Genomic profiling of NSCLC may be predictive of immunotherapy response

In patients with non-small-cell lung cancer (NSCLC) who had been treated with immune checkpoint inhibitors, patients with neurofibromin 1 (NF1)-mutant and high tumour mutation burden (TMB) NSCLC had longer progression-free survival (PFS) than patients with NF1-wild type/high TMB NSCLC [1].

NF1 is a RAS GTPase-activating protein that regulates nucleotide cycling; if inactivated, carcinogenesis ensues. Although NF1 mutations are known to occur in NSCLC (5­–11%), NF1-mutant NSCLC has yet to be genomically profiled. There is also a paucity of data about the response of this subgroup to immune checkpoint inhibitors. Investigators sought to address these gaps.

To characterise the genomic landscape of NF1-mutant NSCLC, Dr Marcelo Negrao (MD Anderson Cancer Center, TX, USA) and colleagues utilised the FMI FoundationCore NSCLC database, which had >4,500 samples covering the NF1-mutant variant. NF1 alterations were assessed for functionality using a proprietary artificial intelligence-based algorithm. Genomic profiling for all samples was performed via next-generation targeted panel sequencing, and PD-L1 expression was assessed via Dako 22C3 assay. Highlights of their findings included:

• Loss-of-function NF1 mutations were prevalent in NSCLC
• NF1-mutant lung adenocarcinomas (LUAD) were positively enriched for TP53 mutations, and negatively enriched for oncogene alterations
• Co-alterations in TP53 and/or CDKN2A/B were highly prevalent in NF1-mutant LUAD and nearly universal in NF1-mutant lung squamous cell carcinomas (LUSC)
• NF1-mutant non-squamous NSCLC were significantly enriched for high TMB
• NF1-mutant non-squamous NSCLC were significantly enriched for high PD-L1 expression

To assess PFS outcomes achieved with single-agent PD-1/PDL-1 inhibitors, the investigators leveraged the publicly availably OAK/POPLAR (n=765) and Rizvi cohort (n=185) databases. In both cohorts, they found that NF1-mutant/high TMB NSCLC had prolonged PFS as compared with NF1-wild type/high TMB NSCLC.

The investigators concluded that their findings demonstrate the impact of cancer gene mutations and the influence of TMB on clinical outcomes. NF1-mutant/high TMB NSCLC seem to be highly sensitive to immune checkpoint inhibitors.

1. Negrao M. Genomic landscape and clinical outcomes with immune checkpoint inhibitors in NF1-mutant NSCLC. MA 09.07, WCLC 2021, 8–14 September.

 

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Posted on 21 September, 202115 February, 2024