Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRAS^G12D-mutated non-small-cell lung cancer

Background: Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS-mutant (KRAS^MUT) 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 KRAS^non-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 KRAS^non-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 KRAS^MUT 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 KRAS^non-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 KRAS^G12D lung cancers will have to take these differences into account.