LBA74 - Genomic biomarkers in peripheral blood (PB) from patients (pts) enrolled in the JAVELIN Bladder 100 trial of avelumab first-line (1L) maintenance in advanced urothelial carcinoma (aUC)

Background

The relationship between blood biomarkers, tumor immunity, and benefit from immune checkpoint inhibitors (ICIs) is not well understood. The JAVELIN Bladder 100 trial (NCT02603432) demonstrated that avelumab 1L maintenance prolongs overall survival (OS) in pts with aUC that has not progressed with 1L chemotherapy. Blood biomarkers associated with tumor immune gene signatures in this trial may provide mechanistic insight into the development of antitumor immunity and indicate patient subpopulations that could benefit from ICIs. We used EpiSwitch analysis of PB to identify structural-functional epigenetic changes in genomic architecture, designated chromatin conformation signatures (CCSs).

Methods

PB from 496 pts in the JAVELIN Bladder 100 trial underwent EpiSwitch analysis by PCR assay of 3D genomic templates prepared from fixed intact nuclei. Tumor immune activity was scored using a gene expression signature (JAVELIN Renal 101 Immune [JR101I]). CCS association with tumor JR101I scores was determined via univariate and multivariate analyses of a training set of 80 specimens.

Results

We identified 25 CCSs from the training set. One CCS was proximal to POU2F2, a transcription factor instrumental in B cell development. Patients whose PB lacked the POU2F2 CCS had elevated tumor JR101I scores, corresponding to increased gene expression associated with tertiary lymphoid structures (TLSs). The POU2F2 CCS may therefore influence key steps in TLS formation. In patients with a median tumor mutation burden (TMB) of ≤ 7.66 non-synonymous SNVs per Mb, the avelumab+BSC vs BSC hazard ratios in the CCS-absent subpopulation was 0.56 (95% CI, 0.32–0.96; p=0.037; n=83); and in the CCS-present population was 1.2 (95% CI, 0.83–1.75; P=0.34; n=158). CCSs affecting the ability to form TLSs may influence response to avelumab at low TMB.

Conclusions

PB CCSs may be associated with TLS, tumor JR101I scores, and the degree of OS benefit. These findings support further analysis of CCSs to assess potential clinical utility.

Clinical trial identification

Editorial acknowledgement

Medical writing support was provided by Abhijith Thippeswamy of ClinicalThinking, and was funded by Pfizer as part of an alliance between Pfizer and Merck.

Legal entity responsible for the study

Pfizer, as part of an alliance between Pfizer and Merck.

Funding

Pfizer, as part of an alliance between Pfizer and Merck (CrossRef Funder ID: 10.13039/100009945).

Disclosure

T.B. Powles: Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb, Merck, AstraZeneca, Ipsen, Pfizer, Novartis, Incyte, Seattle Genetics, Roche, Exelixis, MSD, Astellas Pharma, Johnson & Johnson, Eisai; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pfizer, MSD, AstraZeneca, Roche, Ipsen; Financial Interests, Personal, Research Grant: AstraZeneca, Roche, Bristol-Myers Squibb, Exelixis, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Astellas Pharma, Johnson & Johnson, Eisai. S. Sridhar: Financial Interests, Personal, Advisory Role, Consulting: Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Hoffmann-La Roche, Immunomedics, Ipsen, Janssen, Merck, Pfizer, Seagen, Roche, Seattle Genetics; Financial Interests, Personal, Research Grant: Bayer, Janssen, Seagen. J. Bellmunt: Financial Interests, Personal, Other, Honoraria (Self): Pfizer, MSD, BMS, AstraZeneca, Pierre Fabre; Financial Interests, Institutional, Other, Honoraria (Institution): Takeda, MSD; Financial Interests, Personal, Advisory Board: Pfizer, MSD, BMS, AstraZeneca, Roche /Genentech, Pierre Fabre; Financial Interests, Institutional, Research Grant: Takeda, Pfizer; Financial Interests, Personal, Other, Travel/Accommodations/Expenses: Pfizer; Financial Interests, Personal, Licensing Fees: UpToDate. C. Sternberg: Financial Interests, Personal, Advisory Role: Pfizer, MSD, Merck, AstraZeneca, Astellas, Sanofi-Genzyme, Roche-Genentech, Incyte, Medscape, Janssen, UroToday, Foundation, Medicine, Immunomedics, NCI, Impact Pharmaceuticals, Bristol Myers Squibb. P. Grivas: Financial Interests, Personal, Advisory Role: AstraZeneca, Astellas Pharma, Bayer, Bristol Myers Squibb, Dyania Health, Merck, Exelixis, Foundation Medicine, Genentech/Roche, Genzyme, GlaxoSmithKline, Guardant Health, Gilead Sciences, Infinity Pharmaceuticals, Janssen, Lucence Health, Mirati Therapeutics, Pfizer, QED Therapeutics, Regeneron Pharmaceuticals, SilverBack Therapeutics, UroGen, 4D Pharma PLC, EMD Serono; Financial Interests, Institutional, Advisory Role: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: Bavarian Nordic; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Clovis Oncology, Debiopharm, Merck, G1 Therapeutics, Gilead Sciences, GlaxoSmithKline, Mirati Therapeutics, Pfizer, QED Therapeutics, EMD Serono. E. Hunter: Financial Interests, Personal, Full or part-time Employment: Oxford Biodynamics Plc; Financial Interests, Personal, Stocks/Shares: Oxford Biodynamics Plc. M. Dezfouli: Financial Interests, Personal, Full or part-time Employment: Oxford BioDynamics Plc. M. Salter: Financial Interests, Personal, Full or part-time Employment: Oxford Biodynamics Plc; Financial Interests, Personal, Stocks/Shares: Oxford BioDynamics Plc. R. Powell: Financial Interests, Personal, Full or part-time Employment: Oxford Biodynamics Plc; Financial Interests, Personal, Stocks/Shares: Oxford Biodynamics Plc. A. Dring: Financial Interests, Personal, Full or part-time Employment: Oxford BioDynamics Plc; Financial Interests, Personal, Stocks/Shares: Oxford BioDynamics Plc. J. Green: Financial Interests, Personal, Full or part-time Employment: Oxford Biodynamics Plc; Financial Interests, Personal, Stocks/Shares: Oxford Biodynamics Plc. A. Akoulitchev: Financial Interests, Personal, Full or part-time Employment: Oxford Biodynamics Plc; Financial Interests, Institutional, Research Grant: PACT-FNIH; Financial Interests, Personal, Stocks/Shares: Oxford Biodynamics Plc, Sibelius Natural Products Ltd. R. Amezquita: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. K. Ching: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. J. Pu: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. S. Deng: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. A. di Pietro: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. C.B. Davis: Financial Interests, Personal, Full or part-time Employment: Pfizer.