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KRASG12D-Mutated NSCLC is Subtype with Distinct Co-mutations, a Colder Immune Microenvironment, and Worse Outcomes to PD-1 Blockade Monotherapy

Findings from a comprehensive analysis of the clinicopathologic, genomic, and immunophenotypic correlates of KRASG12D-mutated non-small cell lung cancer
03 Aug 2022
Cancer Immunology and Immunotherapy;  Lung and other thoracic tumours;  Personalised medicine

Analysis of KRASG12D-mutated non-small cell lung cancer (NSCLC) published on 21 July 2022 in the Annals of Oncology is the first and largest report characterising this specific subset. The study team led by Dr. Jia Luo of the Lowe Center for Thoracic Oncology, Harvard Medical School in Boston, MA, US confirmed that KRASG12D-mutated NSCLC is enriched for individuals with a never/light pack-year smoking history (less than 10 pack years) compared to other KRAS subtypes. KRASG12D-mutated NSCLC has lower tumour mutation burden (TMB). Biologically, this potentially leads to fewer tumour neoantigens that are being presented to tumour antigen-specific T cells in KRASG12D-mutated NSCLC compared to KRASnon-G12D-mutated NSCLC. The tumour microenvironment of KRASG12D-mutated NSCLC reflected these findings, with significantly lower CD8-positive, PD-1-positive T cells, and lower PD-L1 expression on both tumour and immune cells, compared to KRASnon-G12D. Future retrospective and prospective clinical studies of KRAS-mutated NSCLC should consider these unique features into analysis and study design.

The authors wrote in the background that ability to target KRAS, which was considered as ‘undruggable’ oncogene, has ushered in a new era of drug development for KRAS-mutated tumours. The registrational study led to regulatory approval of the direct KRASG12C inhibitor sotorasib in patients with NSCLC. Several allele-specific KRAS inhibitors are currently under investigation for patients with KRASnon-G12C-mutated cancers, in particular, those targeting KRASG12D. While KRAS-mutated NSCLC is often considered as one subgroup in research studies, the biology of individual oncogenic KRAS drivers is context dependent.

KRASG12D is the most common mutated oncogenic form of KRAS in human cancers and is present in 4% of NSCLC. This alteration is associated with a low/never-smoking status. The underlying missense mutation leading to KRASG12D is a transition mutation, as opposed to a transversion mutation, the predominant form of nucleotide substitutions observed with tobacco exposure. However, the genomic, transcriptomic, and immunophenotypic profile of KRASG12D-mutated NSCLC has not been characterised. Similarly, whether KRASG12D-mutated NSCLC is associated with different outcomes to standard of care PD-(L)1 blockade is unknown. The authors underlined that characterising the unique features of KRASG12D is critical for precision medicine development in the era of direct KRAS inhibition.

Clinicopathologic and genomic information were collected from patients with NSCLCs harbouring a KRAS mutation at Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center and Imperial College of London. Multiplexed immunofluorescence for CK7, PD-1, PD-L1, Foxp3, and CD8 was performed on a subset of samples with available tissue at the Dana-Farber Cancer Institute. The authors analyzed clinical outcomes to PD-(L)1 inhibition with or without chemotherapy according to KRAS mutation subtype.

Of 2,327 patients with KRAS-mutated NSCLC, 354 (15%) harboured KRASG12D. Compared to KRASnon-G12D-mutated NSCLC, KRASG12D-mutated NSCLC had a lower pack-year smoking history with median 22.5 pack-year versus 30.0 pack year (p < 0.0001) and was enriched in never smokers, 22% versus 5% (p < 0.0001). KRASG12D-mutated tumours compared to KRASnon-G12D had lower PD-L1 tumour proportion score (TPS) with median 1% versus 5% (p < 0.01) and lower TMB with median 8.4 versus 9.9 mt/Mb (p < 0.0001). Of samples which underwent multiplexed immunofluorescence, KRASG12D-mutated tumours had lower intratumoural and total CD8-positive, PD-1-positive T cells (p < 0.05).

Among 850 patients with advanced KRAS-mutated NSCLC who received PD-(L)1-based treatments, 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, 95% CI 1.05-1.99; p = 0.02) to PD-(L)1 inhibition alone, but not to chemo-immunotherapy combinations in terms of ORR (30.6% versus 35.7%; p = 0.51), PFS HR 1.28, 95% CI 0.92-1.77; p = 0.13) and OS (HR 1.36, 95% CI 0.95-1.96; p =0.09) compared to KRASnon-G12D.

The authors concluded that their findings suggest that within KRAS-mutated NSCLC, KRASG12D-mutated NSCLCs are immunologically colder tumours and may not benefit as much from PD-1 blockade compared to other KRAS subtypes. Patients with KRASG12D-mutated NSCLC had significantly worse outcomes to immunotherapy, compared to KRASnon-G12D-mutated NSCLC. This was the case even after controlling for baseline features, including PD-L1 TPS and TMB, suggesting that KRASG12D-mutated NSCLC is a distinct entity, and the outcomes cannot be solely explained by existing biomarkers.

The study team noticed the bimodal smoking history within KRASG12D-mutated NSCLC, with approximately a third of individuals with a never/light pack year smoking history (less than 10 pack years) and a third with heavy pack-year smoking history (at least 30 pack years). This suggests that pack year smoking history correlates with PD-L1 expression and TMB within KRASG12D-mutated NSCLC and has implications for response to PD-1 blockade in KRASG12D-mutated NSCLC. The authors commented that despite bias associated with self-reported history, assessment of smoking history should continue be a routine part of the history even in KRASG12D-mutated NSCLC, especially when TMB is not routinely assessed.

Furthermore, NSCLCs harbouring KRASG12D were significantly enriched in mutations in NKX2-1/TTF-1, compared to KRASnon-G12D-mutated tumours. This observation is consistent with previous reports showing that NKX2-1 haploinsufficiency induces mucinous adenocarcinoma of the lung to enhance KRASG12D tumour development and warrants further study. The study team also found that compared KRASnon-G12D-mutated NSCLCs, KRASG12D-mutated NSCLC was significantly enriched for loss-of-function mutations in CDKN2A.

The results from this analysis have important implications both for existing treatment for KRASG12D-mutated NSCLC and for future drug development. 

First author, Dr. Biagio Ricciuti was supported by the Society for Immunotherapy of Cancer (SITC) AstraZeneca Clinical Lung Fellowship Award.


Ricciuti B, Alessi JV, Elkrief A, et al. Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRASG12D mutated non-small cell lung cancer. Annals of Oncology; Published online 21 July 2022. DOI: https://doi.org/10.1016/j.annonc.2022.07.005

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