TP53, KRAS Mutations May Predict Lung Adenocarcinoma Immunotherapy Response

Presence of TP53 and KRAS mutations could help guide treatment with checkpoint blockade agents in lung adenocarcinoma patients

medwireNews: Patients with adenocarcinoma of the lung who harbour TP53 and KRAS mutations have a better response to treatment with programmed cell death protein 1 (PD-1) inhibitors than those with wild-type forms of the genes, research shows.

These findings suggest that TP53 and KRAS mutations could serve as “a pair of potential predictive factors” to identify patients who would benefit most from anti-PD-1 immunotherapy, say lead author Yi-Long Wu, from Guangdong General Hospital and Guangdong Academy of Medical Sciences in Guangzhou, China, and co-workers.

They analysed publicly available data on 34 patients with advanced non-small-cell lung cancer (NSCLC; of whom 29 had adenocarcinoma) who were given the PD-1 inhibitor pembrolizumab as part of the KEYNOTE-001 trial.

Progression-free survival (PFS) was significantly longer for patients with TP53 and KRAS mutations than those harbouring the wild-type forms, at a median of 14.5 and 14.7 months, respectively, versus 3.5 months.

And significantly more individuals with TP53 and KRAS mutations versus those without achieved durable clinical benefit, the team reports in Clinical Cancer Research.

The results were similar in a prospective cohort of 20 NSCLC patients (15 with adenocarcinoma) treated with pembrolizumab or the PD-1 blocker nivolumab at a single centre in Guangzhou. Specifically, all but one of the six patients who achieved a partial response harboured mutations in TP53 and/or KRAS and median PFS was prolonged for participants with versus without the mutations.

Yi-Long Wu and colleagues also provide evidence to support their contention that TP53 and KRAS mutations could serve as a more robust biomarker of PD-1 blockade response than other markers identified thus far, such as tumour mutational load, the intensity of CD8+ T cell infiltrates and PD-L1 expression.

Using RNA expression data from 462 lung adenocarcinomas from The Cancer Genome Atlas (TCGA) and 442 from the gene Expression Omnibus repository, they found that programmed cell death ligand 1 (PD-L1) expression was increased in samples with TP53 mutations, either alone or alongside KRAS mutations.

Furthermore, analysis of data from TCGA and the Broad database showed that lung adenocarcinomas with TP53 and/or KRAS mutations had a higher mutational burden than other groups, a finding that was replicated in a prospective validation cohort comprising 85 lung adenocarcinoma patients treated at the Guangzhou centre.

And the presence of TP53 mutations seemed to facilitate CD8+ T cell infiltration, say the investigators.

Given that TP53 and KRAS mutations appear to simultaneously affect all of the previously identified biomarkers, Yi-Long Wu et al believe that they could “provide stronger predictive value for therapeutic outcomes.”

Reference

Dong Z-Y, Zhong W, Zhang X-C, et al. Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma. Clin Cancer Res; Advance online publication 30 December 2016. doi:10.1158/1078-0432

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