L1–positive NSCLC (any histology) without EGFR/ALK alterations. KEYNOTE-189 (NCT02578680) evaluated pembrolizumab plus platinum-based chemotherapy versus platinum-based chemotherapy alone for metastatic nonsquamous NSCLC without EGFR/ALK alterations irrespective of tumor PD-L1 expression. Whole-exome sequencing of tumor tissue and matched normal DNA (blood) was performed for patients with nonsquamous histology. PD-L1 TPS was evaluated using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA, USA). Prevalence of KRAS mutations and their relationships with TMB, PD-L1 TPS, and smoking status were analyzed descriptively.

Results 590 patients with nonsquamous NSCLC were included in these analyses (KEYNOTE-042, n=301; KEYNOTE-189, n=289). Overall, 42.9% of patients had tTMB ≥175 mut/exome, 81.4% were current/former smokers and, 40.3%, 42.7%, and 16.9% had PD-L1 TPS ≥50%, 1–49% and <1% respectively. KRAS G12C, G12D, and G12V mutations occurred in 11.0%, 4.1%, and 5.4% of patients, respectively. Prevalence of KRAS mutations by patient characteristics is summarized in the table (table 1). KRAS G12C mutations occurred almost exclusively in current/former smokers. KRAS G12C was enriched in tumors with tTMB ≥175 mut/exome and tumors with PD-L1 TPS ≥50%. Prevalence was highest in tumors with both tTMB ≥175 mut/exome and PD-L1 TPS ≥50%.

Abstract 364 Table 1

KRAS Mutation Prevalence

Conclusions KRAS G12C mutations occurred with moderate frequency in patients with nonsquamous NSCLC, with most occurring in current/former smokers. KRAS G12C mutations occurred at higher frequency in patient subgroups defined by higher tTMB and PD-L1 TPS.

Acknowledgements Medical writing assistance was provided by Christabel Wilson, MSc, of ICON plc (North Wales, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Trial Registration KEYNOTE-042,, NCT02220894; KEYNOTE-189,, NCT02578680


  1. Gadgeel S, Rodriguez-Abreu D, Felip E, et al. KRAS mutational status and efficacy in KEYNOTE-189: pembrolizumab (pembro) plus chemotherapy (chemo) vs placebo plus chemo as first-line therapy for metastatic non-squamous NSCLC. Ann Oncol 2019;30(suppl 11):xi64-xi5.

  2. Herbst RS, Lopes G, Kowalski DM, et al. Association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in KEYNOTE-042. Ann Oncol 2019;30(suppl 11):xi63-xi4.

Ethics Approval For both trials, the protocol and all amendments were approved by the appropriate ethics committee at each center, the study was conducted in accordance with the standards of Good Clinical Practice. Patients provided written informed consent before enrollment.

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