Study Suggests POLE-Mutation May Represent Biomarker for ICI Therapy in Advanced Cancers

In a retrospective analysis of next-generation sequencing data conducted at The University of Texas MD Anderson Cancer Center, investigators found the presence of pathogenic POLE mutations to be associated with clinical benefit in immune checkpoint inhibitor (ICI) therapy.¹

Patients harboring POLE mutations had a clinical benefit rate (CBR) of 82.4% vs 30.0% in patients with benign variants (P = .013). Progression-free survival (PFS) also favored patients who harbor pathogenic POLE mutations as they had a median progression-free survival (PFS) of 15.1 months vs 2.2 months in patients who do benign pathogenic POLE mutations (P < .001). The overall survival was 29.5 months in patients who harbor pathogenic POLE mutations vs 6.8 months in those who harbor benign POLE mutations (P < .001), and the median duration of treatment was 15.5 months vs2.5 months, respectively (P < .001).

Using the InterVar2 and ClinVar3 tools, investigators measured the pathogenicity of each tumor mutation. POLE pathogenicity status informed the differences in therapeutic response to ICI, survival and co-occurring mutations.The study identified 458 patients with POLE mutations from among 14,229 next-generation sequencing reports, and 453 patients had available data from the electronic medical record.

POLE mutations were pathogenic in 68 patients (15%), benign in 72 patients (15.9%), or were a variant of unknown significance (VUS) in 313 patients (69.1%). Sixty-eight patients had a tumor with a mutation in the POLE exonuclease domain with 47.1% of the tumors being pathogenic, benign (8.8%), or VUS (50%).

Of 121 who received treatment with either a PD-1 or PD-L1 treatment, 64 patients received PD-1/L1 inhibitors as monotherapy, 18 as combination therapy with a CTLA-4 inhibitor, and 39 received a combination with either chemotherapy, a molecular targeted agent, or a vaccine.

The CBR was 55.4% (95% CI, 46.5 to 64.2) for all 121 patients who received PD-1/L1 inhibitor–based therapy. The overall response rate (ORR) was higher in patients with pathogenic mutations vs those with benign mutations (52.4% v 11.1%, respectively; P = .008). The ORR comparing pathogenic vs nonactionable variants was 52.4% and 31.0%, respectively (P = .061). Eight patients (7%) had a complete response (CR), 34 patients (28%) had a partial response (PR), 25 patients (21%) had stable disease (SD), and 54 patients (45%) had progressive disease (PD). Among patients who received immuno-therapy only who had pathogenic POLE mutation status (n = 17), no patients had CR, 8 patients (48%) had PR, 6 patients had SD (35%), and 3 patients had PD (18%). 

For the 121 patients who were administered an anti–PD-1/L1-based regimen, the median PFS was 5.4 months (95% CI, 3.5-7.9) and PFS at 12 months was 35% (95% CI, 26-44). Patients harboring VUS had a median PFS of 4.9 months (95% CI, 3.1-11.4).

Among the 82 patients who received immunotherapy-only regimens, consisting of either PD-1/L1 inhibitor as monotherapy or in combination with a CTLA-4 inhibitor, 8 had pathogenic POLE mutations in the exonuclease domain.

Patients who received immunotherapy were 81% male. The median age of patients at the start of ICI therapy was 64 years (range, 16-90). Of this patient population, POLE mutation status was 68% VUS, 8% benign, 7% that were likely benign, 12% pathogenic, and 5% that were likely pathogenic. The most common histology in this group was non–small cell lung cancer (22%), colorectal adenocarcinoma (17%), melanoma (16%), and breast cancer (7%). Microsatellite instability status was 44% proficient mismatch repair, 10% deficient mismatch repair, and 38% unknown.

These study data warrant further exploration and testing to confirm POLE mutations as a valid biomarker for ICI therapy.

_REFERENCE:

_{1. Garmezy B, Gheeya J, Lin HY, et al. Clinical and molecular characterization of POLE mutations as predictive biomarkers of response to immune checkpoint inhibitors in advanced cancers. JCO Precis Oncol. 2022;6:e2100267. doi:10.1200/PO.21.00267}

_{2. Li Q, Wang K. InterVar: Clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines. Am J Hum Genet. 2017;100(2):267-280. doi:10.1016/j.ajhg.2017.01.004}

_{3. Landrum MJ, Chitipiralla S, Brown GR, et al. ClinVar: improvements to accessing data. Nucleic Acids Res. 2020;48(D1):D835-D844. doi:10.1093/nar/gkz972}