Background: First-line FL treatments typically include an anti-CD20 monoclonal antibody with alkylator-based chemotherapy. Despite encouraging efficacy, most patients (pts) eventually relapse; novel therapies that improve outcomes and prolong remission in 1L FL are needed. Also, chemotherapy-containing regimens may have substantial toxicities, emphasizing the need for new therapies with improved safety. Mosunetuzumab (M), a CD20xCD3 bispecific antibody that redirects T cells to eliminate malignant B cells, has shown manageable safety with high complete remission rates in pts with relapsed/refractory (R/R) FL after ≥2 prior lines of therapy (Budde et al. Lancet Oncol 2022). Lenalidomide (Len), a potent immunomodulatory agent, may have synergistic effects with M. Initial results from the CO41942 Phase Ib/II trial (NCT04246086) showed that M (intravenous) combined with Len had a manageable safety profile and encouraging chemotherapy-free anti-lymphoma activity in pts with R/R FL who had ≥1 prior line of therapy (Morschhauser et al. ASH 2021). We present preliminary safety, efficacy, and biomarker data from this ongoing trial of M (subcutaneous [SC]) combined with oral Len in pts with 1L FL who require systemic therapy.

Methods: Pts with 1L FL requiring systemic therapy (investigator-assessed using GELF criteria) with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2 are included; target enrollment is 40 pts. Pts received 12 cycles of M+Len (cycle [C] 1, 21 days; C2-12, 28 days); in C1, 5mg of M was given on Day (D) 1, with the target dose (45mg) given on C1D8, C1D15, and on D1 of C2-12; Len (20mg) was given on D1-21 of C2-12 ( Figure A). Cytokine release syndrome (CRS) was reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Responses by PET-CT were investigator-assessed using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014). Flow cytometry (fluorescence-activated cell sorting) on whole blood was used to assess peripheral biomarkers.

Results: At clinical cutoff date (CCOD; May 2, 2023), 37 pts were enrolled: 21 (56.8%) had been on the study for 0-3 months, 12 (32.4%) for 3-6 months, and 4 (10.8%) for 6-9 months.

Median age was 62.0 (range 28-83) years and 20 (54.1%) pts were male. All pts had a baseline ECOG PS of ≤1; 32 (86.5%) had Ann Arbor stage III-IV; and 7 (18.9%), 13 (35.1%), and 17 (45.9%) had a FL International Prognostic Index score of 0-1 (low), 2 (intermediate), and 3-5 (high risk), respectively. All pts reported ≥1 treatment-emergent adverse event (TEAE); 12 (32.4%) had ≥1 serious TEAE. Two pts discontinued study treatment after the C1D15 dose, one pt due to uveitis and one pt due to tumor flare. TEAEs related to M or Len occurred in 36 (97.3%) and 29 (78.4%) pts, respectively. At least one Grade (Gr) 3-4 TEAE occurred in 16 (43.2%) pts, the most common being neutropenia (seven pts). No pts reported Gr 5 AEs. CRS occurred in 20 (54.1%) pts; all were Gr 1, except for one pt with Gr 2 CRS, and all events resolved (median CRS duration: 2 days [range 1-26]). CRS frequency was highest after C1D1 (32.4%), and steadily declined over subsequent days and cycles. No immune effector cell-associated neurotoxicity syndrome events were observed.

To date, 27 pts were efficacy evaluable ( Figure B). Of 24 (88.9%) responders, 22 (81.5%) had a complete metabolic response (21 achieved by the first response assessment at end of C3), and two (7.4%) had a partial metabolic response. One pt (3.7%) had no response assessment by CCOD, and two (7.4%) had progressive disease but were recognized to have biopsy-proven transformed FL during C1 and C2. All responses were maintained at CCOD.

Preliminary biomarker analyses of pt blood samples showed: increased CD69 and sustained HLA-DR expression in CD8 T cells, with modulation of CD8 subsets favoring central/effector memory phenotypes; sustained natural killer-cell activity; and minimal effects on CD4 T cells (except for lower PD-1 expression).

Conclusions: This fixed-duration, chemotherapy-free M+Len regimen offers a convenient means for outpatient SC administration, and has a manageable early safety profile with promising anti-lymphoma activity in pts with 1L FL requiring systemic therapy, based on the preliminary data. Advancing M+Len into the first-line setting offers potential benefits in chemotherapy-naïve pts. Safety, efficacy, biomarker, and pharmacokinetic data from the complete cohort (40 pts) will be presented.

Morschhauser:F. Hoffmann-La Roche Ltd, AbbVie, BMS, Genmab, Gilead, Novartis: Consultancy; F. Hoffmann-La Roche Ltd, Gilead, AbbVie: Membership on an entity's Board of Directors or advisory committees. Patel:AstraZeneca, Bristol Myers Squibb, Kite, TG Therapeutics: Speakers Bureau; Adaptive Biotechnelogies, AstraZeneca, Bristol Myers Squibb, CRISPR Therapeutics, Curis, Inc, Epizyme, Fate Therapeutics, Genentech, Inc. / F. Hoffmann-La Roche Ltd, Kite, Loxo Oncology, MEI Pharma, Merck, Nurix, Pharmacyclics/Janssen, Sunesis Pharmaceuti: Research Funding; Abbvie, ADC Therapeutics, AstraZeneca, BeiGene, Bristol Myers Squibb, Caribou Biosciences, Epizyme, Genentech, Inc. / F. Hoffmann-La Roche Ltd, Kite, Loxo Oncology, MEI Pharma, Merck, Morphosys, Nurix, Pharmacyclics/Janssen, Sana Biotechnology, TG Therape: Consultancy. Bobillo:AstraZeneca, Abbvie: Honoraria; Vall d'Hebron University Hospital: Current Employment. Cordoba:F. Hoffmann-La Roche Ltd, Takeda, Abbvie, Janssen, AstraZeneca, Lilly, BeiGene, BMS, Genmab, Incyte, Gilead: Speakers Bureau; European Hematology Association (EHA), Spanish Society Hematology (SEHH): Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd, Takeda, Abbvie, Janssen, AstraZeneca, Lilly, BeiGene, BMS, Genmab, Incyte, Gilead: Consultancy; Fundacion Jimenez Diaz University Hospital: Current Employment. Eyre:Loxo Lilly: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PeerView: Speakers Bureau; Medscape: Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Autolus: Consultancy; KITE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eli Lilly and Company: Consultancy, Honoraria, Speakers Bureau; Loxo Oncology: Consultancy, Honoraria, Other, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Secura Bio: Membership on an entity's Board of Directors or advisory committees. Bishton:Abbvie: Consultancy; Celltrion, F. Hoffmann-La Roche Ltd, Takeda, Gilead: Honoraria; Lilly, F. Hoffmann-La Roche Ltd, Incyte: Membership on an entity's Board of Directors or advisory committees. Houot:Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, ADC Therapeutics, Incyte, Miltenyi: Consultancy; Kite/Gilead, Novartis, Incyte, Janssen, MSD, Takeda, F. Hoffmann-La Roche Ltd: Honoraria. Osborne:F. Hoffmann-La Roche Ltd, Takeda, Servier, Kite Gilead, MSD, Novartis, BeiGene, AstraZeneca, Syneos, Autolus, Kyowa Kirin, Abbvie, Incyte, BMS/Celgene, Janssen, Sobi: Consultancy; F. Hoffmann-La Roche Ltd, Takeda, Pfizer, Servier, Kite Gilead, MSD, Novartis, BeiGene, AstraZeneca, Syneos, Autolus, Kyowa Kirin, Abbvie, Incyte, BMS/Celgene, Janssen, Sobi: Honoraria; F. Hoffmann-La Roche Ltd, Takeda, Pfizer, Kite Gilead, MSD, Novartis, AstraZeneca, Kyowa Kirin, Abbvie, Incyte, BMS/Celgene, Janssen: Speakers Bureau. Gálvez-Carvajal:Medical Oncologist, Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria University Hospitals: Current Employment. Thieblemont:Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Bayer: Honoraria; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Hospira: Research Funding; Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Paris University, Assistance Publique, hopitaux de Paris (APHP): Current Employment; Kyte, Gilead, Novartis, BMS, Abbvie, F. Hoffmann-La Roche Ltd, Amgen: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Janssen: Honoraria, Other: Travel Expenses. Yee:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc. / F. Hoffmann-La Roche Ltd: Current Employment. Knapp:F. Hoffmann-La Roche Ltd: Current Employment. Purev:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Li:Hoffmann-La Roche Ltd (Canada): Current Employment. Chen:F. Hoffmann-La Roche Ltd / Genentech, Inc.: Current Employment; University of California, San Francisco (UCSF): Ended employment in the past 24 months. Banta:Genentech, Inc.: Current Employment. Sit:F. Hoffmann-La Roche Ltd: Current equity holder in private company; F. Hoffmann- La Roche Ltd: Current holder of stock options in a privately-held company. Bachy:Roche: Consultancy, Honoraria; Amgen: Research Funding; Bristol Myers Squibb: Honoraria, Other: Personal Fees, Research Funding; Novartis: Honoraria, Other: Personal Fees; Hospices Civils de Lyon Claude Bernard Lyon 1 University: Current Employment; Pfizer: Honoraria, Other: Personal Fees; Takeda: Honoraria; Incyte: Honoraria; Kite, a Gilead Company: Honoraria, Other: Personal Fees.

Mosunetuzumab (Lunsumio) is a bispecific CD20-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory FL after two or more lines of systemic therapy.

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2023
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