Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster Discussion 2 – Translational research

1433 - Comprehensive pan-cancer analysis of KRAS genomic alterations (GA) including potentially targetable subsets

Date

30 Sep 2019

Session

Poster Discussion 2 – Translational research

Presenters

Sai-Hong Ou

Citation

Annals of Oncology (2019) 30 (suppl_5): v25-v54. 10.1093/annonc/mdz239

Authors

S.I. Ou1, E.S. Sokol2, R. Madison3, J. Chung3, J.S. Ross4, V.A. Miller3, B.M. Alexander3, S.M. Ali3, A.B. Schrock3, S.S. Ramalingam5

Author affiliations

  • 1 Medicine, Chao Family Comprehensive Cancer Center, 92697 - Orange/US
  • 2 Cancer Genomics, Foundation Medicine, 02141 - Cambridge/US
  • 3 Clinical Development, Foundation Medicine, 02141 - Cambridge/US
  • 4 Pathology, Foundation Medicine, 02141 - Cambridge/US
  • 5 Medical Oncology, Emory University Winship Cancer Institute, 30322 - Atlanta/US

Resources

Login to access the resources on OncologyPRO.

If you do not have an ESMO account, please create one for free.

Abstract 1433

Background

KRAS GA are common oncogenic drivers. Effective systemic treatment of KRAS altered cancers has been largely elusive; however covalent inhibitors of G12C (AMG510, MRTX849) and SHP2 inhibitors (TNO155, RMC-4630) have recently entered the clinic in multiple tumor types.

Methods

Hybrid capture-based comprehensive genomic profiling (CGP) was performed on tumor samples from 213,312 unique patients with solid or hematological malignancies. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA. PD-L1 expression was determined by IHC (22C3 or SP142 antibodies) for 17% of cases.

Results

KRAS GA were detected in 22% (n = 46,182) of cases: 88% mutations (m; >99% substitutions and <0.2% indels), 8.3% amplification (a) and 3.8% both. KRASm were most common in pancreatic (83%, 8,063/9,723) gastrointestinal (GI; 39%, 13,507/35,019) and lung adenocarcinoma (LUAD; 35%, 9,159/25,968). KRASa (median 10 copies, range 6-421) was most common in esophageal adenocarcinomas (17%, 673/3,920) and testicular germ cell tumors (25%, 46/185). Co-KRASm+a was most common in pulmonary sarcomatoid carcinoma (PSC; 7.4%, 26/353). Median TMB was 3.5, 6.1, and 4.3 mut/Mb in cases with KRASm, KRASa, or KRASm+a. 124 unique KRASm were identified, most commonly G12D/V/C and G13D (26%, 21%, 14%, 6.9% of KRAS GA). G12D resulted from transitions (primarily G>A), and G12V (primarily G>T) and G12C (exclusively G>T) from transversions. G12C was most frequent in LUAD (14%, 3,613/25,968) and PSC (11%, 40/353) but uncommon in pancreatic (1.7%, 161/9,723) and GI (2.7%, 941/35,019) where G12D/V were most common. Tobacco signature (TS; 20% vs 4.5% vs 3.5%), elevated TMB (median 7.0 vs 3.5 vs 3.5 mut/Mb) and PD-L1 positivity (56% vs 29% vs 31%) were all significantly associated with G12C vs non-G12C KRASm and non-KRASm cancers (all p < 0.0001). In LUAD, TS was present in 25% G12C, 19% non-G12C KRASm and 15% non-KRASm (all p < 0.0001).

Conclusions

Diverse KRAS GA are frequent across cancers and subtypes are associated with different solid malignancies. G12C is most common in LUAD and associated with smoking, elevated TMB and PD-L1 positivity. As multiple trials of novel therapeutic agents are currently enrolling for KRAS GA, CGP to identify these alterations is needed.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Foundation Medicine.

Disclosure

S.I. Ou: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Genentech; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Ariad; Research grant/Funding (institution): Ignyta; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Takeda; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): Clovis; Research grant/Funding (institution): Peregrine; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): TP Therapeutics; Research grant/Funding (institution): Blueprint Medicines. E.S. Sokol: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. R. Madison: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. J. Chung: Shareholder/Stockholder/Stock options: Roche; Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine. J.S. Ross: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. V.A. Miller: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche; Advisory/Consultancy: Revolution Medicines. B.M. Alexander: Leadership role, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. S.M. Ali: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche; Advisory/Consultancy: Revolution Medicines. A.B. Schrock: Full/Part-time employment: Foundation Medicine; Shareholder/Stockholder/Stock options: Roche. S.S. Ramalingam: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Brystol Myers Squib; Advisory/Consultancy: Genentech/Roche; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Research grant/Funding (institution): Tesaro; Advisory/Consultancy: Takeda; Advisory/Consultancy: Nektar.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.