26 maart 2021: Bron: Annals of oncology

Uit ervaringen en eerder onderzoek bij longkanker, melanomen en blaaskanker - urineleiderkanker wordt ervan uitgegaan dat als een kankerpatiënt een zogeheten hoge tumormutatiebelasting (TMB-H) heeft dat immuuntherapie met een anti-PD medicijn - checkpointremmer dan de meeste kans geeft op goede resultaten. 

Uit een groot onderzoek bij meer dan 10.000 kankerpatiënten met ook andere vormen van kanker waaronder borstkanker, prostaatkanker en hersentumoren van het type glioblastoma blijkt dat een hoge tumormutatiebelasting nauwelijks betere resultaten geeft in de praktijk voor aanslaan van immuuntherapie met anti-PD medicijnen dan bij patiënten met een lage tumormutatiebelasting. 

Ook de overall overleving (OS) gaf weinig verschil verschil te zien tussen hoge en lage tumormutatiebelasting. 

Belangrijkste punt uit deze studie:

Hoge tumormutatiebelasting (TMB-H) kon geen verbeterde of klinisch relevante respons op immuuntherapie met checkpointremmers - anti-PD medicijnen voorspellen bij alle vormen van kanker.​
Vormen van kanker waarbij TMB-H geen respons voorspelt, vertonen over het algemeen geen verband tussen tumor neoantigen belasting en CD8 T-celinfiltratie.​
Verdere studies moeten worden uitgevoerd voordat TMB-H wordt toegepast als biomarker voor ICB bij alle kankertypes.

Het studieverslag van deze studie is in PDF vorm te downloaden
Hier het abstract van de studie:

High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types

Highlights

  • TMB-H failed to predict improved or clinically relevant response to ICB in all cancer types.
  • Cancer types where TMB-H does not predict response generally show no relationship between tumor neoantigen load and CD8 T-cell infiltration.
  • Further studies should be carried out before application of TMB-H as a biomarker for ICB in all cancer types.

Background

High tumor mutation burden (TMB-H) has been proposed as a predictive biomarker for response to immune checkpoint blockade (ICB), largely due to the potential for tumor mutations to generate immunogenic neoantigens. Despite recent pan-cancer approval of ICB treatment for any TMB-H tumor, as assessed by the targeted FoundationOne CDx assay in nine tumor types, the utility of this biomarker has not been fully demonstrated across all cancers.

Patients and methods

Data from over 10 000 patient tumors included in The Cancer Genome Atlas were used to compare approaches to determine TMB and identify the correlation between predicted neoantigen load and CD8 T cells. Association of TMB with ICB treatment outcomes was analyzed by both objective response rates (ORRs, N = 1551) and overall survival (OS, N = 1936).

Results

In cancer types where CD8 T-cell levels positively correlated with neoantigen load, such as melanoma, lung, and bladder cancers, TMB-H tumors exhibited a 39.8% ORR to ICB [95% confidence interval (CI) 34.9-44.8], which was significantly higher than that observed in low TMB (TMB-L) tumors [odds ratio (OR) = 4.1, 95% CI 2.9-5.8, P < 2 × 10−16]. In cancer types that showed no relationship between CD8 T-cell levels and neoantigen load, such as breast cancer, prostate cancer, and glioma, TMB-H tumors failed to achieve a 20% ORR (ORR = 15.3%, 95% CI 9.2-23.4, P = 0.95), and exhibited a significantly lower ORR relative to TMB-L tumors (OR = 0.46, 95% CI 0.24-0.88, P = 0.02). Bulk ORRs were not significantly different between the two categories of tumors (P = 0.10) for patient cohorts assessed. Equivalent results were obtained by analyzing OS and by treating TMB as a continuous variable.

Conclusions

Our analysis failed to support application of TMB-H as a biomarker for treatment with ICB in all solid cancer types. Further tumor type-specific studies are warranted.

References

    • Wei S.C.
    • Duffy C.R.
    • Allison J.P.
    Fundamental mechanisms of immune checkpoint blockade therapy.
    Cancer Discov. 2018; 81069-1086
    • Chan T.A.
    • Yarchoan M.
    • Jaffee E.
    • et al.
    Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic.
    Ann Oncol. 2019; 3044-56
    • Gubin M.M.
    • Artyomov M.N.
    • Mardis E.R.
    • Schreiber R.D.
    Tumor neoantigens: building a framework for personalized cancer immunotherapy.
    J Clin Invest. 2015; 1253413-3421
    • Cristescu R.
    • Mogg R.
    • Ayers M.
    • et al.
    Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy.
    Science. 2018; 362eaar3593
    • Alexandrov L.B.
    • Kim J.
    • Haradhvala N.J.
    • et al.
    The repertoire of mutational signatures in human cancer.
    Nature. 2020; 57894-101
    • Lemery S.
    • Keegan P.
    • Pazdur R.
    First FDA approval agnostic of cancer site—when a biomarker defines the indication.
    N Engl J Med. 2017; 3771409-1412
    • Prasad V.
    • Addeo A.
    The FDA approval of pembrolizumab for patients with TMB >10 mut/Mb: was it a wise decision? No.
    Ann Oncol. 2020; 311112-1114
    • Subbiah V.
    • Solit D.B.
    • Chan T.A.
    • Kurzrock R.
    The FDA approval of pembrolizumab for adult and pediatric patients with tumor mutational burden (TMB) ≥10: a decision centered on empowering patients and their physicians.
    Ann Oncol. 2020; 311115-1118
    • U.S. Food and Drug Administration
    FDA approves pembrolizumab for adults and children with TMB-H solid tumors.
    2020 (Accessed June 17, 2020)
    • Marabelle A.
    • Fakih M.
    • Lopez J.
    • et al.
    Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.
    Lancet Oncol. 2020; 20451-13
    • Siegel R.L.
    • Miller K.D.
    • Jemal A.
    Cancer statistics, 2020.
    CA Cancer J Clin. 2020; 707-30
    • Overman M.J.
    • McDermott R.
    • Leach J.L.
    • et al.
    Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.
    Lancet Oncol. 2017; 181182-1191
    • Le D.T.
    • Uram J.N.
    • Wang H.
    • et al.
    PD-1 blockade in tumors with mismatch-repair deficiency.
    N Engl J Med. 2015; 3722509-2520
    • Sha D.
    • Jin Z.
    • Budczies J.
    • Kluck K.
    • Stenzinger A.
    • Sinicrope F.A.
    Tumor mutational burden as a predictive biomarker in solid tumors.
    Cancer Discov. 2020; 101808-1825
    • Addeo A.
    • Banna G.L.
    • Weiss G.J.
    Tumor mutation burden—from hopes to doubts.
    JAMA Oncol. 2019; 5934-935
    • Strickler J.H.
    • Hanks B.A.
    • Khasraw M.
    Tumor mutational burden as a predictor of immunotherapy response: is more always better?.
    Clin Cancer Res. 2020;https://doi.org/10.1158/1078-0432.CCR-20-3054
    • Merino D.M.
    • McShane L.M.
    • Fabrizio D.
    • et al.
    Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project.
    J Immunother Cancer. 2020; 8e000147
    • Echeverria G.V.
    • Powell E.
    • Seth S.
    • et al.
    High-resolution clonal mapping of multi-organ metastasis in triple negative breast cancer.
    Nat Commun. 2018; 95079
    • Chen X.
    • Chang J.T.
    Planning bioinformatics workflows using an expert system.
    Bioinformatics. 2017; 331210-1215
    • Li H.
    • Durbin R.
    Fast and accurate short read alignment with Burrows-Wheeler transform.
    Bioinformatics. 2009; 251754-1760
    • DePristo M.A.
    • Banks E.
    • Poplin R.
    • et al.
    A framework for variation discovery and genotyping using next-generation DNA sequencing data.
    Nat Genet. 2011; 43491-498
    • McKenna A.
    • Hanna M.
    • Banks E.
    • et al.
    The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.
    Genome Res. 2010; 201297-1303
    • Wang K.
    • Li M.
    • Hakonarson H.
    ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data.
    Nucleic Acids Res. 2010; 38e164
    • Cingolani P.
    • Platts A.
    • Wang L.L.
    • et al.
    A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3.
    Fly (Austin). 2012; 680-92
    • Ellrott K.
    • Bailey M.H.
    • Saksena G.
    • et al.
    Scalable open science approach for mutation calling of tumor exomes using multiple genomic pipelines.
    Cell Syst. 2018; 6271-281.e7
    • Thorsson V.
    • Gibbs D.L.
    • Brown S.D.
    • et al.
    The immune landscape of cancer.
    Immunity. 2018; 48812-830.e14
    • Jurtz V.
    • Paul S.
    • Andreatta M.
    • Marcatili P.
    • Peters B.
    • Nielsen M.
    NetMHCpan-4.0: improved peptide–MHC class I interaction predictions integrating eluted ligand and peptide binding affinity data.
    J Immunol. 2017; 1993360-3368
    • Gentles A.J.
    • Newman A.M.
    • Liu C.L.
    • et al.
    The prognostic landscape of genes and infiltrating immune cells across human cancers.
    Nat Med. 2015; 21938-945
    • McGrail D.J.
    • Federico L.
    • Li Y.
    • et al.
    Multi-omics analysis reveals neoantigen-independent immune cell infiltration in copy-number driven cancers.
    Nat Commun. 2018; 91317
    • Vokes N.I.
    • Liu D.
    • Ricciuti B.
    • et al.
    Harmonization of tumor mutational burden quantification and association with response to immune checkpoint blockade in non–small-cell lung cancer.
    JCO Precis Oncol. 2019; 31-12
    • Stenzinger A.
    • Endris V.
    • Budczies J.
    • et al.
    Harmonization and standardization of panel-based tumor mutational burden measurement: real-world results and recommendations of the quality in pathology study.
    J Thorac Oncol. 2020; 151177-1189
    • Rooney M.S.
    • Shukla S.A.
    • Wu C.J.
    • Getz G.
    • Hacohen N.
    Molecular and genetic properties of tumors associated with local immune cytolytic activity.
    Cell. 2015; 16048-61
    • Liu D.
    • Schilling B.
    • Liu D.
    • et al.
    Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma.
    Nat Med. 2019; 251916-1927
    • Hellmann M.D.
    • Nathanson T.
    • Rizvi H.
    • et al.
    Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer.
    Cancer Cell. 2018; 33843-852.e4
    • Chalabi M.
    • Fanchi L.F.
    • Dijkstra K.K.
    • et al.
    Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers.
    Nat Med. 2020; 26566-576
    • Voorwerk L.
    • Slagter M.
    • Horlings H.M.
    • et al.
    Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.
    Nat Med. 2019; 25920-928
    • Yam C.
    • Hess K.R.
    • Litton J.K.
    • et al.
    A randomized, triple negative breast cancer enrolling trial to confirm molecular profiling improves survival (ARTEMIS).
    J Clin Oncol. 2017; 35TPS590
    • Mariathasan S.
    • Turley S.J.
    • Nickles D.
    • et al.
    TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.
    Nature. 2018; 554544-548
    • Braun D.A.
    • Hou Y.
    • Bakouny Z.
    • et al.
    Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma.
    Nat Med. 2020; 26909-918
    • Kazdal D.
    • Endris V.
    • Allgäuer M.
    • et al.
    Spatial and temporal heterogeneity of panel-based tumor mutational burden in pulmonary adenocarcinoma: separating biology from technical artifacts.
    J Thorac Oncol. 2019; 141935-1947
    • Zehir A.
    • Benayed R.
    • Shah R.H.
    • et al.
    Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.
    Nat Med. 2017; 23703-713
    • Marabelle A.
    • Le D.T.
    • Ascierto P.A.
    • et al.
    Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 study.
    J Clin Oncol. 2020; 381-10
    • Gromeier M.
    • Brown M.C.
    • Zhang G.
    • et al.
    Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.
    Nat Commun. 2021; 12352
    • Touat M.
    • Li Y.Y.
    • Boynton A.N.
    • et al.
    Mechanisms and therapeutic implications of hypermutation in gliomas.
    Nature. 2020; 580517-523
    • Khasraw M.
    • Walsh K.M.
    • Heimberger A.B.
    • Ashley D.M.
    What is the burden of proof for tumor mutational burden in gliomas?.
    Neuro Oncol. 2020; 2317-22
    • McGranahan N.
    • Furness A.J.S.
    • Rosenthal R.
    • et al.
    Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.
    Science. 2016; 3511463-1469
    • Venkatesan S.
    • Swanton C.
    • Taylor B.S.
    • Costello J.F.
    Treatment-induced mutagenesis and selective pressures sculpt cancer evolution.
    Cold Spring Harb Perspect Med. 2017; 7a026617
    • Daniel P.
    • Sabri S.
    • Chaddad A.
    • et al.
    Temozolomide induced hypermutation in glioma: evolutionary mechanisms and therapeutic opportunities.
    Front Oncol. 2019; 91-7
    • Pesch B.
    • Kendzia B.
    • Gustavsson P.
    • et al.
    Cigarette smoking and lung cancer-relative risk estimates for the major histological types from a pooled analysis of case-control studies.
    Int J Cancer. 2012; 1311210-1219
    • FDA
    KEYTRUDA prescribing information.
    (Available at:) (Accessed June 17, 2020)
    • Chung H.C.
    • Schellens J.H.M.
    • Delord J.-P.
    • et al.
    Pembrolizumab treatment of advanced cervical cancer: updated results from the phase 2 KEYNOTE-158 study.
    J Clin Oncol. 2018; 365522
    • Goodman A.M.
    • Kato S.
    • Bazhenova L.
    • et al.
    Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers.
    Mol Cancer Ther. 2017; 162598-2608
    • Hugo W.
    • Zaretsky J.M.
    • Sun L.
    • et al.
    Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma.
    Cell. 2016; 16535-44
    • Miao D.
    • Margolis C.A.
    • Vokes N.I.
    • et al.
    Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors.
    Nat Genet. 2018; 501271-1281
    • Snyder A.
    • Nathanson T.
    • Funt S.A.
    • et al.
    Contribution of systemic and somatic factors to clinical response and resistance to PD-L1 blockade in urothelial cancer: an exploratory multi-omic analysis.
    PLoS Med. 2017; 141-24
    • Rizvi H.
    • Sanchez-Vega F.
    • La K.
    • et al.
    Molecular determinants of response to anti–programmed cell death (PD)-1 and anti–programmed death-ligand 1 (PD-L1) blockade in patients with non–small-cell lung cancer profiled with targeted next-generation sequencing.
    J Clin Oncol. 2018; 36633-641
    • Samstein R.M.
    • Lee C.-H.
    • Shoushtari A.N.
    • et al.
    Tumor mutational load predicts survival after immunotherapy across multiple cancer types.
    Nat Genet. 2019; 51202-206
    • Marabelle A.
    • Cassier P.A.
    • Fakih M.
    • et al.
    Pembrolizumab for advanced anal squamous cell carcinoma (ASCC): results from the multicohort, phase II KEYNOTE-158 study.
    J Clin Oncol. 2020; 381
    • Kim S.T.
    • Cristescu R.
    • Bass A.J.
    • et al.
    Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer.
    Nat Med. 2018; 241449-1458
    • Rizvi N.A.
    • Hellmann M.D.
    • Snyder A.
    • et al.
    Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer.
    Science. 2015; 348124-128
    • Subudhi S.K.
    • Vence L.
    • Zhao H.
    • et al.
    Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer.
    Sci Transl Med. 2020; 12eaaz3577

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