526O High activity of nivolumab in patients with pathogenic exonucleasic domain POLE (edPOLE) mutated Mismatch Repair proficient (MMRp) advanced tumours

Rousseau, Benoît; Bièche, Ivan; Pasmant, Éric; Simmet, Victor; Hamzaoui, Nadim; Masliah‐Planchon, Julien; Pouessel, Damien; Bruyas, A.; Augereau, Paule; Grob, J.J.; Rolland, Frédéric; Sâada-Bouzid, Esma; Cohen, Romain; Bouché, Olivier; Hoog-Labouret, Natalie; Legrand, Frédéric; Simon, Clotilde; Lamrani-Ghaouti, Assia; Chevret, Sylvie; Marabelle, Aurélien

doi:10.1016/j.annonc.2020.08.640

Cited by 25 publications

(16 citation statements)

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“…Data from an early phase trial of 16 patients with POLE mutations treated with nivolumab were recently presented. 38 At 84 days after treatment, ORR was 50% for patients with pathogenic mutations (n = 8) compared to 0% in patients with benign mutations (n = 5), consistent with our findings. A phase II trial is randomizing patients with POLE- or POLD1- mutated solid tumors to treatment with nivolumab plus ipilimumab versus nivolumab monotherapy ( NCT03461952 ).…”

Section: Discussionsupporting

confidence: 90%

Clinical and Molecular Characterization ofPOLEMutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers

Garmezy

Gheeya

Lin

et al. 2022

JCO Precision Oncology

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PURPOSE DNA polymerase epsilon is critical to DNA proofreading and replication. Mutations in POLE have been associated with hypermutated tumors and antitumor response to immune checkpoint inhibitor (ICI) therapy. We present a clinicopathologic analysis of patients with advanced cancers harboring POLE mutations, the pattern of co-occurring mutations, and their response to ICI therapy within the context of mutation pathogenicity. METHODS We conducted a retrospective analysis of next-generation sequencing data at MD Anderson Cancer Center to identify patient tumors with POLE mutations and their co-occurring mutations. The pathogenicity of each mutation was annotated using InterVar and ClinVar. Differences in therapeutic response to ICI, survival, and co-occurring mutations were reported by POLE pathogenicity status. RESULTS Four hundred fifty-eight patient tumors with POLE mutations were identified from 14,229 next-generation sequencing reports; 15.0% of POLE mutations were pathogenic, 15.9% benign, and 69.1% variant of unknown significance. Eighty-two patients received either programmed death 1 or programmed death ligand-1 inhibitors as monotherapy or in combination with cytotoxic T-cell lymphocyte-4 inhibitors. Patients with pathogenic POLE mutations had improved clinical benefit rate (82.4% v 30.0%; P = .013), median progression-free survival (15.1 v 2.2 months; P < .001), overall survival (29.5 v 6.8 months; P < .001), and longer treatment duration (median 15.5 v 2.5 months; P < .001) compared to those with benign variants. Progression-free survival and overall survival remained superior when adjusting for number of co-occurring mutations (≥ 10 v < 10) and/or microsatellite instability status (proficient mismatch repair v deficient mismatch repair). The number of comutations was not associated with response to ICI (clinical benefit v progressive disease: median 13 v 11 comutations; P = .18). CONCLUSION Pathogenic POLE mutations were associated with clinical benefit to ICI therapy. Further studies are warranted to validate POLE mutation as a predictive biomarker of ICI therapy.

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Section: Discussionsupporting

confidence: 90%

Clinical and Molecular Characterization ofPOLEMutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers

Garmezy

Gheeya

Lin

et al. 2022

JCO Precision Oncology

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“…While any threshold used for dichotomization of a continuous variable is intrinsically arbitrary and difficult to justify [ 21 ], the current FDA-approved threshold for TMB is especially problematic, as a patient’s TMB cannot be measured with confidence near the 10 mut/Mb threshold with many currently used assays. However, for highly mutated tumors, such as those with DNA mismatch repair deficiency or POLE/POLD1 mutations (also populations where the benefit of ICI is most clear [ 9 , 22 , 23 , 24 ]), the clinical performance of assays with small panel sizes may be clinically adequate, as the plausible interval for the true TMB value will be unlikely to contain the TMB-high threshold in spite of the increasing variation in the actual numerical TMB result generated by the assay [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Visualization of the Effect of Assay Size on the Error Profile of Tumor Mutational Burden Measurement

Bailey

2022

Genes

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Tumor mutational burden (TMB) refers to the number of somatic mutations in a tumor per megabase and is a biomarker for response to immune checkpoint inhibitor therapy. Immune checkpoint inhibitors are currently approved for tumors with TMB greater than or equal to 10 mutations/megabase. Many laboratories are currently reporting TMB values based upon targeted resequencing panels with limited genomic coverage. Due to sampling variation, this leads to significant uncertainty in the assay’s TMB result, particularly at relatively low TMB levels near the 10 mutation per megabase therapeutic threshold. In order to allow clinicians and laboratorians to explore this uncertainty, we built a novel web application that allows a user to view the potential error of a TMB result given the sequencing panel size. This application also allows the user to explore the effect of incorporating knowledge of a specific tumor type’s typical TMB distribution on the error profile of the TMB result.

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“…Germline mutations in the proofreading exonuclease domain of DNA polymerase epsilon (POLE) have been associated with a predisposition to colonic polyposis and CRC, 77 and somatic POLE proofreading domain mutations lead to extreme accumulation of missense and nonsense mutations without indels, resulting in tumors that are pMMR/MSS with a high TMB (ranging 50 to ≥200 mutations/Mb) 22,78 . POLE mutations leading to proofreading defects are predominantly missense mutations, 79 and the AsCé immunotherapy program investigated the efficacy and tolerance of PD‐1 blockade with nivolumab in a phase II single‐arm cohort of patients with exonuclease domain POLE (edPOLE)‐mutated tumors 78 . The preliminary results presented at ESMO 2020 demonstrated an ORR of 50% ( N = 3/6) among patients with pathogenic edPOLE mutations (P286R, N363K, V411L).…”

Section: Predictors Of Response To Immunotherapymentioning

confidence: 99%

Immunotherapy for the treatment of colorectal cancer

Lumish

Cercek

2021

Journal of Surgical Oncology

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Immune checkpoint inhibition (ICI) has transformed the management of metastatic colorectal cancer (mCRC) with mismatch‐repair deficiency (dMMR) and microsatellite instability (MSI‐H), though this constitutes on average less than 5% of mCRC, and ICI is ineffective in preserved MMR/microsatellite stable disease (pMMR/MSS). Here we review the efficacy of ICI in dMMR/MSI‐H mCRC, poor response to ICI in pMMR/MSS mCRC, role for ICI in locally advanced disease, biomarkers of response, novel immunotherapies, and future directions in targeting resistance mechanisms.

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526O High activity of nivolumab in patients with pathogenic exonucleasic domain POLE (edPOLE) mutated Mismatch Repair proficient (MMRp) advanced tumours

Cited by 25 publications

References 0 publications

Clinical and Molecular Characterization ofPOLEMutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers

Clinical and Molecular Characterization ofPOLEMutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers

Visualization of the Effect of Assay Size on the Error Profile of Tumor Mutational Burden Measurement

Immunotherapy for the treatment of colorectal cancer

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