Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRASG12D-mutated non-small-cell lung cancer

被引：63

作者：

Ricciuti, B. ^{[1
]}

Alessi, J., V ^{[1
]}

Elkrief, A. ^{[2
]}

Wang, X. ^{[3
]}

Cortellini, A. ^{[4
]}

Li, Y. Y. ^{[5
,6
]}

Vaz, V. R. ^{[1
]}

Gupta, H. ^{[5
]}

Pecci, F. ^{[1
]}

Barrichello, A. ^{[1
]}

Lamberti, G. ^{[1
]}

Nguyen, T. ^{[1
]}

Lindsay, J. ^{[7
]}

Sharma, B. ^{[8
]}

Felt, K.

Rodig, S. J. ^{[8
,9
]}

Nishino, M. ^{[1
,10
]}

Sholl, L. M. ^{[9
]}

Barbie, D. A. ^{[1
]}

V. Negrao, M. ^{[11
]}

Zhang, J. ^{[11
]}

Cherniack, A. D. ^{[5
]}

V. Heymach, J. ^{[11
]}

Meyerson, M.

Ambrogio, C. ^{[12
]}

Jaenne, P. A. ^{[1
]}

Arbour, K. C. ^{[2
]}

Pinato, D. J.

Skoulidis, F. ^{[11
]}

Schoenfeld, A. J. ^{[2
,12
]}

Awadt, M. M. ^{[1
]}

Luo, J. ^{[1
,13
]}

机构：

[1] Lowe Ctr Thorac Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Med, Thorac Oncol Serv, New York, NY USA

[3] Harvard Sch Publ Hlth, Boston, MA USA

[4] Hammersmith Hosp, Imperial Coll London, Dept Surg & Canc, Div Canc, London, England

[5] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA

[6] Broad Inst Harvard, Massachusetts Inst Technol MIT, Canc Program, Cambridge, England

[7] Dana Farber Canc Inst, Knowledge Syst Grp, Boston, MA USA

[8] Brigham & Women s Hosp, Dana Farber Canc Inst, ImmunoProfi, Boston, MA USA

[9] Brigham & Womens Hosp, Dept Pathol, Boston, MA USA

[10] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiol, Dept Imaging, Boston, MA USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX USA

[12] Univ Turin, Mol Biotechnol & Hlth Sci, Turin, Italy

[13] Harvard Med Sch, 450 Brookline Ave LC4116, Boston, MA 02215 USA

来源：

ANNALS OF ONCOLOGY | 2022年 / 33卷 / 10期

关键词：

KRAS; G12D; PD-(L)1 blockade; NSCLC; KRAS MUTATIONS; K-RAS; ADENOCARCINOMA; SUPPRESSION; PROGRESSION; SMOKING; ASSAY;

D O I：

10.1016/j.annonc.2022.07.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 KRAS(G12C) NSCLC, KRAS(G12D) 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 (KRAS(MUT)) NSCLC, 15% (n = 354) harbored KRAS(G12D). Compared to KRASnon-G12D NSCLC, KRAS(G12D) 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). KRAS(G12D) 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, KRAS(G12D) 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, KRAS(G12D) 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: KRAS(G12D )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.

引用

页码：1029 / 1040

页数：12

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