Mutations affect efficacy of avelumab in advanced endometrial cancer

Avelumab immunotherapy may perform poorly in advanced endometrial cancer (EC) patients with TP53 mutation but has positive effects in those with mutations of PTEN and ARID1A, suggest the results of the MITO END-3 trial.

“Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced EC, with a much larger effect size in microsatellite instability-high (MSI-H) cases,” the investigators said. “New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumour.”

This preplanned translational analysis of the MITO END-3 trial examined the significance of genomic abnormalities in 125 patients who were randomly assigned to receive carboplatin/paclitaxel with or without avelumab. Of these, 109 had eligible samples for next-generation sequencing analysis and 102 had MSI tested.

Based on The Cancer Genome Atlas, 29 patients had MSI-H, 26 had MSS TP53 wild type (wt), 47 had MSS TP53 mutated (mut), and one had POLE mutation. More than 30 percent of patients presented with four mutated genes, namely TP53, PIK3CA, ARID1A, and PTEN. In addition, 11 patients (10 percent) had a BRCA1/2 mutation (five in MSI-H and six in MSS).

There was high tumour mutational burden (≥10 muts/Mb) seen in all MSI-H patients, in four out of 47 MSS/TP53 mut, but none in the MSS/TP53 wt category.

Of note, avelumab had a significantly varied effect on PFS depending on TCGA categories: it was favourable in MSI-H and worse in MSS/TP53 mut (p=0.003 for interaction). The survival analysis also revealed a similar nonsignificant trend.

Additionally, “ARID1A and PTEN [had] a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A: p=0.01; PTEN: p=0.002),” the investigators said.