Identification of a genetic signature enriching for response to ibrutinib in relapsed/refractory follicular lymphoma in the DAWN phase 2 trial

Sriram Balasubramanian, Brendan Hodkinson, Stephen J Schuster, Nathan H Fowler, Judith Trotman, Georg Hess, Bruce D Cheson, Michael Schaffer, Steven Sun, Sanjay Deshpande, Jessica Vermeulen, Gilles Salles, Ajay K Gopal, Sriram Balasubramanian, Brendan Hodkinson, Stephen J Schuster, Nathan H Fowler, Judith Trotman, Georg Hess, Bruce D Cheson, Michael Schaffer, Steven Sun, Sanjay Deshpande, Jessica Vermeulen, Gilles Salles, Ajay K Gopal

Abstract

Background: The single-arm DAWN trial (NCT01779791) of ibrutinib monotherapy in patients with relapsed/refractory follicular lymphoma (FL) showed an overall response rate (ORR) of 20.9% and a median response duration of 19.4 months. This biomarker analysis of the DAWN dataset sought to determine genetic classifiers for prediction of response to ibrutinib treatment.

Methods: Whole exome sequencing was performed on baseline tumor samples. Potential germline variants were excluded; a custom set of 1216 cancer-related genes was examined. Responder- versus nonresponder-associated variants were identified using Fisher's exact test. Classifiers with increasing numbers of genes were created using a greedy algorithm that repeatedly selected genes, adding the most nonresponders to the existing "predicted nonresponders" set and were evaluated with 10-fold cross-validation.

Results: Exome data were generated from 88 patient samples and 13,554 somatic mutation variants were inferred. Response data were available for 83 patients (17 responders, 66 nonresponders). Each sample showed 100 to >500 mutated genes, with greater variance across nonresponders. The overall variant pattern was consistent with previous FL studies; 75 genes had mutations in >10% of patients, including genes previously reported as associated with FL. Univariate analysis yielded responder-associated genes FANCA, HISTH1B, ANXA6, BTG1, and PARP10, highlighting the importance of functions outside of B-cell receptor signaling, including epigenetic processes, DNA damage repair, cell cycle/proliferation, and cell motility/invasiveness. While nonresponder-associated genes included well-known TP53 and CARD11, genetic classifiers developed using nonresponder-associated genes included ATP6AP1, EP400, ARID1A, SOCS1, and TBL1XR1, suggesting resistance to ibrutinib may be related to broad biological functions connected to epigenetic modification, telomere maintenance, and cancer-associated signaling pathways (mTOR, JAK/STAT, NF-κB).

Conclusion: The results from univariate and genetic classifier analyses provide insights into genes associated with response or resistance to ibrutinib in FL and identify a classifier developed using nonresponder-associated genes, which warrants further investigation.

Trial registration: NCT01779791.

Keywords: biomarkers; genetic variants; lymphoma; mutations.

Conflict of interest statement

SB: Employment: Janssen Research & Development; Equity ownership: Janssen Research & Development. BH, MS, SS, SD, and JV: Employment: Janssen Research & Development. SJS: Consultancy and research funding: Novartis, Pharmacyclics, Celgene; Research funding: Gilead, Janssen Research & Development, Hoffmann‐La Roche, Merck; Board of directors or advisory committees: Nordic Nanovector; Consultancy: Genentech, Acerta. NHF: Consulting or advisory role: Pharmacyclics, Janssen; Research funding: Pharmacyclics, Janssen. JT: Research funding to institution: Janssen, PCYC, Roche, BeiGene, Takeda, Celgene; Cooperative group funding: Janssen; Advisory role (unremunerated): Janssen, Roche, Celgene, Takeda. GH: Research support: Roche, Pfizer, Celgene, CTI; Consultant: Roche, Pfizer, Janssen, Celgene, AbbVie; Honoraria: Roche, Pfizer, Janssen, Celgene, AbbVie; Advisory board: Roche, Pfizer, Janssen, Celgene, AbbVie. BDC: Advisory board: Acerta, AbbVie, Roche‐Genentech, Celgene, TG Therapeutics; Research funding to institution: Gilead, Pharmacyclics, Acerta, TG Therapeutics, AbbVie. GS: Research funding: Roche, Celgene; Consultancy: Novartis; Honoraria: AbbVie, Acerta, Amgen, Celgene, Epizyme, Gilead, Janssen, Merck, Morphosys, Novartis, Pfizer, Roche, Servier, Takeda, Celgene, Mundipharma. AKG: Research funding: Merck, Janssen, Spectrum, Takeda, Bristol Myers Squibb, Pfizer, Seattle Genetics, Gilead; Donations: Frank and Betty Vandermeer; Consulting fees: Seattle Genetics, Gilead, Janssen, Brim, Aptevo, Genzyme.

© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
Cancer‐associated genes of interest that are mutated in more than three patients with follicular lymphoma. Left panel shows the percentage of individuals with a mutation in each gene; right panel shows the distribution of mutations in those genes in the 83 patients with response/nonresponse data
FIGURE 2
FIGURE 2
Heatmap of ranked nonresponder gene mutations in ibrutinib‐treated patients with follicular lymphoma
FIGURE 3
FIGURE 3
Mean overall response rate (ORR) of predicted responders (gray line) based on 10‐fold cross‐validation for different responder/nonresponder classification models containing an increasing number of genes. The dotted blue line represents the ORR of the entire patient cohort regardless of classification. ORR, overall response rate
FIGURE 4
FIGURE 4
Plots of somatic mutations in the genes of interest associated with the lack of response to ibrutinib: (A) ATP6AP1, (B) EP400, (C) ARID1A, (D) SOCS1, (E) TBL1XR1, and (F) CARD 11. DEL = the mutation was predicted to be deleterious by metaSVM

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