CIRCULATING TUMOR DNA (CTDNA) STATUS AND CLINICAL OUTCOMES IN PATIENTS (PTS) WITH PREVIOUSLY UNTREATED DIFFUSE LARGE B‐CELL LYMPHOMA (DLBCL) IN THE POLARIX STUDY

Introduction: In the POLARIX study, pts with previously untreated DLBCL were randomized to Pola-R-CHP or R-CHOP (NCT03274492; Tilly et al., 2022). We previously validated the prognostic value of ctDNA at baseline and after one cycle of therapy in POLARIX (Herrera et al., 2022); here, we evaluate the relationship between ctDNA clearance and PFS and OS. Methods: Pts were included if baseline and longitudinal ctDNA results were available. Plasma ctDNA was measured at baseline, Cycle (C) 5 Day (D) 1, and end of treatment (EOT), with the AVENIO NHL CAPP-Seq assay (Stokowski et al. 2022). ctDNA clearance was determined as previously described (Herrera et al. 2022). PFS and OS according to ctDNA status were reported as landmarked hazard ratios (HR) and 3-yr rates. HRs were adjusted for IPI score (>2), region, bulky disease (>7.5 cm), age (>60 years), and cell of origin. Results: At baseline, 654 pts had ctDNA results; 494 (76%) and 519 (79%) pts were evaluable at C5D1 and EOT, respectively. Undetectable ctDNA (ctDNA−) was achieved by 57% (152/265) of Pola-R-CHP-treated pts and 59% (135/229) of R-CHOP-treated pts at C5D1 (p = 0.79), and by 66% (172/262) of Pola-R-CHP-treated pts and 67% (172/257) of R-CHOP-treated pts at EOT (p = 0.83). Achieving ctDNA—was prognostic for PFS and OS in each treatment arm at C5D1 and EOT (Table). Pts in the Pola-R-CHP arm who had complete response (CR) with PET-CT and ctDNA—at EOT had superior PFS and OS compared with pts with CR and detectable ctDNA (ctDNA+) at EOT (PFS HR 0.30, 95% confidence interval [CI]: 0.14–0.66; OS HR 0.20, 95% CI: 0.07–0.60). This was not observed with R-CHOP (PFS HR 0.74, 95% CI: 0.34–1.63; OS HR 1.11, 95% CI: 0.30–4.16). Among pts with CR and ctDNA—at EOT, pts treated with Pola-R-CHP had superior PFS versus R-CHOP (HR 0.41, 95% CI: 0.21–0.82); this was not observed with OS (HR 0.41, 95% CI: 0.14–1.18). There was no statistically significant difference in PFS between treatment arms in pts with CR and ctDNA+ at EOT (PFS HR 1.20, 95% CI: 0.49–2.83). Conclusions: Achieving ctDNA—at C5D1 and EOT was prognostic for longer survival. Although no difference was observed in the number of pts with ctDNA—at EOT between arms, pts achieving CR and ctDNA—at EOT had superior PFS in the Pola-R-CHP versus the R-CHOP arm, suggesting deeper molecular responses in pts treated with Pola-R-CHP beyond the detection sensitivity of the assay used in this analysis. Encore Abstract—previously submitted to ASCO 2023 The research was funded by: 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 Carla Smith, MSc, of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd. Keywords: aggressive B-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers, minimal residual disease Conflicts of interests pertinent to the abstract A. F. Herrera Consultant or advisory role: Bristol-Myers Squibb, Seattle Genetics, Merck, Genentech, Inc./F. Hoffmann-La Roche Ltd, AstraZeneca/MedImmune, Karyopharm Therapeutics, ADC Therapeutics, Takeda, Regeneron, Genmab, Tubulis GmbH, Pfizer, Adicet Bio, Caribou Biosciences, AbbVie Research funding: Bristol-Myers Squibb, Merck, Genentech, Inc./F. Hoffmann-La Roche Ltd, Kite (a Gilead company), AstraZeneca, Seattle Genetics, Gilead Sciences, ADC Therapeutics Educational grants: Bristol-Myers Squibb S. Tracy Employment or leadership position: Genentech, Inc. Stock ownership: F. Hoffmann-La Roche Ltd L. H. Sehn Consultant or advisory role: Celgene, AbbVie, Seattle Genetics, TG Therapeutics, Janssen, Amgen, F. Hoffmann-La Roche Ltd/Genentech, Inc., Gilead Sciences, Lundbeck, Amgen, Apobiologix, Karyopharm Therapeutics, Kite (a Gilead Company), Merck, Takeda, Teva, TG therapeutics, AstraZeneca, Acerta Pharma, MorphoSys, Incyte, Debiopharm Group, Sandoz-Novartis, Genmab, Verastem Honoraria: Amgen, Apobiologix, AbbVie, Celgene, Gilead Sciences, Janssen-Ortho, Karyopharm Therapeutics, Kite (a Gilead Company), Lundbeck, Merck, F. Hoffmann-La Roche Ltd/Genentech, Inc., Seattle Genetics, Takeda, Teva, TG Therapeutics, AstraZeneca, Acerta Pharma, MorphoSys, Incyte, Debiopharm Group, Sandoz-Novartis, Verastem, Genmab Research funding: F. Hoffmann-La Roche Ltd/Genentech, Inc., Teva F. Jardin Consultant or advisory role: F. Hoffmann-La Roche Ltd Honoraria: F. Hoffmann-La Roche Ltd, Celgene, Janssen, AbbVie/Genentech, Inc. Educational grants: F. Hoffmann-La Roche Ltd G. Lenz Consultant or advisory role: F. Hoffmann-La Roche Ltd, Gilead, Janssen, Bristol-Myers Squibb, Novartis, AbbVie, Incyte, Genmab, Constellation, ADC Therapeutics, Karyopharm, Miltenyi, PentixaPharm, Sobi, Immagene, Genase, Hexal/Sandoz, Lilly Research funding: Janssen, Bayer, AstraZeneca, MorphoSys Educational grants: AbbVie, Janssen, F. Hoffmann-La Roche Ltd Other remuneration: F. Hoffmann-La Roche Ltd, Gilead, Novartis, Takeda, Bristol-Myers Squibb, AbbVie, Incyte, ADC Therapeutics, Sobi, Hexal/Sandoz (Speaker's Bureau). F. Hoffmann-La Roche Ltd (Expert Testimony) M. Trněný Consultant or advisory role: Takeda, Bristol-Myers Squibb, Incyte, AbbVie, Amgen, F. Hoffmann-La Roche Ltd, Gilead Sciences, Janssen, MorphoSys, Novartis Honoraria: Janssen, Gilead Sciences, Takeda, Bristol-Myers Squibb, Amgen, AbbVie, F. Hoffmann-La Roche Ltd, MorphoSys, Novartis Educational grants: Gilead Sciences, Takeda, Bristol-Myers Squibb, F. Hoffmann-La Roche Ltd, Janssen, AbbVie G. Salles Consultant or advisory role: F. Hoffmann-La Roche Ltd/Genentech, Inc., Janssen, Novartis, MorphoSys, Epizyme, Genmab, Debiopharm Group, Velosbio, Bristol-Myers Squibb, BeiGene, Incyte, Miltenyi Biotec, Ipsen, AbbVie, Kite/Gilead, Loxo/Lilly, Molecular Partners, Nordic Nanovector, RAPT Therapeutics, Takeda, Incyte Stock ownership: Owkin Honoraria: AbbVie, Bayer, Regeneron, Incyte C. R. Flowers Consultant or advisory role: Bayer, Gilead Sciences, Spectrum Pharmaceuticals, AbbVie, Celgene, Denovo Biopharma, BeiGene, Karyopharm Therapeutics, Pharmacyclics/Janssen, Genentech, Inc./F. Hoffmann-La Roche Ltd, Epizyme, Genmab, Seattle Genetics, Foresight Diagnostics, Bristol-Myers Squibb/Celgene, Curio Science, AstraZeneca, MorphoSys Stock ownership: Foresight Diagnostics, N Power Research funding: Acerta Pharma, Janssen Oncology, Gilead Sciences, Celgene, TG Therapeutics, Genentech, Inc./F. Hoffmann-La Roche Ltd, Pharmacyclics, AbbVie, Millennium, Alimera Sciences, Xencor, 4D Pharma, Adaptimmune, Amgen, Bayer, Cellectis, EMD Serono, Guardant Health, Iovance Biotherapeutics, Kite/Gilead, MorphoSys, Nektar, Novartis, Pfizer, Sanofi, Takeda, ZIOPHARM Oncology H. Tilly Consultant or advisory role: F. Hoffmann-La Roche Ltd, Incyte, Celgene/Bristol-Myers Squibb Honoraria: Bristol-Myers Squibb, F. Hoffmann-La Roche Ltd Research funding: F. Hoffmann-La Roche Ltd/Genentech, Inc. Educational grants: F. Hoffmann-La Roche Ltd, Janssen J. P. Sharman Consultant or advisory role: TG Therapeutics, Genentech, Inc., AbbVie, Acerta Pharma/AstraZeneca, BeiGene, Bristol-Myers Squibb, Merck Research funding: Pharmacyclics, Genentech, Inc., Celgene, Acerta Pharma, Gilead Sciences, Seattle Genetics, TG Therapeutics, Merck, Takeda S. Balasubramanian Employment or leadership position: F. Hoffmann-La Roche Ltd/Genentech, Inc. Stock ownership: AbbVie V. Raghavan Employment or leadership position: F. Hoffmann-La Roche Ltd J. Hirata Employment or leadership position: Genentech, Inc. Stock ownership: F. Hoffmann-La Roche Ltd C. Lee Employment or leadership position: F. Hoffmann-La Roche Ltd Stock ownership: F. Hoffmann-La Roche Ltd Y. Jiang Employment or leadership position: F. Hoffmann-La Roche Ltd/Genentech, Inc. Stock ownership: F. Hoffmann-La Roche Ltd/Genentech, Inc. F. Morschhauser Consultant or advisory role: F. Hoffmann-La Roche Ltd/Genentech, Inc., Gilead Sciences, Celgene, Bristol-Myers Squibb, AbbVie, Epizyme, Servier, AstraZeneca, Novartis, Genmab Honoraria: F. Hoffmann-La Roche Ltd/Genentech, Inc., Chugai, Eisai Other remuneration: F. Hoffmann-La Roche Ltd/Genentech, Inc. (Expert Testimony)

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