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Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

2287 - Predicting toxicity and response to pembrolizumab (P) through germline genomic HLA class I analysis

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Presenters

Marco Iafolla

Citation

Annals of Oncology (2018) 29 (suppl_8): viii14-viii57. 10.1093/annonc/mdy269

Authors

M. Iafolla1, C. Yang2, V. Chandran3, M. Pintilie4, A. Hansen5, P. Bedard1, S. Lheureux1, A. Spreafico5, A. Razak1, P. Ohashi6, S. Hakgor1, A. Giesler1, T. Pugh4, L.L. Siu5

Author affiliations

  • 1 Medical Oncology, Princess Margaret Cancer Centre, University Health Network, M5G2M9 - Toronto/CA
  • 2 Medical Biophysics, Princess Margaret Cancer Centre, University Health Network, M5G2M9 - Toronto/CA
  • 3 Laboratory Medicine And Pathobiology, University Health Network, M5T 2S8M5T 2S8 - Toronto/CA
  • 4 Biostatistics, Princess Margaret Cancer Centre, University Health Network, M5G2M9 - toronto/CA
  • 5 Medical Oncology, Princess Margaret Cancer Center, M5G2M9 - Toronto/CA
  • 6 Immunology, Campbell Family Institute for Cancer Research, University Health Network, M5G2M9M5G2M9 - Toronto/CA
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Resources

Abstract 2287

Background

HLA class I-dependent immune activity is linked to autoimmune diseases, and HLA class I-dependent CD8+ T cells are required for immune checkpoint blockade (ICB) anti-tumor activity. It is unknown if HLA class I is predictive of toxicity to ICB.

Methods

100 patients (pts) with mixed solid tumors received single agent P (anti-PD-1) 200 mg IV Q 3 weeks in the investigator-initiated Phase II trial (INSPIRE study, NCT02644369). Germline whole exome sequencing (WES) of peripheral blood mononuclear cells was analyzed using the Illumina HiSeq2500 platform. Consensus HLA class I alleles were predicted from WES using HLAminer and HLAVBSeq. Using univariate Fisher’s exact test and logistic models adjusting for HLA features, heterozygosity of HLA-A, -B and -C, individual HLA alleles and HLA haplotype dimorphism at positions −21M and -21T of the HLA-A and -B leader sequence were analyzed as predictors of: 1) toxicity defined as ≥ Gr 2 immune-related adverse events (irAE) with at least possible attribution to P; and 2) clinical benefit (CBR) defined as either partial response or stable disease lasting ≥ 6 cycles of P.

Results

In the overall cohort of 100 pts, the frequency of irAE and CBR from P was 21% and 25%, respectively. Thus far, 99 patients had their HLA class I genotype determined. Univariate analysis showed heterozygosity of HLA-A, -B and -C, compared to homozygosity of at least one HLA locus, was not predictive of toxicity (≥ Gr 2 irAE 16.7% vs 27.3%, p = 0.29) but did trend to less response (CBR 19.7% vs 36.4%, p = 0.088). Individual heterozygosity of HLA-A, -B or -C, and HLA-A and -B haplotype dimorphism was not predictive of either toxicity or response. HLA-A*02 allele showed a trend to toxicity (≥ Gr 2 irAE 26.8% vs 11.6%, p = 0.079). A pertinent exploratory toxicity model is summarized in the table.Table: 95P

Toxicity
A*01 and A*02 (n = 7)4(57%)
A*01 and no A*02 (n = 13)2(15%)
A*02 and no A*01 (n = 49)11(22%)
Neither A*01 nor A*02 (n = 30)3(10%)

Table Fisher exact p-value=0.0503

Conclusions

This study is the first to assess the association between HLA class I genotype and toxicity to P. There is a possible association of HLA-A*01 and HLA-A*02 with toxicity to P.

Clinical trial identification

Trial protocol number: NCT02644369.

Legal entity responsible for the study

Lillian Siu.

Funding

Merck.

Editorial Acknowledgement

Disclosure

P. Bedard: Research funding: Bristol-Myers Squibb, Sanofi, AstraZeneca, Genentech/Roche, Servier, GlaxoSmithKline, Novartis, SignalChem, PTC Therapeutics, Nektar, Merck, Seattle Genetics. A. Spreafico: Support for clinical trials: Merck, Novartis, BMS. A. Razak: Research funding: Merck, BMS, Pfizer, Karyopharm, Deciphera, Eli Lilly, Boehringer, Boston Biomedicals, Roche, Novartis and Genentech; Consultancy: Eli Lilly, Eisai, Boeringher Ingelheim, Merck. P. Ohashi: Consultancy/advisory: Symphogen Inc., Providence Pharmaceuticals, Inc., Baxalta US. Inc., Lion Biotechnologies, Inc. T. Pugh: Honoraria: Merck, Prosigna, Chrysalis Biomedical Advisors; Consulting: DynaCare Research. Funding: Boehringer Ingelheim; Patents, royalties; other intellectual property: Hybrid-capture sequencing for determining immune cell clonality, combined hybrid-capture DNA sequencing for disease detection. L.L. Siu: Advisory board and funding for clinical trials: Merck. All other authors have declared no conflicts of interest.

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