Lung cancer

Australian oncologists identify a new biomarker to guide immunotherapy in NSCLC


HLA-I homozygosity is linked to poor outcomes with immunotherapy in patients with lung cancer and may have value in guiding treatment decisions, according to WA researchers.

A study involving 170 patients with advanced NSCLC showed that homozygosity at one or more HLA-I loci was associated with poor survival outcomes with anti-PD1 or anti-PDL1 therapy.

The study investigators, led by medical oncologist Dr Afaf Abed, said their findings suggested that HLA-I may be a non-invasive and economical biomarker that can be used as adjunct to tumour PDL1 expression to guide treatment personalisation in patients with NSCLC.

Published in the BMJ: Journal for Immunotherapy of Cancer, their study aimed to aimed to assess the impact of genomic HLA-I/II homozygosity on the survival benefit of patients with unresectable locally advanced, metastatic NSCLC treated with single-agent PD1/PDL1 inhibitors.

HLA typing was performed on white blood cells obtained from 170 patients being treated with pembrolizumab (first line) or nivolumab or atezolizumab (second and subsequent lines) at two cancer centres in Perth.

In a prognostic analysis, NSCLC patients who were homozygous at one or more HLA-I loci were shown to have reduced overall survival (OS) compared with those who were heterozygous at all HLA-I loci (HR=1.96, 95% CI 1.02 to 3.78, p=0.04).

HLA homozygosity was associated with shorter survival especially in older patients (over 65), those who have high ECOG status (≥2) and those treated with anti-PD1 rather than anti-PDL1 immunotherapy.

The poor survival outcomes with HLA-I homozygosity were also more apparent for patients with tumours expressing PDL1 ≥50% (HR=3.93, 95% CI 1.30 to 11.85, p<0.001).

There was no adverse effect of HLA-I homozygosity on PFS except after controlling for interactions between PDL1 status and HLA-I genotype (HR=2.21, 95% CI 1.04 to 4.70, p=0.038).

When the effects of HLA-I supertypes were evaluated, only HLA-A02 had a statistically significant association with improved survival (HR=0.56, 95% CI 0.34 to 0.93, p=0.023).

The study investigators said their findings added to the understanding of how cancer cells may use HLA downregulation to evade the immune system, and were notable for showing that patients with PDL1 <50% in particular may use this immune evasion mechanism.

“Our study provides enough evidence that [HLA-I] genomic homozygosity is associated with a worse prognosis in patients with NSCLC treated with single-agent immunotherapy,” they wrote.

They said this was of special importance in NSCLC, which often relies on fine needle aspiration for diagnosis and therefore tumour material may be exhausted after performing mutational profiling and PDL1 staining.

“We propose that, in addition to PDL1 TPS, HLA-I typing should be considered as a non-invasive and cost-effective biomarker to guide treatment personalisation,” they concluded.

“Given that patients with HLA-I homozygosity are less likely to derive clinical benefit from single-agent anti-PD1/PDL1 therapy, consideration of a more aggressive treatment combinations may be needed to improve their prognosis, especially among those with PDL1 TPS of 50% or more.”

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