Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRAS(G12D)-mutated non-small-cell lung cancer Journal Article

   


Authors: Ricciuti, B.; Alessi, J. V.; Elkrief, A.; Wang, X.; Cortellini, A.; Li, Y. Y.; Vaz, V. R.; Gupta, H.; Pecci, F.; Barrichello, A.; Lamberti, G.; Nguyen, T.; Lindsay, J.; Sharma, B.; Felt, K.; Rodig, S. J.; Nishino, M.; Sholl, L. M.; Barbie, D. A.; Negrao, M. V.; Zhang, J.; Cherniack, A. D.; Heymach, J. V.; Meyerson, M.; Ambrogio, C.; Jänne, P. A.; Arbour, K. C.; Pinato, D. J.; Skoulidis, F.; Schoenfeld, A. J.; Awad, M. M.; Luo, J.
Article Title: Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRAS(G12D)-mutated non-small-cell lung cancer
Abstract: Background: Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS-mutant (KRASMUT) non-small-cell lung cancers (NSCLCs) exhibit heterogeneous outcomes, driven by differences in underlying biology shaped by co-mutations. In contrast to KRASG12C NSCLC, KRASG12D NSCLC is associated with low/never-smoking status and is largely uncharacterized. Patients and methods: Clinicopathologic and genomic information were collected from patients with NSCLCs harboring a KRAS mutation at the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and Imperial College of London. Multiplexed immunofluorescence for CK7, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Foxp3, and CD8 was carried out on a subset of samples with available tissue at the DFCI. Clinical outcomes to PD-(L)1 inhibition ± chemotherapy were analyzed according to KRAS mutation subtype. Results: Of 2327 patients with KRAS-mutated (KRASMUT) NSCLC, 15% (n = 354) harbored KRASG12D. Compared to KRASnon-G12D NSCLC, KRASG12D NSCLC had a lower pack-year (py) smoking history (median 22.5 py versus 30.0 py, P < 0.0001) and was enriched in never smokers (22% versus 5%, P < 0.0001). KRASG12D had lower PD-L1 tumor proportion score (TPS) (median 1% versus 5%, P < 0.01) and lower tumor mutation burden (TMB) compared to KRASnon-G12D (median 8.4 versus 9.9 mt/Mb, P < 0.0001). Of the samples which underwent multiplexed immunofluorescence, KRASG12D had lower intratumoral and total CD8+PD1+ T cells (P < 0.05). Among 850 patients with advanced KRASMUT NSCLC who received PD-(L)1-based therapies, KRASG12D was associated with a worse objective response rate (ORR) (15.8% versus 28.4%, P = 0.03), progression-free survival (PFS) [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.45-2.00, P = 0.003], and overall survival (OS; HR 1.45, 1.05-1.99, P = 0.02) to PD-(L)1 inhibition alone but not to chemo-immunotherapy combinations [ORR 30.6% versus 35.7%, P = 0.51; PFS HR 1.28 (95%CI 0.92-1.77), P = 0.13; OS HR 1.36 (95%CI 0.95-1.96), P = 0.09] compared to KRASnon-G12D. Conclusions: KRASG12D lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS-mutated lung cancers and worse outcomes to PD-(L)1 blockade. Drug development for KRASG12D lung cancers will have to take these differences into account. © 2022 European Society for Medical Oncology
Keywords: adult; cancer chemotherapy; controlled study; human tissue; treatment outcome; aged; middle aged; gene mutation; major clinical study; overall survival; genetics; mutation; clinical feature; cd8 antigen; transcription factor foxp3; cd8+ t lymphocyte; forkhead transcription factors; carboplatin; progression free survival; carcinoma, non-small-cell lung; lung neoplasms; cohort analysis; smoking; immunofluorescence; pathology; drug design; carcinogenesis; lung tumor; oncogene; genomics; immunophenotyping; cancer tissue; kras; protein p21; proto-oncogene proteins p21(ras); forkhead transcription factor; pemetrexed; kras protein, human; personalized medicine; programmed death 1 ligand 1; programmed death 1 receptor; non small cell lung cancer; nsclc; never smoker; very elderly; humans; human; male; female; article; programmed cell death 1 receptor; b7-h1 antigen; tumor mutational burden; genetic profile; pd-(l)1 blockade; population structure; g12d; krasg12d gene
Journal Title: Annals of Oncology
Volume: 33
Issue: 10
ISSN: 0923-7534
Publisher: Oxford University Press  
Date Published: 2022-10-01
Start Page: 1029
End Page: 1040
Language: English
DOI: 10.1016/j.annonc.2022.07.005
PUBMED: 35872166
PROVIDER: scopus
PMCID: PMC11006449
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85136309871&doi=10.1016%2fj.annonc.2022.07.005&partnerID=40&md5=7abc8feab67a73dee7ff9190063fd926
Notes: Article -- Export Date: 1 November 2022 -- Source: Scopus
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MSK Authors
  1. Kathryn Cecilia Arbour
    88 Arbour
  2. Adam Jacob Schoenfeld
    131 Schoenfeld
  3. Arielle Elkrief
    41 Elkrief
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