Nivolumab Shows Activity in edPOLE-Mutated, MMR-Proficient Advanced Cancers

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Nivolumab monotherapy showed high response and disease control rates in patients with pathogenic exonuclease domain POLE (edPOLE)-mutated, mismatch repair (MMR)-proficient advanced tumors containing confirmed pathogenic mutations, according to findings presented by Benoit J.C. Rousseau, MD, PhD, of Memorial Sloan Kettering Cancer Center, at the ESMO Virtual Congress 2020 (Abstract 526O).

Dr. Rousseau explained that hotspots due to edPOLE mutations generate proofreading defects and hypermutated genomic profiles that may serve as targets for existing therapies. These hotspots occur rarely in advanced disease, and have not been fully investigated; therefore, the efficacy of nivolumab in patients with MMR-proficient tumors and edPOLE mutations has not been established.

Benoit J.C. Rousseau, MD, PhD

Benoit J.C. Rousseau, MD, PhD


To this end, Dr. Rousseau and colleagues conducted an investigation of nivolumab in this population in conjunction with the AcSé Immunotherapy Programme, a nationwide program launched by the French National Cancer Institute and sponsored by the French network of comprehensive cancer centers (UNICANCER). This program is investigating the efficacy and tolerance of anti–PD1 agents such as nivolumab in multiple phase II single-arm cohorts of patients with rare tumors.

At ESMO 2020, the initial results were presented from the edPOLE cohort participating in the first trial to investigate immunotherapy in patients harboring missense POLE within or close to the exonucleasic domain. Mutation pathogenicity in patients was prospectively selected by an ad hoc molecular tumor board.

All patients in this cohort received intravenous nivolumab at 240 mg every 2 weeks until disease progression, toxicity, or for up to 2 years in their absence.

The primary endpoint was the objective response rate (ORR) assessed per Response Evaluation Criteria in Solid Tumors version 1.1 at 12 weeks.

From January 2018 to April 2020, 16 patients with a mean age of 57 years were enrolled. Of these, seven patients had colorectal cancer; four, endometrial; two, gastric; and one each had pancreatic, biliary, and glial tumors. The patients had received a mean of 2.6 prior lines of therapy.


The ad hoc committee confirmed the pathogenicity of the edPOLE mutation in the tumors of eight (50%) patients, which included two patients with P286R, two with N363K, two with V411L, one with S459F, and one with A463V mutations. Three patients had unknown significance mutations, and five had nonpathogenic mutations.

At 12 weeks, among the 16 patients, the ORR was 38%, which was comprised of five partial responses and six reports of stable disease. Five patients experienced disease progression at this time; these responses were observed exclusively in patients with MMR-proficient colorectal and endometrial cancers. The median follow-up was 7.0 months (range = 1.0–21.9 months).

In the group of eight patients stratified by pathogenic mutations, four patients showed response, for an ORR of 50%. Stable disease was achieved in two patients, which yielded a disease control rate of 75%. Moreover, for the three patients with unknown significance mutations, two had responses and one had stable disease.


  • Activity of nivolumab appears promising in patients with edPOLE-mutated, MMR-proficient advanced cancer, but may be limited to tumors containing pathogenic mutations.
  • Researchers also emphasized the importance of individual mutational functional assessment by a molecular tumor board.

In contrast, at 12 weeks, all five patients with nonpathogenic tumors progressed, including two patients that had died prior to the first evaluation.

When comparing nonpathogenic mutation and pathogenic/unknown mutations groups, the respective median progression-free survival and overall survival were 1.1 vs 5.6 months (hazard ratio = 0.19, 95% confidence interval = 0.06–0.62) and 5.3 months vs not reached.

The safety evaluation showed that the nivolumab profile was in accordance with safety data reported in other tumor types.

According to the authors, these data represent the first clinical study assessing an anti–PD1 agent in POLE-mutated, MMR-proficient tumors. They concluded that activity of nivolumab appears promising in patients with edPOLE-mutated, MMR-proficient advanced cancer, but may be limited to tumors containing pathogenic mutations.

They emphasized that this result underscored the importance of individual mutational functional assessment by a molecular tumor board. Tumor mutational burden assessment is ongoing.

Disclosure: This UNICANCER study was funded by Bristol Myers Squibb. For full disclosures of the study authors, visit

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