Genomic profiling in a subgroup analysis of patients (pts) with diffuse large B-cell lymphoma (DLBCL) and extranodal (EN) sites of involvement in the phase 3 Pola-R-CHP versus R-CHOP (POLARIX) study.

person Jennifer Kimberly Lue Memorial Sloan Kettering Cancer Center, New York, NY info_outline Jennifer Kimberly Lue, Franck Morschhauser, Herve Tilly, Georg Lenz, Fabrice Jardin, Alex Francisco Herrera, Jeff Porter Sharman, Christopher Flowers, Jonathan W. Friedberg, Marek Trneny, Charles Herbaux, Mark Yan, Yanwen Jiang, Jamie Hirata, Connie Lee Batlevi, Deniz Sahin, Wilfred Leung, Will Harris, Gilles A. Salles, Laurie Helen Sehn

Authors person Jennifer Kimberly Lue Memorial Sloan Kettering Cancer Center, New York, NY info_outline Jennifer Kimberly Lue, Franck Morschhauser, Herve Tilly, Georg Lenz, Fabrice Jardin, Alex Francisco Herrera, Jeff Porter Sharman, Christopher Flowers, Jonathan W. Friedberg, Marek Trneny, Charles Herbaux, Mark Yan, Yanwen Jiang, Jamie Hirata, Connie Lee Batlevi, Deniz Sahin, Wilfred Leung, Will Harris, Gilles A. Salles, Laurie Helen Sehn Organizations Memorial Sloan Kettering Cancer Center, New York, NY, University of Lille, Lille, France, Centre Henri-Becquerel and University of Rouen, Rouen, France, University Hospital Münster, Münster, Germany, City of Hope, Duarte, CA, Willamette Valley Cancer Institute and Research Center, Florence, OR, M.D. Anderson Cancer Center, Houston, TX, University of Rochester, Rochester, NY, Charles University General Hospital, Prague, Czech Republic, University of Montpellier, Montpellier, France, Hoffmann-La Roche Ltd, Mississauga, ON, Canada, Genentech, Inc., South San Francisco, CA, F. Hoffmann-La Roche Ltd, Basel, Switzerland, BC Cancer Centre for Lymphoid Cancer, Vancouver, BC, Canada Abstract Disclosures Research Funding The POLARIX study (NCT03274492) was sponsored by F. Hoffmann-La Roche Ltd and Genentech, Inc. Third-party editorial assistance, under the direction of the authors, was provided by Jacob Lea, MSc, of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd. Background: The prognosis and survival outcomes of pts with EN involvement remain a challenge for DLBCL management. In the Phase 3 POLARIX study (NCT03274492), Pola-R-CHP demonstrated significantly improved progression-free survival (PFS) compared with R-CHOP in previously untreated DLBCL (Tilly et al. 2022). This retrospective analysis assessed clinical outcomes and genomic patterns of pts with DLBCL and EN disease. Methods: POLARIX methods were previously described (Tilly et al. 2022). Using a data cutoff of June 15, 2022, this analysis assessed pts with EN involvement as determined by investigators. Additional outcomes and genomics analyses were performed on pts whose EN status was confirmed from documented radiographic lesions or bone marrow biopsy with denotation of EN disease sites. Hazard ratios (HRs) for investigator-assessed PFS were adjusted for age (≤60 vs >60) and sex. Cell of origin (COO) by NanoString, mutation analysis by whole exome sequencing, and global gene expression profiling by RNAseq were performed centrally. Results: In POLARIX, 616/879 pts (70%) had identified EN involvement. After a median follow-up of 39.7 months, pts showed improved PFS with Pola-R-CHP vs R-CHOP (HR 0.72, 95% confidence interval [CI]: 0.55–0.96), with a 2-year PFS of 75% vs 66%. A total of 556 pts (Pola-R-CHP, n=279; R-CHOP, n=277) had confirmed sites of EN involvement, defined as pts with EN radiographic lesions or bone marrow disease. In these pts, PFS favored Pola-R-CHP vs R-CHOP but the difference was not statistically significant (HR 0.84, 95% CI: 0.63–1.13). Of pts with confirmed EN disease, 429 had COO results (activated B-cell, 145 [34%]; germinal center B-cell, 223 [52%]; unclassified DLBCL, 61 [14%]). Mutation data and frequencies of select clinically relevant mutations (Ptashkin, 2023) across EN sites were available for 364 pts (Table). Gene expression data were available for 418 pts; genes involved in proliferation (E2F or PI3K signaling targets and checkpoint genes) and regulated by IRF4, OCT2 and XBP1, were commonly upregulated in pts with EN disease. Conclusions: Results in pts with DLBCL with EN involvement suggest superior PFS with Pola-R-CHP vs R-CHOP. Ongoing analyses will further assess the independent impact of EN status on outcome. POLARIX represents the largest cohort of pts with annotated EN disease and systematic genomic analysis, providing new insights into the genomics of these pts. Clinical trial information: NCT03274492. Mutation Frequency, % Liver n=39 Gastric n=23 Other GI n=54 Thorax n=79 Endocrine and Reproductive n=46 Head and Neck n=34 Kidney n=24 All EN n=364 Not EN n=161 KMT2D 38 22 44 38 28 29 33 32 29 TP53 36 17 31 23 15 18 29 20 22 PIM1 26 26 30 28 43 29 46 30 30 TNFRSF14 10 22 26 25 22 12 8 21 19 MYD88 8 30 22 18 41 32 29 21 20 BCL2 3 22 30 27 11 12 4 18 24 B2M 13 22 22 14 13 6 8 14 16 CREBBP 18 9 24 13 13 15 12 18 21 CD79B 8 9 24 14 26 24 25 17 17