MANAGING CYTOKINE RELEASE SYNDROME (CRS) AND NEUROTOXICITY WITH STEP‐UP DOSING OF MOSUNETUZUMAB IN RELAPSED/REFRACTORY (R/R) B‐CELL NON‐HODGKIN LYMPHOMA (NHL)

Introduction: T-cell directed therapies (e.g., CAR-T, blinatumomab) are associated with significant risk of Grade (Gr) ≥3 neurotoxicity and CRS/infusion-related reaction (IRR). Mosunetuzumab is a CD20/CD3 bispecific antibody that directs T-cells to engage and eliminate malignant B-cells. We report safety results from an ongoing Phase 1/1b study (NCT02500407) of mosunetuzumab in patients (pts) with R/R B-cell NHL. Methods: Pts received ascending doses on Day 1, Day 8, and Day 15 of Cycle 1 (step-up dosing), then a fixed dose on Day 1 of every 21-day cycle thereafter, up to a maximum of 17 cycles. Primary outcome measures included safety and efficacy. Results: As of October 23, 2018, 114 pts who received step-up dosing of mosunetuzumab were evaluable for safety (Table). The majority of adverse events (AE) occurred during Cycle 1 and 2. Neurologic AEs (NAE), defined from Nervous System or Psychiatric System Organ Classes, were mostly low grade, transient (median duration 4 days) and reversible; most common ones were headache (14%) and dizziness (8%). Gr ≥3 NAEs occurred in 4 pts (4%) with only 1 treatment-related event (hepatic encephalopathy). CRS/IRR was reported in 25% of pts, with only 1 Gr 3 event. Most common CRS symptoms were pyrexia (86%), chills (38%), and tachycardia and headache (14% each). There were no Gr 5 events related to CRS or NAEs. No apparent dose toxicity relationship was observed with step-up dosing in these pts, despite escalation of the Cycle 1 Day 15 dose to 20 mg, consistent with observed peak IL-6 levels after a low Cycle 1 Day 1 dose. In these pts, objective responses were observed in 24/73 (33%; complete response [CR], 13 [18%]) aggressive NHL and 17/32 (53%; CR, 10 [31%]) indolent NHL pts. Conclusions: Step-up dosing has enabled continued dose escalation of mosunetuzumab with no apparent increases in toxicity, exhibiting a promising risk-benefit profile. Acknowledgement: This work was funded by F. Hoffmann-La Roche Ltd. Third-party medical writing assistance, under the direction of Laurie Sehn, was provided by Louise Profit and Russell Craddock of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. © 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 ASCO Annual Meeting. All rights reserved. Keywords: CD20; CD3; non-Hodgkin lymphoma (NHL). Disclosures: Sehn, L: Consultant Advisory Role: AbbVie, Amgen, Roche/Genentech, Inc., Apobiologix, AstraZeneca, Acerta, Celgene, Gilead, Janssen, Kite, Karyopharm, Lundbeck, Merck, MorphoSys, Seattle Genetics, Teva, Takeda, TG Therapeutics; Honoraria: /Genentech, Inc., Apobiologix, AstraZeneca, Acerta, Celgene, Gilead, Janssen, Kite, Karyopharm, Lundbeck, Merck, MorphoSys, Seattle Genetics, Teva, Takeda, TG Therapeutics; Research Funding: Roche/Genentech, Inc. Assouline, S: Employment Leadership Position: No; Consultant Advisory Role: Yes. Pfizer, Roche; Stock Ownership: No; Honoraria: No; Research Funding: No; Other Remuneration: Travel, Accommodation, Expenses: Roche; Speakers' bureau: Pfizer, Roche. Bartlett, N: Consultant Advisory Role: Pfizer, Seattle Genetics, ADC Therapeutics; Research Funding: Seattle Genetics, Genentech, Kite Pharma, Merck, Bristol-Myers Squibb, Celgene, Immune Design, Forty Seven, Affirmed Therapeutics, Janssen, Pharmacyclics, Millennium, Gilead Sciences. Bosch, F: Consultant Advisory Role: Roche, Janssen, Celgene, Abbvie, Novartis, Gilead; Honoraria: Roche, Janssen, Celgene, Abbvie, Novartis, Gilead; Research Funding: Roche, Janssen, Celgene, Abbvie, Novartis, Gilead, Sobi, Bayer; Other Remuneration: Roche, Janssen, Celgene, Abbvie, Novartis, Gilead (speakers' bureau). Diefenbach, C: Consultant Advisory Role: Seattle Genetics, Bayer, Bristol-Myers Squibb, Genentech/Roche, Merck; Stock Ownership: Gilead Sciences; Research Funding: Seattle Genetics, Genentech, Incyte, LAM Therapeutics, Merck, Bristol-Myers Squibb, Millennium, MEI Pharma. Flinn, I: Consultant Advisory Role: AbbVie, Seattle Genetics, TG Therapeutics, Verastem; Research Funding: Acerta, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Inc., Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals, Roche, Seattle Genetics, TG Therapeutics, Trillim Therapeutics, AbbVie, ArQule, BeiGene, Curis, FoRMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem. Hong, J: Consultant Advisory Role: Takeda, Roche; Honoraria: Takeda, Roche, Janssen, Celgene, Mundipharma, Celtrion, Eisai; Research Funding: Janssen, Boryung Pharmaceutical. Kim, W: Research Funding: Roche, Takeda, Eisai, Mundipharma, Pfizer, Celtrion, Kyowa-Kirin, J&J. Matasar, M: Consultant Advisory Role: Genentech, Bayer, Merck, Juno Therapeutics, Roche, Teva, Rocket Medical, Seattle Genetics; Stock Ownership: Merck; Honoraria: Genentech, Roche, Bayer, Pharmacyclics, Janssen, Seattle Genetics; Research Funding: Genentech, Roche, Bayer, Pharmacyclics, Janssen, Seattle Genetics; Other Remuneration: Genentech, Roche, Seattle Genetics, Bayer (travel, accommodation and expenses). Nastoupil, L: Honoraria: Celgene, Genentech, Gilead, Janssen, Novartis, Spectrum, TG Therapeutics; Research Funding: Celgene, Genentech, Janssen, Merck, TG Therapeutics. Schuster, S: Consultant Advisory Role: Celgene, Genentech, Inc., Gilead, Pfizer, Novartis, Nordic Nanovector, Acerta; Honoraria: Celgene, Genentech, Inc., Gilead, Pfizer, Novartis, Nordic Nanovector, Acerta; Research Funding: Celgene, Genentech, Inc., Novartis, Acerta, Gilead. Shadman, M: Consultant Advisory Role: AbbVie, Genentech, Inc., Sound Biologics, Verastem, ADC Therapeutics, Atara Biotherapeutics; Research Funding: Mustang Biopharma, Celgene, Pharmacyclics, Gilead, Genentech, Inc., AbbVie, TG Therapeutics, Beigene, Acerta Pharma, Merck. Yoon, S: Consultant Advisory Role: Novartis, AbbVie, Amgen, Celgene, Roche; Research Funding: Roche. Bender, B: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Genentech, Inc.; Other Remuneration: Genentech, Inc.. Chu, W: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Roche. Hernandez, G: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Genentech, Inc.. Kwan, A: Employment Leadership Position: Genentech, Inc./Roche; Stock Ownership: Genentech, Inc./Roche. McCall, B: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Roche. Sison, I: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Genentech, Inc.. Wang, C: Employment Leadership Position: Ultragenyx Pharmaeuticals, Inc.. Wei, M: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Roche. Yin, S: Employment Leadership Position: Genentech, Inc.; Stock Ownership: Genentech, Inc.; Other Remuneration: Genentech, Inc. (travel, accommodation, expenses). Yousefi, K: Employment Leadership Position: Roche; Other Remuneration: Roche (travel, accommodation and expenses). Budde, L: Consultant Advisory Role: Gilead, Genentech, AstraZeneca; Research Funding: Mustang Therapeutics, Merck & Co, Amgen; Other Remuneration: Gilead, AstraZeneca (speakers' bureau).

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