Mosunetuzumab is a CD20xCD3 T-cell engaging bispecific antibody approved in Europe and the United States for relapsed/refractory (R/R) follicular lymphoma (FL) after ≥ 2 prior therapies.
We present ...interim safety data from the mosunetuzumab GO29781 (NCT02500407) phase I/II dose-escalation study in R/R non-Hodgkin lymphoma (NHL), focusing on FL.
Overall, 218 patients with R/R NHL, including 90 with R/R FL, received a median of eight 21-day cycles of intravenous mosunetuzumab with step-up dosing in Cycle (C) 1 (C1 Day D 1, 1 mg; C1D8, 2 mg; C1D15/C2D1, 60 mg; C3D1 and onwards, 30 mg). Cytokine release syndrome (CRS) was the most common adverse event (AE), occurring in 39.4% (NHL) and 44.4% (FL) of patients. Events occurred predominantly during C1 at the first loading dose; the majority were grade 1/2. CRS events were managed at the investigator's discretion with supportive care, steroids, and tocilizumab, based on protocol management guidelines. Immune effector cell-associated neurotoxicity syndrome was uncommon, reported in 0.9% (NHL) and 1.1% (FL) of patients. Neutropenia occurred in 27.5% (NHL) and 28.9% (FL) of patients (mostly grade 3/4) and could be effectively managed using granulocyte colony-stimulating factor. Tumor lysis syndrome occurred in 0.9% (NHL) and 1.1% (FL) of patients (all grade 3/4 with CRS; all resolved).
Mosunetuzumab monotherapy as treatment for R/R B-cell NHL, including FL, was associated with low rates of severe AEs (including CRS) and is suitable for outpatient administration in the community setting. Adapted protocol guidance for the management of select AEs during mosunetuzumab treatment is included.
Mosunetuzumab is approved in Europe and the United States for the treatment of patients with R/R FL after ≥ 2 prior therapies. We evaluated the safety of mosunetuzumab in the phase I/II GO29781 study, in 218 patients with R/R non-Hodgkin lymphoma, including 90 with FL. Mosunetuzumab demonstrated a manageable safety profile, supporting its administration as an outpatient regimen.
•Mosunetuzumab is active as a single agent and yields CRs in 24% of heavily pretreated patients with R/R DLBCL.•Step-up dosing mitigated CRS events with mosunetuzumab, which has a manageable ...tolerability profile in R/R DLBCL.
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As part of a phase 1 or 2 study, this single-arm expansion cohort established the efficacy and safety of mosunetuzumab monotherapy in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (received ≥2 previous lines of therapy). Intravenous mosunetuzumab was administered with cycle (C) 1 step-up dosing for cytokine release syndrome (CRS) mitigation: C1 day (D) 1: 1 mg; C1D8 2 mg; C1D15 and C2D1: 60 mg; C3 + D1: 30 mg. Hospitalization was not mandatory. Patients with complete response (CR) completed treatment after C8; those with partial response or stable disease continued treatment for a total of 17 cycles. The primary end point was CR rate (best response), assessed against a historical control CR rate (20%) by independent review facility. Eighty-eight patients (73.9% de novo DLBCL; 26.1% transformed follicular lymphoma) were enrolled; all had received previous anthracycline and anti-CD20 therapy. Overall response and CR rates were 42.0% (95% confidence interval CI, 31.6-53.1) and 23.9% (95% CI, 15.4-34.1), respectively; CR rate did not reach statistical significance vs the historical control (P = .36). Median time to first response was 1.4 months. Median progression-free survival was 3.2 months (95% CI, 2.2-5.3). The CR rate in 26 patients who received previous chimeric antigen receptor T-cell (CAR-T) therapy was 12%. CRS was one of the most common adverse events (26.1% of patients); predominantly grade 1 to 2 and primarily in C1. Four patients (4.5%) discontinued mosunetuzumab owing to adverse events. Mosunetuzumab demonstrated notable efficacy and a manageable safety profile in patients with R/R DLBCL, including those previously treated with CAR-Ts. This trial was registered at www.clinicaltrials.gov as #NCT02500407.
We conducted a phase II clinical trial to develop an autologous EBV-specific T cell product (baltaleucel T) for advanced, relapsed ENKTL. Among 47 patients who provided whole blood starting material ...for manufacturing the product, 15 patients received a median of 4 doses of baltaleucel T. Thirty-two (68%) patients did not receive baltaleucel-T due to manufacturing failure, rapid disease progression, and death. Of the 15 patients, 10 patients had measurable disease at baseline (salvage cohort), and 5 patients had no disease at baseline assessment (adjuvant cohort). In the 15 patients, the median follow-up duration was 10.2 months (range 2.0–23.5 months), median progression-free survival (PFS) was 3.9 months, and the median overall survival (OS) was not reached. Patients in the salvage cohort achieved a 30% complete response (CR) and a 50% overall response rate (ORR). In the adjuvant cohort, disease progression was reported in three patients and two patients did not relapse during study follow-up. When we compared survival outcomes of seven responders and eight non-responders, the PFS (
P
= 0.001) and OS (
P
= 0.014) of responders proved statistically superior to that of non-responders. Baltaleucel-T was well tolerated. We have performed a phase II clinical trial of autologous EBV-specific T cell treatment (baltaleucel-T) in R/R ENKTL. Autologous EBV-specific T cells were well tolerated and demonstrated single-agent activity in R/R ENTKL.
Lymphomas with central nervous system (CNS) involvement confer a worse prognosis than those without CNS involvement, and patients currently have limited treatment options. T cells genetically ...engineered with CD19-targeted chimeric antigen receptors (CAR) are effective against B-cell malignancies and show tremendous potential in the treatment of systemic lymphoma. We aimed to leverage this strategy toward a more effective therapy for patients with lymphoma with CNS disease. NOD-
IL2Rgamma
(NSG) mice with CNS and/or systemic lymphoma were treated with CD19-CAR T cells via intracerebroventricular (ICV) or intravenous (IV) injection. CAR T cells isolated after treatment were rigorously examined for phenotype, gene expression, and function. We observed that CAR T cells infused ICV, but not IV, completely and durably eradicated both CNS and systemic lymphoma. CAR T cells delivered ICV migrated efficiently to the periphery, homed to systemic tumors, and expanded
, leading to complete elimination of disease and resistance to tumor rechallenge. Mechanistic studies indicated that ICV-delivered CAR T cells are conditioned by exposure to cerebrospinal fluid in the ICV environment for superior antilymphoma activity and memory function compared with IV-delivered CAR T cells. Further analysis suggested that manipulating cellular metabolism or preactivating therapeutic CAR T cells with antigen
may improve the efficacy of CAR T cells
Our demonstration that ICV-delivered CD19-CAR T cells had activity against CNS and systemic lymphoma could offer a valuable new strategy for treatment of B-cell malignancies with CNS involvement.
Relapsed Mantle cell lymphoma (MCL) is often treated with Bruton's tyrosine kinase inhibitors (BTKi); however, post-BTKi relapse can be challenging. Adding venetoclax (VEN) to ibrutinib (IBR) has ...shown synergy in preclinical MCL models. Prior MCL studies of the combination show promising efficacy but have conducted limited dose finding. We sought to identify the optimal dosing combination, based on efficacy and toxicity, utilizing a continual reassessment method of 6 combinations of IBR (280 mg, 420 mg, and 560 mg by mouth daily) and VEN (max dose of 200 mg and 400 mg by mouth daily). Eligible participants were not previously exposed to BTKi and not high risk for tumor lysis syndrome (TLS). VEN, initiated first at 100 mg, then at 20 mg by mouth daily after a TLS event, was started prior to adding IBR and ramped-up based on the dose level assigned. Combination treatment continued for six 28-day cycles. Thirty-five participants were enrolled and treated. One TLS event occurred with starting dose of 100 mg VEN; no TLS was seen with 20 mg. The optimal dosing combination was considered to be VEN 200 mg and IBR 420 mg with an overall response rate (ORR) of 93.8% (95% CI: 73.6% to 99.7%) and DLT incidence of 6.2% (95% CI: 0.3% to 26.4%). ORR for all arms was 82.3% (28/34; 95% CI: 65.5% to 93.2%) with a complete response (CR) rate of 42.4% (14/33; 95% CI: 25.5% to 60.8%). A participant was not allocated to IBR 560 mg and VEN 400 mg. ORR benefit was not seen with higher dosing combinations and toxicity was higher; a comparison made within the limitations of small cohorts. Resistance was seen in nearly all arms. This trial was registered at www.clinicaltrials.gov #NCT02419560.
•IBR 420 mg daily in combination with VEN 200 mg daily were identified as having the highest response and lowest toxicty in relapsed MCL.•Additional benefit was not seen at higher doses. Resistance was seen at all dosing combinations, suggesting a biologic resistance mechanism.
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The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The ...NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions, consisting of medical and hematologic oncologists with expertise across a wide range of disease sites, and experts from the areas of dermatology, gastroenterology, endocrinology, neurooncology, nephrology, cardio-oncology, ophthalmology, pulmonary medicine, and oncology nursing. The content featured in this issue is an excerpt of the recommendations for managing toxicities related to CAR T-cell therapies and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to immune checkpoint inhibitors, visit NCCN.org.
Approximately 90% of limited-stage Hodgkin lymphoma (HL) patients are projected to be cured with standard therapy, but many do not live their expected life span because of late treatment–related ...complications. New treatment paradigms are needed to reduce the use of radiation therapy (RT) as well as conventional chemotherapy drugs while improving upon current standard-of-care survival outcomes. In this phase 2 multicenter study, patients with non-bulky limited-stage HL received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by brentuximab vedotin (BV) consolidation. Forty-one patients were enrolled, and patient characteristics included median age of 29 years (range, 19 to 67 years), 58% were female, 45% had unfavorable disease, and 98% had stage II disease. Based on positron emission tomography (PET)–based risk stratification, patients received 2 to 6 cycles of ABVD followed by 6 cycles of BV. After ABVD followed by BV, 95% of evaluable patients (37 out of 39; 95% confidence interval CI, 83%-99%) achieved PET-negative status. In the intent-to-treat patient population, the estimated 3-year progression-free survival (PFS) rate was 92%, and the overall survival (OS) rate was 97%, with a median follow-up of 47 months. All 37 patients who achieved negative PET status after BV consolidation effectively avoided RT and remain in remission with estimated 3-year PFS and OS rates of 100%. In conclusion, BV demonstrates encouraging clinical activity when it follows ABVD therapy in limited-stage HL. Early incorporation of BV may reduce the use of RT as well as conventional chemotherapy drugs while achieving favorable survival outcomes in risk-stratified patients with non-bulky limited-stage HL. This trial was registered at www.clinicaltrials.gov as #NCT01578967.
•This multicenter phase 2 study explores BV as consolidation after ABVD in the first-line setting for treating non-bulky limited-stage HL.•BV consolidation led to high PET negativity and favorable survival outcomes in risk-stratified patients with limited-stage HL.
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Introduction: Mosunetuzumab is a full-length bispecific CD20/CD3 antibody that redirects endogenous T-cells to kill malignant B-cells by concomitantly binding to CD3 on T-cells and CD20 on B-cells. ...We report results of an ongoing multicenter Phase 1/1b study (NCT02500407) evaluating mosunetuzumab in relapsed/refractory (R/R) B-cell NHL patients (pts).
Methods: Pts received mosunetuzumab intravenously (IV) as follows: Group A, mosunetuzumab administered on day (D) 1 of each 21-day cycle (C); and Group B, ascending doses of mosunetuzumab administered on D1, D8, and D15 of C1, then at a fixed dose on D1 of every 21-day cycle thereafter, up to a maximum of 17 cycles. Single-pt dose escalation converting to a 3+3 design was used in Group A; standard 3+3 escalation was used in Group B. Additional pts were enrolled to further characterize clinical activity at cleared dose levels. Primary outcome measures are maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs), tolerability, pharmacokinetics (PK), and best objective response.
Results: As of 13 April 2018, 98 pts were enrolled to receive mosunetuzumab (diffuse large B-cell lymphoma DLBCL/transformed tr follicular lymphoma FL n=55, FL n=29, mantle cell lymphoma n=3; other NHL n=11; Table 1). The median duration of treatment was 81 days (range 8-162 days) in Group A and 68 days (range 1-306 days) in Group B. 26 pts remain on treatment and 18 completed treatment, of whom 10 remain in follow-up. 54 pts (55%) discontinued treatment due to disease progression (n=43, 44%), withdrawal of consent (n=5, 5%), adverse events (AEs) (n=2, 2%), use of another anticancer agent (n=2, 2%), physician decision (n=1, 1%) or death (n=1, 1%; hemophagocytic lymphohistiocytosis). Doses up to 2.8mg were assessed in Group A (n=33) and up to 1.0/2.0/13.5mg in Group B (the C1D1/C1D8/C1D15 dose; subsequent doses = C1D15 dose; n=65). DLTs were reported in 6 pts: neutropenia (n=2, both grade 4), cytokine release syndrome (CRS; n=1, grade 2), increased liver transaminases (grade 4) and hepatic encephalopathy (grade 3) (n=1), hypotension (n=1, grade 3) and anemia (n=1, grade 3). The MTD has not yet been reached in either group. Safety was similar in both groups even with higher dose levels tested in Group B (Table 2). The majority of treatment-emergent AEs occurred during Cycle 1. CRS was the most frequently reported drug-related AE; occurred in 21/98 (21%) pts and mostly occurred with the first dose. All cases of CRS were grade 1-2 per Lee et al. (Blood 2014) grading criteria. Grade ≥3 AEs occurred in 51/98 (52%) pts, of which 22/98 (22%) were considered treatment-related. Grade ≥3 treatment-emergent neutropenia was observed in 13/98 (13%) pts. One case of febrile neutropenia was reported (assessed as unrelated to study drug); no neutropenia-related infections were reported. Only one treatment-related grade ≥3 neurotoxicity was reported (grade 3 hepatic encephalopathy). One fatality from hemophagocytic lymphohistiocytosis in a pt with suspected chronic active Epstein-Barr virus infection was attributed to study treatment and one pt died of hepatic failure 26 days after the first dose; considered possibly related to treatment. Mosunetuzumab displayed a half-life of 6-11 days. Pharmacodynamic activity was evident from peripheral CD8+ and CD4+ T-cell activation following mosunetuzumab administration. Mosunetuzumab exhibited anti-tumor activity at doses ≥1.2mg (Figure 1). Among pts receiving doses ≥1.2mg, 66 patients (18 FL, 39 DLBCL/trFL and 9 other histologies) had at least 3-month follow-up and were considered efficacy-evaluable. Objective responses were observed in 27/66 (41%) evaluable pts, including 11/18 (61%) FL pts and 13/39 (33%) DLBCL/ trFL. 18 pts (27%) had a complete response (CR), including 50% (9/18) of FL pts and 21% (8/39) of DLBCL/trFL pts. Responses were observed in pts considered refractory to anti-CD20 therapy and in pts who had relapsed following CD19-directed CAR-T therapy. CRs appear durable, with all pts achieving a CR remaining in remission (median follow-up 372 days, range 95- 690 days).
Conclusions: Mosunetuzumab is clinically active in R/R B-cell NHL. The safety profile, with MTD not yet reached and with most AEs being low-grade and manageable, appears favorable compared to current standard anti-lymphoma therapies including T-cell directed agents. Mosunetuzumab monotherapy shows promising and durable efficacy in FL and in DLBCL.
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Sehn:Morphosys: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Assouline:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Flinn:Agios: Research Funding; Seattle Genetics: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; BeiGene: Research Funding; Trillium: Research Funding; Gilead: Research Funding; ArQule: Research Funding; Verastem: Consultancy, Research Funding; Curis: Research Funding; Forma: Research Funding; Merck: Research Funding; Kite: Research Funding; Calithera: Research Funding; Takeda: Research Funding; Constellation: Research Funding; TG Therapeutics: Research Funding; Verastem: Research Funding; Pharmacyclics: Research Funding; Portola: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Infinity: Research Funding. Isufi:Genentech: Consultancy; Novartis: Consultancy. Kim:Kyowa-Kirin: Research Funding; Celltrion: Honoraria, Research Funding; J&J: Research Funding; Celgene: Research Funding; Eisai: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Merck: Research Funding. Matasar:Seattle Genetics: Honoraria. Nastoupil:Karus: Research Funding; TG Therappeutics: Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Juno: Honoraria; Gilead: Honoraria; Genentech: Honoraria, Research Funding; Spectrum: Honoraria; Janssen: Research Funding. Hernandez:Genentech: Employment. Li:Genentech: Employment, Equity Ownership. Kulkarni:Genentech: Employment. McCall:Genentech: Employment. McClellan:Genentech: Employment. Yin:Genentech: Employment, Equity Ownership. Gupta:Genentech: Employment, Equity Ownership. Chu:Genentech: Employment, Equity Ownership. Bartlett:Millennium: Research Funding; ImaginAB: Research Funding; Astra Zeneca: Research Funding; Immune Design: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck & Co: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding.
We investigated relationships among chimeric TCR (cTCR) expression density, target Ag density, and cTCR triggering to predict lysis of target cells by cTCR(+) CD8(+) T human cells as a function of Ag ...density. Triggering of cTCR and canonical TCR by Ag could be quantified by the same mathematical equation, but cTCR represented a special case in which serial triggering was abrogated. The magnitude of target lysis could be predicted as a function of cTCR triggering, and the predicted minimum cTCR density required for maximal target lysis by CD20-specific cTCR was experimentally tested. cTCR density below approximately 20,000 cTCR/cell impaired target lysis, but increasing cTCR expression above this density did not improve target lysis or Ag sensitivity. cTCR downmodulation to densities below this critical minimum by interaction with Ag-expressing targets limited the sequential lysis of targets in a manner that could be predicted based on the number of cTCRs remaining. In contrast, acute inhibition of lysis of primary, intended targets (e.g., leukemic B cells) due to the presence of an excess of secondary targets (e.g., normal B cells) was dependent on the Ag density of the secondary target but occurred at Ag densities insufficient to promote significant cTCR downmodulation, suggesting a role for functional exhaustion rather than insufficient cTCR density. This suggests increasing cTCR density above a critical threshold may enhance sequential lysis of intended targets in isolation, but will not overcome the functional exhaustion of cTCR(+) T cells encountered in the presence of secondary targets with high Ag density.
Summary
Given the poor outcomes of relapsed aggressive lymphomas and preclinical data suggesting that ≥2·5 μmol/l concentrations of vorinostat synergize with both etoposide and platinums, we ...hypothesized that pulse high‐dose vorinostat could safely augment the anti‐tumour activity of (R)ICE (rituximab), ifosphamide, carboplatin, etoposide chemotherapy. We conducted a phase I dose escalation study using a schedule with oral vorinostat ranging from 400 mg/d to 700 mg bid for 5 d in combination with the standard (R)ICE regimen (days 3, 4 and 5). Twenty‐nine patients median age 56 years, median 2 prior therapies, 14 chemoresistant (of 27 evaluable), 2 prior transplants were enrolled and treated. The maximally tolerated vorinostat dose was defined as 500 mg twice daily × 5 d. Common dose limiting toxicities included infection (n = 2), hypokalaemia (n = 2), and transaminitis (n = 2). Grade 3 related gastrointestinal toxicity was seen in 9 patients. The median vorinostat concentration on day 3 was 4·5 μmol/l (range 4·2–6·0 μmol/l) and in vitro data confirmed the augmented antitumour and histone acetylation activity at these levels. Responses were observed in 19 of 27 evaluable patients (70%) including 8 complete response/unconfirmed complete response. High‐dose vorinostat can be delivered safely with (R)ICE, achieves potentially synergistic drug levels, and warrants further study, although adequate gastrointestinal prophylaxis is warranted.
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