Search

Mosunetuzumab is a novel bispecific antibody targeting epitopes on CD3 on T cells and CD20 on B cells with the goal of inducing T-cell mediated elimination of malignant B cells. A recent pivotal phase I/II clinical trial (GO29781) demonstrated that mosunetuzumab induced an overall response rate (ORR) of 80%, complete response (CR) rate of 60%, and a median progression-free survival (PFS) of 17.9 months in patients with relapsed/refractory (R/R) follicular lymphoma (FL) following at least two prior lines of systemic therapy, including alkylator and anti-CD20 antibody-based therapy. Historical data from cohorts receiving therapy for R/R FL can provide some context for interpretation of single-arm trials. We compared the results from the mosunetuzumab trial to outcomes from a cohort of patients with R/R FL from the LEO Consortium for Real World Evidence (LEO CReWE). We applied clinical trial eligibility criteria to the LEO CReWE cohort and utilized matching- adjusted indirect comparison weighting to balance the clinical characteristics of the LEO CReWE cohort with those from the mosunetuzumab trial. ORR (73%, 95% CI: 65-80%) and CR rates (53%, 95% CI: 45-61%) observed in the weighted LEO CReWE cohort were lower than those reported on the mosunetuzumab trial (ORR=80%, 95% CI: 70-88%; CR=60%, 95% CI: 49-70%, respectively). PFS at 12 months was similar in the weighted LEO CReWE (60%, 95% CI: 51-69%) and the mosunetuzumab (58%, 95% CI: 47-68%) trial. Sensitivity analyses examining the impact of matching variables, selection of line of therapy, and application of eligibility criteria provide context for best practices in this setting.

Background: No established standard of care exists for relapsed/refractory (RR) follicular lymphoma (FL) after ≥2 prior therapies. We conducted indirect treatment comparisons (ITCs) to compare the efficacy and tolerability of mosunetuzumab with those of available treatments used in this setting., Methods: A systematic literature review (SLR) and subsequent feasibility assessments were conducted to identify the most suitable comparator studies in terms of design, available endpoints and populations. Imbalances in patient characteristics between NCT02500407 and studies featuring aggregate or patient-level data availability were accounted for using matching-adjusted indirect comparison (MAIC) and propensity score-based methodologies, respectively., Results: ZUMA-5, ELARA, DELTA, DYNAMO, UNITY-NHL, AUGMENT and NCT01897571 passed the MAIC feasibility assessment. Patient-level data were available from GADOLIN, CONTRALTO and NCT02257567. MAIC results generally favored mosunetuzumab over tazemetostat in EHZ2wild-type patients for all outcomes and over PI3K inhibitors for complete response (CR), objective response rate (ORR), discontinuations due to adverse events and progression-free survival (PFS) with umbralisib. MAICs favored CART therapies for PFS and, to a lesser extent, ORR and CR. Comparisons with anti-CD20 antibody-based regimens yielded mixed results., Conclusions: ITCs suggest that mosunetuzumab may lead to superior outcomes over tazemetostat (in EHZ2wild-type patients) and PI3K inhibitors and may be a promising alternative to re-challenging with a different anti-CD20 regimen in patients who relapse after ≥2 prior anti-CD20 lines. Although preliminary results somewhat favored CART therapies, limitations and uncertainties remain because of intrinsic differences in study design. Mosunetuzumab could thus be a promising treatment option for patients with RR FL after ≥2 prior therapies., Competing Interests: Disclosure F. Bosch: Roche, Novartis, Janssen, AbbVie, Gilead, Mundipharma, AstraZeneca, Celgene/BMS, Takeda, BeiGene (Honoraria); Roche, Celgene, Karyopharm, Takeda, AstraZeneca, Novartis, AbbVie, Janssen (Consulting or advisory role); Roche, Novartis, Janssen, AbbVie, Gilead, Mundipharma, AstraZeneca, Celgene/BMS, Takeda, BeiGene (Speaker's bureau); Roche, Celgene, Karyopharm, Takeda, AstraZeneca, Novartis, AbbVie, Janssen (Research funding); AbbVie (Expert testimony); AbbVie, Roche, Janssen, AstraZeneca, Celgene/BMS (Travel, accommodation, expenses). J. Kuruvilla: AbbVie, Amgen, AstraZeneca, BMS, Gilead, Incyte, Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche, Seattle Genetics (Honoraria); AbbVie, Antengene, BMS, Gilead, Karyopharm, Medison Ventures, Merck, Roche, Seattle Genetics (Consulting or advisory role); Canadian Cancer Society Research Institute (CCSRI), Canadian Institutes of Health Research (CIHR), Leukemia and Lymphoma Society Canada, Princess Margaret Cancer Foundation, Roche, AstraZeneca, Merck (Research funding); DSMB—Karyopharm, SAB—Lymphoma Canada (Other). T.P. Vassilakopoulos: Takeda, Roche, Genesis Pharma, Merck, Novartis, Amgen, GSK, AbbVie, Integris, AstraZeneca, Gilead (Honoraria); Takeda, Roche, Genesis Pharma, Novartis, Gilead (Consulting or advisory role); Merck, Roche, Takeda, Amgen, Pfizer, Dr. Reddy's, Karyopharm, BMS, AbbVie, Mei Pharma (Research funding). D. Di Maio: Hoffman-La Roche AG (Current employment); Hoffman-La Roche AG (Stock Ownership). M. C. Wei: Genentech (Current employment); Roche (Stock ownership); Genentech/Roche (Travel, accommodation, expenses). M-H. Blanchet Zumofen: Roche Holding AG (Current employment); Roche (Leadership); Roche, Moderna (Stock ownership); Roche (Travel, accommodation, expenses). L.J. Nastoupil: ADC Therapeutics, Atara, BMS, Caribou Biosciences, Epizyme, Genentech, Gilead/Kite, Janssen, Novartis, Takeda (Honoraria); Sirpant, Interius Bio (Consulting or advisory role); BMS, Caribou Biosciences, Epizyme, Genentech, Gilead/Kite, IGM Bioscience, Janssen, Novartis, Takeda (Research funding); Genentech/Roche (Travel, accommodation, expenses)., (Copyright © 2023. Published by Elsevier Inc.)

A comparison of clinical outcomes in the third or subsequent line (3 L+) of systemic therapy between a real-world data (RWD) external control cohort and a mosunetuzumab single-arm clinical trial cohort is presented. Data for 3 L + patients with relapsed/refractory follicular lymphoma (FL) were obtained from the mosunetuzumab single-arm trial ( n  = 90) and a US electronic health records database ( n  = 158), with patients meeting key eligibility criteria from the trial, balanced on pre-specified prognostic factors. Overall response and complete response rates were 80% and 60% in the mosunetuzumab cohort and 75% and 33% in the RWD cohort, odds ratios of 1.23 (95% CI, 0.52-2.93) and 3.18 (95% CI, 1.41-7.17), respectively. Hazard ratios for progression-free survival and overall survival were 0.82 (95% CI, 0.53-1.27) and 0.43 (95% CI, 0.19-0.94). These findings support a clinically meaningful benefit of mosunetuzumab monotherapy as a chemotherapy-free option for the 3 L + FL population.

Background: Mosunetuzumab is a CD20 × CD3 T-cell-engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells. In a phase 1 study, mosunetuzumab was well tolerated and active in patients with relapsed or refractory B-cell lymphoma. We, therefore, aimed to evaluate the safety and anti-tumour activity of fixed-duration mosunetuzumab in patients with relapsed or refractory follicular lymphoma who had received two or more previous therapies., Methods: We conducted a single-arm, multicentre, phase 2 study at 49 centres in seven countries (Australia, Canada, Germany, South Korea, Spain, UK, and USA). All patients were aged 18 years or older with histologically confirmed follicular lymphoma (grade 1-3a) and an Eastern Cooperative Oncology Group performance status of 0-1. Patients had disease that was relapsed or refractory to two or more previous lines of treatment, including an anti-CD20 therapy and an alkylating agent. Intravenous mosunetuzumab was administered in 21-day cycles with cycle 1 step-up dosing: 1 mg on cycle 1 day 1, 2 mg on cycle 1 day 8, 60 mg on cycle 1 day 15 and cycle 2 day 1, and 30 mg on day 1 of cycle 3 and onwards. Patients with a complete response by investigator assessment using the International Harmonisation Project criteria completed treatment after cycle 8, whereas patients with a partial response or stable disease continued treatment for up to 17 cycles. The primary endpoint was independent review committee-assessed complete response rate (as best response) in all enrolled patients; the primary efficacy analysis compared the observed IRC-assessed complete response rate with a 14% historical control complete response rate in a similar patient population receiving the pan class I PI3K inhibitor copanlisib. Safety was assessed in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02500407, and is ongoing., Findings: Between May 2, 2019, and Sept 25, 2020, we enrolled 90 patients. As of the data cutoff date (Aug 27, 2021), the median follow-up was 18·3 months (IQR 13·8-23·3). According to independent review committee assessment, a complete response was recorded in 54 patients (60·0% [95% CI 49·1-70·2]). The observed complete response rate was significantly higher than the historical control complete response rate with copanlisib of 14% (p<0·0001), thereby meeting the primary study endpoint. Cytokine release syndrome was the most common adverse event (40 [44%] of 90 patients) and was predominantly grade 1 (23 [26%] of 90) and grade 2 (15 [17%]), and primarily confined to cycle 1. The most common grade 3-4 adverse events were neutropenia or neutrophil count decreased (24 [27%] of 90 patients), hypophosphataemia (15 [17%]), hyperglycaemia (seven [8%]), and anaemia (seven [8%]). Serious adverse events occurred in 42 (47%) of 90 patients. No treatment-related grade 5 (ie, fatal) adverse event occurred., Interpretation: Fixed-duration mosunetuzumab has a favourable safety profile and induces high rates of complete remissions, allowing potential administration as an outpatient regimen, in patients with relapsed or refractory follicular lymphoma and two or more previous therapies., Funding: F Hoffmann-La Roche and Genentech., Competing Interests: Declaration of interests LEB reports consulting fees from Genentech, ADC Therapeutics, Merck, AstraZeneca, and Amgen; and participation on a data safety monitoring board for Ziopharm Oncology. LHS reports research grants from Roche/Genentech and Teva; consulting fees from AbbVie, Acerta, Amgen, AstraZeneca, Celgene/Bristol-Myers Squibb (BMS), Gilead/Kite/Incyte, Janssen, Roche/Genentech, MorphoSys, Sandoz, and TG therapeutics; and honoraria from AbbVie, Acerta, Amgen, AstraZeneca, Celgene/BMS, Gilead/Kite/Incyte, Janssen, Roche/Genentech, MorphoSys, Sandoz, and TG therapeutics. MM reports research grants from AstraZeneca, Genentech, Janssen, Roche, Bayer, IGM Biosciences, Pharmacyclics, and Seattle Genetics; payment or honoraria from lectures, presentations, speaker's bureaus or manuscript writing, or educational events from ADC Therapeutics, Bayer, Daiichi Sankyo, MEI Pharma, Genentech, Seattle Genetics, Epizyme, IMV Therapeutics, Janssen, Pharmacyclics, and Roche; payment from expert testimony from Bayer; and owns stock or stock options in Merck. SJS reports grants or contracts from Genentech, AbbVie, Acerta, AstraZeneca, Celgene/BMS/Juno, Incyte, Merck, Novartis, TG Therapeutics, and Theredex; consulting fees from AstraZeneca, BeiGene, Celgene/BMS/Juno, Genentech/Roche, Genmab, Incyte, Janssen, MorphoSys, Mustang Biotech, Novartis, and Regeneron; payment or honoraria from lectures, presentations, speaker's bureaus or manuscript writing, or educational events for Incyte, Novartis, and Takeda; participation on a monitoring board or advisory board for AstraZeneca, BeiGene, Celgene/BMS/Juno, Genentech/Roche, Genmab, Incyte, Janssen, MorphoSys, Mustang Biotech, Novartis, and Regeneron; a role in board, society, committee, or advocacy groups for Genentech, Legend Biotech, Novartis, and Nordic Nanovector; and research support for Genentech and Merck. SA reports research grants from AbbVie, Roche, Genentech, Takeda, Lilly, and Merck; speaker's bureau from Pfizer; and is chair of the haematology group (unpaid) of the Canadian Cancer Trials Group. JK reports research grants from Roche, AstraZeneca, and Merck; consulting fees from AbbVie, Antengene, BMS, Gilead, Karyopharm, Medison Ventures, Merck, Roche, and Seattle Genetics; payment or honoraria from lectures, presentations, and educational events for AbbVie, Amgen, AstraZeneca, BMS, Gilead, Incyte, Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche, and Seattle Genetics; participation in a data safety monitoring board for Karyopharm; and participation as chair, scientific advisory board, and director in the board of directors for Lymphoma Canada. MC reports consulting fees from BeiGene, BMS, Incyte, Janssen, Kite, Kyowa, Miltenyi Biotec, Novartis, Roche, and Takeda; payment from lectures, presentations, speaker's bureaus or manuscript writing, or educational events from Amgen, Eusa Pharma, Janssen, Kite, Kyowa, Roche, and Takeda; and meeting attendance or travel support, or both, from Kite, Janssen, Roche, Sanofi, and Takeda. LN reports grants from BMS, Caribou Biosciences, Epizyme, Gilead/Kite, Janssen, IGM Biosciences, Takeda, and TG Therapeutics; payment or honoraria from lectures, presentations, speaker's bureaus or manuscript writing, or educational events from Genentech, Gilead/Kite, and Takeda; meeting attendance or travel, or both, support from Genentech; and participation in data safety monitoring board or advisory board for ADC Therapeutics, Bayer, Epizyme, BMS, MorphoSys, Novartis, Genentech, Takeda, MEI, DeNovo, and TG Therapeutics. CYC reports payment or honoraria from lectures, presentations, speaker's bureaus or manuscript writing, or educational events for Janssen, AstraZeneca, Roche, and Beigene; and participation in data safety monitoring board or advisory board for Roche, Janssen, TG Therapeutics, AstraZeneca, Lilly, and Gilead. MCW reports meeting attendance or travel support, or both, from Roche/Genentech; and stocks and stock options in Roche. SY reports meeting attendance or travel support, or both, for Genentech; patents planned, issued, or pending from Genentech; and stocks and stock options in Genentech. C-CL reports stocks and stock options in Roche; and patents planned, issued, or pending for Genentech. AK reports stocks or stock options in Roche. EP reports stocks or stock options in Genentech. NLB reports research funding from ADC Therapeutics, Affimed, Autolus, BMS, Celgene, Forty Seven, Immune Design, Janssen, Kite Pharma, Merck, Millennium, Pfizer, Pharmacyclics, Roche/Genentech, and Seattle Genetics. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Novel therapies for relapsed or refractory follicular lymphoma are commonly evaluated in single-arm studies without formal comparison with other treatments or historical controls. Consequently, rigorously defined treatment outcomes informing expectations for novel therapeutic strategies in this population are sparse. To inform outcome expectations, we aimed to describe treatment patterns, survival outcomes, and duration of response in patients with relapsed or refractory follicular lymphoma receiving three or more lines of systemic therapy., Methods: In this multicentre cohort study, we developed a database of patients with relapsed or refractory follicular lymphoma from eight academic centres in the USA using data collected in the LEO Cohort study (NCT02736357) and the LEO Consortium. For this analysis, eligible patients were aged at least 18 years, had non-transformed grade 1-3a follicular lymphoma, and were receiving systemic therapy in the third line or later after previous therapy with an anti-CD20 antibody and an alkylating agent. Clinical data and patient outcomes were abstracted from medical records by use of a standard protocol. The index therapy for the primary analysis was defined as the first line of systemic therapy after the patient had received at least two previous systemic therapies that included an alkylating agent and an anti-CD20 therapy. The main endpoints of interest were overall response rate, progression-free survival, and overall survival. Outcomes were also evaluated in subsets of clinical interest (index therapy characteristics, patient and disease characteristics, treatment history, and best response assessment)., Findings: We screened 933 patients with follicular lymphoma, of whom 441 were included and diagnosed between March 6, 2002, and July 20, 2018. Index therapies included immunochemotherapy (n=133), anti-CD20 antibody monotherapy (n=53), lenalidomide with or without anti-CD20 (n=37), and phosphoinositide 3-kinase inhibitors with or without anti-CD20 (n=25). 57 (13%) of 441 patients received haematopoietic stem-cell transplantation and 98 (23%) of 421 patients with complete data received therapy on clinical trials. After a median follow-up of 71 months (IQR 64-79) from index therapy, 5-year overall survival was 75% (95% CI 70-79), median progression-free survival was 17 months (15-19), and the overall response rate was 70% (65-74; 280 of 400 patients evaluable for response). Patients who were refractory to therapy with an alkylating agent had a lower overall response rate (170 [68%] of 251 patients vs 107 [77%] of 139 patients) and a significantly lower 5-year overall survival (72%, 95% CI 66-78 vs 81%, 73-89; hazard ratio 1·60, 95% CI 1·04-2·46) than patients who were not refractory to therapy with an alkylating agent., Interpretation: Patients with relapsed or refractory follicular lymphoma receive heterogeneous treatments in the third-line setting or later. We observed high response rates to contemporary therapies that were of short duration. These data identify unmet needs among patients with follicular lymphoma, especially those who are refractory to alkylating agents, and might provide evidence by which clinical trials evaluating novel treatments could be assessed., Funding: Genentech and the National Cancer Institute., Competing Interests: Declaration of interests CC reports research funding from Gilead Sciences, Bristol Myers Squibb, Verastem, and GNE. ISL is on advisory boards for Seattle Genetics, Janssen Scientific, and Verastem. YW reports that research funding has been provided to his institution from Incyte, InnoCare, LOXO Oncology, Novartis, and Genentech, and advisory board membership for Lilly Oncology, Incyte/MorphoSys, and TG Therapeutics (but was not personally compensated for his participation). LJN reports honorarium from ADC Therapeutics, Bayer, Bristol Myers Squibb/Celgene, Epizyme, Genentech, Janssen, Gilead Sciences/Kite, Morphosys, Novartis, Pfizer, Takeda, and TG Therapeutics, and research funding from Bristol Myers Squibb/Celgene, Caribou Biosciences, Epizyme, Genentech, Janssen, Gilead Sciences/Kite, IGM Biosciences, Novartis, Pfizer, Takeda, and TG Therapeutics. CS reports honorarium from Bristol Myers Squibb. DC reports honorarium from AstraZeneca. PM reports research funding from Karyopharm and consultancy for ADC Therapeutics, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Cellectar, Epizyme, Gilead Sciences, Incyte, Janssen, Karyopharm, Regeneron, Takeda, Teneobio, and Verastem. JBC reports research funding and advisory board membership for Genentech. BSK reports research funding and consultancy for F. Hoffmann-La Roche and Genentech. JLK reports research funding from the American Association for Cancer Research (underwritten by Pharmacyclics, an AbbVie Company, and Janssen Biotech), the Lymphoma Research Foundation (underwritten by Celgene), Oncternal Therapeutics, and Viracta Therapeutics, and advisory board membership for Janssen Biotech. YM, AM, MW, MCW, AS, and JL report employment by Genentech and ownership of shares in F. Hoffmann-La Roche. JC reports research funding from GNE, NanoString, and Celgene/Bristol Myers Squibb, and advisory board membership for Celgene/Bristol Myers Squibb. CRF reports research funding from 4D, AbbVie, Acerta, Adaptimmune, Allogene, Amgen, Bayer, Celgene, Cellectis, EMD, Gilead, Genentech, F. Hoffmann-La Roche, Guardant, Iovance, Janssen Pharmaceutical, Kite, Morphosys, Nektar, Novartis, Pfizer, Pharmacyclics, Sanofi, Takeda, TG Therapeutics, Xencor, Ziopharm, Burroughs Wellcome Fund, the Eastern Cooperative Oncology Group, the National Cancer Institute, the V Foundation, and Cancer Prevention and Research Institute of Texas Scholar in Cancer Research, and consultancy for AbbVie, Bayer, BeiGene, Celgene, Denovo Biopharma, Genentech, F. Hoffmann-La Roche, Genmab, Gilead Sciences, Karyopharm, Pharmacyclics/Janssen, SeaGen, and Spectrum. BKL is a consultant for Genentech. MJM reports research funding from Morphosys, Genentech, Bristol Myers Squibb, and Nanostring, and is an advisory board member for Pfizer, Morphosys, and Kite Pharma. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)