Faculty Bibliography

PURPOSE/OBJECTIVE:Mosunetuzumab is a bispecific antibody targeting CD20 and CD3 that redirects T cells to engage and eliminate malignant B cells and is being developed for relapsed or refractory (R/R) B-cell non-Hodgkin lymphomas (B-NHLs). METHODS:This first-in-human trial (ClinicalTrials.gov identifier: NCT02500407) evaluated the safety and tolerability and efficacy of mosunetuzumab in patients with R/R B-NHL and established the recommended phase II dose. Data from dose escalation are presented. Single-agent mosunetuzumab was administered intravenously in 3-week cycles, at full dose in cycle 1 day 1 (group A) or with ascending (step-up) doses during cycle 1 on days 1, 8, and 15 (group B), for eight or 17 cycles on the basis of tumor response. RESULTS:Two hundred thirty patients were enrolled. Doses up to 2.8 mg and 60 mg were assessed in groups A and B, respectively; maximum tolerated dose was not exceeded. In group B (n = 197), common adverse events (≥ 20% of patients) were neutropenia (28.4%), cytokine release syndrome (27.4%), hypophosphatemia (23.4%), fatigue (22.8%), and diarrhea (21.8%). Cytokine release syndrome was mostly low-grade (grade ≥ 3: 1.0%) and mainly confined to cycle 1. Across the doses investigated (group B), best overall response rates were 34.9% and 66.2% in patients with aggressive and indolent B-NHL, respectively, and complete response rates were 19.4% and 48.5%. Among patients with a complete response, the median duration of response was 22.8 months (95% CI, 7.6 to not estimable) and 20.4 (95% CI, 16 to not estimable) in patients with aggressive and indolent B-NHL, respectively. CONCLUSION/CONCLUSIONS:Mosunetuzumab, administered with step-up dosing, has a manageable safety profile and induces durable complete responses in R/R B-NHL. The expansion stage of the study is ongoing at the dose level of 1/2/60/60/30 mg selected for further study.

BACKGROUND:Obinutuzumab with polatuzumab vedotin or lenalidomide showed tolerability and activity in phase 1b/2 trials that recruited patients with relapsed or refractory follicular lymphoma. We aimed to examine whether the novel polatuzumab vedotin-obinutuzumab-lenalidomide (Pola-G-Len) combination might enhance antitumour response in patients with relapsed or refractory follicular lymphoma. METHODS:This multicentre, single-arm phase 1b/2 study tested Pola-G-Len in patients with relapsed or refractory follicular lymphoma, and polatuzumab vedotin in combination with rituximab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Here we report the results from the cohort of patients with follicular lymphoma. The trial was done in 18 cancer centres across three countries (Spain, UK, and USA). Patients (≥18 years old) with CD20-positive relapsed or refractory follicular lymphoma (excluding grade 3b) and Eastern Cooperative Oncology Group performance status of 2 or less who had previously received anti-CD20-containing chemotherapy were eligible for inclusion. During the dose-escalation phase, patients received six 28-day cycles of induction treatment with intravenous obinutuzumab 1000 mg (all cohorts), and intravenous polatuzumab vedotin and oral lenalidomide (Celgene, Summit, NJ, USA) in the following doses: 1·4 mg/kg polatuzumab vedotin and 10 mg lenalidomide (cohort 1); 1·8 mg/kg polatuzumab vedotin and 10 mg lenalidomide (cohort 2); 1·4 mg/kg polatuzumab vedotin and 15 mg lenalidomide (cohort 3); 1·8 mg/kg polatuzumab vedotin and 15 mg lenalidomide (cohort 4); 1·4 mg/kg polatuzumab vedotin and 20 mg lenalidomide (cohort 5); and 1·8 mg/kg polatuzumab vedotin and 20 mg lenalidomide (cohort 6). Polatuzumab vedotin was administered on day 1, lenalidomide on days 1-21, and obinutuzumab on days 1, 8, and 15 of cycle one and day 1 of cycles two to six of each 28-day cycle. During phase 2 (dose expansion phase), patients received six cycles of induction with Pola-G-Len at the recommended phase 2 dose established during dose-escalation. Patients who had a response or stable disease at the end of induction were eligible to enter the maintenance phase, in which they received obinutuzumab for 24 months at 1000 mg on day 1 of every other 28-day cycle for a total of 12 doses, and lenalidomide for 12 months at 10 mg on days 1-21 of each 28-day cycle for a maximum of 12 cycles. The primary activity endpoint was complete response at the end of induction. Adverse events were monitored throughout the study. The primary safety objective was to determine the maximum tolerated dose of Pola-G-Len. Analyses were in the safety population, which included all patients that received at least one dose of any of the component drugs (ie, all patients who entered the induction phases in both the escalation and expansion phases), and activity-evaluable population, which included all patients who received at least one dose of any of the component drugs at the recommended phase 2 dose (ie, all patients who received the recommended phase 2 dose in the dose escalation investigation and all patients who entered induction in the dose expansion investigation). This ongoing trial is registered at ClinicalTrials.gov, NCT02600897. FINDINGS/RESULTS:Between March 24, 2016, and August 23, 2018, 56 patients (33 [59%] men and 23 [41%] women; 49 [88%] non-Hispanic or Latino) were enrolled. Two of four patients in cohort 2 reported dose-limiting toxicity events during dose escalation (one patient had grade 4 amylase and lipase elevation and one patient had grade 4 neutropenia and grade 3 thrombocytopenia), and there were no dose-limiting toxicities observed in cohorts 3 or 5; therefore, the recommended phase 2 dose for the dose-expansion was 1·4 mg/kg polatuzumab vedotin plus 20 mg lenalidomide. 46 (82%) patients were included in the activity-evaluable population. After a median follow up of 26·7 months (IQR 22·2-31·3) the objective response rate was 76% (90% CI 64-86) and complete response rate was 63% (90 CI 50-75). After a median follow-up of 27·0 months (IQR 18·7-34·0), the most common grade 3-4 adverse events were neutropenia (31 [55%] of 56 patients) and thrombocytopenia (14 [25%] patients). 61 serious adverse events were reported in 35 (63%) patients; the most common of which were febrile neutropenia (five [9%] patients; a sixth patient had febrile neutropenia, but this was not considered serious by the investigator), pneumonia (four [7%] patients), and pyrexia (four [7%] patients). One fatal adverse event (grade 5 septic shock) occurred in a patient who had discontinued study treatment due to disease progression and had initiated a new anti-lymphoma tyrosine kinase inhibitor treatment. This was not considered related to study treatment by the investigator. INTERPRETATION/CONCLUSIONS:Pola-G-Len showed high complete response rates, although it did not reached the prespecified threshold for activity, in patients who were heavily pretreated with refractory follicular lymphoma. Our findings compare favourably with available therapies and support future investigation of Pola-G-Len in a larger patient population. FUNDING/BACKGROUND:Genentech/F Hoffmann-La Roche.

[Formula presented] Introduction: Clinical trials of novel salvage therapies (ST) have encouraging outcomes for relapsed/refractory classic Hodgkin lymphoma (R/R cHL) after autologous stem cell transplant (ASCT); yet studies comparing novel ST with conventional salvage chemotherapy are lacking. In a single center cohort, we demonstrated that bendamustine/brentuximab (BBV) had higher overall response rates (ORR) and complete response (CR) rates in ASCT-eligible R/R cHL (Desai et al JCO, 2021). Herein we report comparative outcomes of novel and conventional ST in R/R cHL who undergo ASCT, in a large multicenter retrospective cohort.
Method(s): Consecutive R/R cHL pts who underwent ASCT at 12 institutions across United States were included. Demographics and clinical variables at relapse including age, sex, B symptoms, stage, bulky disease (BD, single mass > 6 cm) extra nodal disease (END), primary refractory disease (PRD) and early relapse (ER, within 1 year) were recorded by electronic health records review. Study objectives were ORR, CR to first ST, post-ASCT PFS and OS by final ST. Time to event endpoints were defined from date of ASCT.
Result(s): From 12 participating institutions, 853 pts of R/R cHL who underwent ASCT were eligible for this study. Median age was 33 (14-72) years, 457 (54%) were male, 446 (52%) had BD, 257 (30%) had advanced stage, 271 (32%) had END, 369 (43%) had B symptoms, 142 (17%) had PRD and 307 (36%) had ER. All 853 received at least 1 ST, 245 received 2 ST, 71 received 3 ST and 26 received 4 ST. Seven groups of ST were identified: 1. Conventional platinum-based chemotherapy (PBC) group including ICE, DHAP and ESHAP 2. BBV 3. Brentuximab Vedotin and nivolumab (BV/Nivo) 4. BV alone (BV) 5. gemcitabine-based chemotherapy (Gem) 6. checkpoint inhibitors (CPI) and 7. other miscellaneous agents (Misc). 1st ST was as follows: 553 had PBC; 69 had BBV; 48 had BV/Nivo; 65 had BV; 49 had Gem; 4 had CPI and 63 had Misc. There was no significant difference in the baseline characteristics by type of 1 ^st ST (data not shown). BBV had significantly higher ORR (92% vs 79%, p<0.001) and CR rate (80% vs 49%, p <0.001) compared to PBC. BV/Nivo had significantly higher CR rate (67% vs 49%, p <0.001) and a trend towards higher ORR (86% vs 79%, p = 0.1) compared to PBC. BV had significantly lower ORR (62% vs 79%, p <0.001) and CR rate (34% vs 49%, p <0.001) compared to PBC. There was no difference in ORR and CR rate of PBC, Gem, CPI and Misc agents. Final ST prior to ASCT was PBC in 451, BBV in 76, BV/Nivo in 48, BV in 87, CPI in 24, Gem in 90 and Misc in 64. Table 1 lists K-M estimates of 2-year survival probabilities for different Final ST groups. Median follow up was 3 (range 0.1-13) years. BV/Nivo group had significantly higher proportion of patients with PRD and BD than PBC, no other differences in baseline characteristics were identified amongst ST groups (data not shown). BV/Nivo (HR: 0.1 (CI 95:0.02-0.4), p<0.01) and CPI (HR: 0.12 (CI 95:0.03-0.5), p<0.01) had significantly higher PFS than PBC. There was no significant difference in PFS between other ST groups (Figure 1a). Type of ST was not significantly associated with difference in OS (Figure 1b). 536 pts underwent ASCT in CR, 273 underwent ASCT in partial response (PR) and 31 underwent ASCT with progressive disease (PD). Pre-ASCT PR (HR 1.6 (CI 95:1.3-2.6), p<0.001) and PD (HR: 4.1 (CI 95: 2.5-6.8), p<0.001) predicted significantly lower PFS compared to CR (Figure 2a). OS was also significantly lower in pts with pre-ASCT PR (HR 1.7 (CI 95: 1.2-1.6), p<0.001) and PD (HR 5.3 (CI 95: 2.8-10), p<0.001) (Figure 2b). Higher number of pre-ASCT ST predicted lower PFS (HR 1.3 (CI 95: 1.1-1.6), p<0.001) and OS (HR 1.5 (CI 95: 1.2-1.8), p<0.001). In pts with pre-ASCT CR, all 36 who had pre-ASCT CR after BV/Nivo were alive and relapse free for follow up of 0.1-5 yrs. BV/Nivo was associated with significantly higher PFS (HR 0.1 (CI 95: 0.01-0.7), p <0.05) but not OS compared to PBC in this subgroup. Increasing number of pre-ASCT ST predicted worse PFS (HR 1.5 (CI 95: 1.2-2.0), p<0.01) and OS (HR 2.2 (CI 95: 1.4-3.4), p<0.001) in this subgroup as well.
Conclusion(s): BV/Nivo has a higher CR rate and better post-ASCT PFS compared to conventional chemotherapy and can lead to durable remissions in pts with pre-ASCT CR. BBV had a higher response rate and similar post-ASCT survival to conventional chemotherapy. BV had lower response rates compared to chemotherapy. Novel ST such as BV/Nivo and BBV may be preferable to conventional chemotherapy in R/R cHL. [Formula presented] Disclosures: Spinner: Notable Labs: Honoraria. Bachanova: FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dorritie: SITC presentation: Honoraria; Genmab: Research Funding; University of Pittsburgh/UPMC Hillman Cancer Center: Current Employment; Janssen: Research Funding; F. Hoffman-La Roche Ltd: Research Funding; Juno/BMS: Research Funding; Kite, a Gilead Company: Research Funding; OncLive/Institutional Perspectives on Cancer presentation: Honoraria. Arai: Magenta Therapeutics: Research Funding. Maurer: Nanostring: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Diefenbach: Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; IMab: Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; AbbVie: Research Funding; IGM Biosciences: Research Funding; Incyte: Research Funding; Trillium: Research Funding; Gilead: Current equity holder in publicly-traded company; MEI: Consultancy, Research Funding. Nowakowski: Kyte Pharma: Consultancy; Ryvu Therapeutics: Consultancy; Selvita: Consultancy; Curis: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MorphoSys: Consultancy; Bantham Pharmaceutical: Consultancy; Daiichi Sankyo: Consultancy; Zai Labolatory: Consultancy; Incyte: Consultancy; Kymera Therapeutics: Consultancy; TG Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Nanostrings: Research Funding. Advani: Astellas/Agensys: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Cell Medica: Membership on an entity's Board of Directors or advisory committees; Forty Seven: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceutical: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millenium: Research Funding; Pharmacyclics: Consultancy, Research Funding; Portola Pharmaceuticals: Consultancy; Regeneron: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees.
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Background Classical Hodgkin lymphoma (cHL) is characterized by rare, malignant Hodgkin/Reed Sternberg (HRS) cells that shape their microenvironment (TME) to inhibit anti-tumor immune response. Systemic immune dysregulation may influence treatment response and toxicity, but the systemic influence of the TME is less well described. The wide variety of proteins measured in high-parmater flow cytometry make it a powerful tool for immune monitoring, but presents challenges in immuno-monitoring. Combinatorial expression of these proteins defines cell types that may influence disease. TerraFlow is a fully automated data analysis platform that evaluates millions of phenotypes and selects the populations that best predict clinical variables. The analysis can be performed using classical Boolean gates or a non-gating approach that approximates gates without using manual thresholds, allowing immunophenotypes to be comprehensively surveyed for disease associations. The platform was used to find phenotypes that discriminate healthy versus cHL patients (AUC = 1) and pre versus post treatment patient phenotypes(AUC = 0.79). Methods Human Subjects: Informed consent was obtained from cHL patients (N=44) treated at the Perlmutter Cancer Center (PCC) at NYU Langone Health and New York Presbyterian Weil Cornell (NYP) between 2011 and 2016. Blood samples were drawn at multiple time-points, for this study pre-treatment and 3 month post-treatment samples were used. Age-matched, cryopreserved healthy donor PBMC (n=25) were obtained from STEMCELL Technologies (Cambridge, MA).Patient-derived blood was processed for isolation of PBMC, stained analyzed on a Symphony Flow Cytometer (BD Biosciences, San Jose, CA). Analysis: Data was analyzed using an original platform called terraFlow. Many immune cell subsets are defined by the combinations of proteins they express. TerraFlow systematically evaluates millions of cell types by generating every possible combination of 1 to 5 markers. A network-based algorithm then selects the "best" phenotype from each set of inter-related combinations based on statistical power and ease of interpretation. Each phenotype is defined using a minimal gating strategy that can be replicated in a diagnostic panel or cell sorter. Together, phenotypes describe all the major differences between patient groups. A new platform developed by Epistemic AI was used to mine scientific literature and interpret selected phenotypes. Results We observed clear perturbations in the cHL systemic T-cell compartment pre-treatment as shown in Figure 1. These include higher levels of activated (CD278+), exhausted (CD366+, PD1+, CD152+), and suppressive (GITR+) T-cells compared to healthy donors, and diminished levels of T-cells producing effector cytokines (like IFNgamma and IL4). Subsets of cytokine-producing cells that co-express markers of exhaustion (i.e., TNF+ CD366+ cells) are also elevated in cHL patients. Finally, T-cells expressing CD127 a receptor for IL7 involved in homeostatic renewal of cells and observed on naive and central memory T-cells are reduced. Taken together, these findings suggest that in cHL the systemic T-cell compartment is shifted toward a more exhausted profile, and away from less differentiated cells, with the potential for self-renewal. Our data also demonstrates a shift from T-helper 1 and T-helper 2 type toward T-helper 17 cells suggesting that T-cell effector function may be reduced. Conclusion Using a novel data analysis platform, TerraFlow we demonstrate dysregulation in systemic T cell function in cHL patients pre-treatment that persists within 3 months of completing therapy. Associations of phenotypes with clinical variables, and post-treatment phenotypes will be described in detail at the meeting. Our results detail new immunotherapy and biomarker research targets, and suggest novel strategies for combination therapies. [Formula presented] Disclosures: Li: BD Bioscience: Current Employment. Ruan: Kite Pharma: Consultancy; AstraZeneca: Research Funding; BMS: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seagen: Consultancy. Diefenbach: Incyte: Research Funding; Trillium: Research Funding; Celgene: Research Funding; IGM Biosciences: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Gilead: Current equity holder in publicly-traded company; AbbVie: Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; MEI: Consultancy, Research Funding; Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; IMab: Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding.
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Introduction: IGM-2323 is the first engineered high-affinity, high-avidity bispecific IgM monoclonal antibody TCE to be tested in the clinic. It has 10 binding domains for CD20 and a single binding domain for CD3 and is designed to bind irreversibly to CD20-high and low-expressing cells with more physiologic stimulation to T cells, which may mitigate cytokine release syndrome (CRS)-related toxicity and broaden the therapeutic window. IGM-2323 may act by multiple mechanisms: T-cell dependent cytotoxicity, complement dependent cytotoxicity, and enhanced immune modulation via IFNgamma-dominant cytokine stimulation. This phase 1 study is exploring the safety and activity of IGM-2323 using a dose titration schedule intended to optimize repeatable immune stimulation while minimizing toxicity.
Method(s): This first-in-human Phase 1 study is a global, multicenter, open-label, dose escalation evaluating safety, tolerability, PK, and preliminary efficacy (NCT04082936). Adults with relapsed or refractory CD20 ⁺ B-cell NHL with >= 2 prior systemic therapies, adequate organ function, and ECOG 0-1 are eligible. IGM-2323 is given IV on Days 1, 8, and 15 of 21-day cycles until disease progression or unacceptable toxicity. Treatment can continue beyond progression if the patient (pt) has benefitted from treatment and intra-patient dose escalation is allowed. This study also utilizes a dose titration scheme where a starting dose is given on Day 1, then higher subsequent doses...
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Despite recent therapeutic advances in the management of non-Hodgkin lymphoma (NHL), up to 50% of patients with diffuse large B-cell lymphoma (DLBCL) relapse after first line therapy, and for DLBCL patients who relapse within 12 months after subsequent stem cell transplant (SCT), the median overall survival (OS) is 6.3 months. Recently, chimeric antigen receptor (CAR) T-cell therapy has shown remarkable activity in relapsed DLBCL with complete response (CR) rate of 40% and 54% for the two of the FDA-approved CAR T-cell products, tisagenlecleucel and axicabtagene ciloleucel, respectively. However, at a median follow-up of 18 months, only 36% of patients treated with tisagenlecleucel remained in CR; with longer follow-up for axicabtagene ciloleucel the median progression free survival (PFS) was 5.9 months. Immune escape and immune evasion are primary mechanisms of CAR-T resistance; clearly improvements are needed to increase response rate and cure. While CRISPR-based loss-of-function screens have shown promise for high-throughput identification of genes that modulate T-cell response, these methods have been limited thus far to negative regulators of T-cell functions, and raise safety concerns due to the permanent nature of genome modification. Here we identify positive T-cell regulators via overexpression of ~12,000 barcoded human open reading frames (ORFs). Using this genome-scale ORF screen, we found modulator genes which increased primary human CD4+ and CD8+ T-cell proliferation, including activation markers like CD25 and CD40L, and secretion of key cytokines like interleukin-2 and interferon-gamma. In addition, we developed a single-cell genomics method (OverCITE-seq) for high-throughput quantification of the transcriptome and surface proteome in ORF-engineered T-cells. The top-ranked ORF, lymphotoxin beta receptor (LTBR), is typically expressed in a subset of myeloid cells but absent in lymphocytes. When expressed in T-cells, LTBR induces a profound transcriptional remodelling, resulting in increased resistance to exhaustion and activation-induced apoptosis, as well as upregulation of a plethora of proinflammatory cytokines, co-stimulatory molecules and antigen presentation machinery. In order to investigate the mechanism of action of LTBR, we developed an epistasis assay which allows for simultaneous gene knockout and LTBR overexpression in primary T cells. Thus, LTBR appears to induce both canonical and non-canonical NFkB pathways - but the phenotype observed in T cells is dependent only on the former. Finally, we co-expressed several top-ranked genes, including LTBR, with FDA approved CD19-targeting CARs utilizing either 4-1BB or CD28 co-stimulatory domains. In line with previous results, co-expression of top-ranked ORFs increased proinflammatory cytokine secretion and cytotoxicity against CD19+ positive cancer cell lines. This functional improvement was also observed when top-ranked ORFs and CARs were delivered to T cells isolated from DLBCL patients as shown in Figure 1. Our results provide several strategies for improving next generation CAR T-cell therapies via induction of new synthetic cell programs which may optimize immune activation and enhance the efficacy of these important therapies, a high priority for patients with relapsed and refractory DLBCL and other lymphomas. [Formula presented] Disclosures: Mimitou: Immunai: Current Employment. Smibert: Immunai: Current Employment. Diefenbach: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; IMab: Research Funding; Gilead: Current equity holder in publicly-traded company; Celgene: Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; MEI: Consultancy, Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; Incyte: Research Funding; Trillium: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Sanjana: Qiagen: Consultancy; Vertex: Consultancy.
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Context: Follicular lymphoma (FL) often presents with recurrent relapses. Treatment options for patients (pts) with FL who have received >=2 prior lines of therapy are limited, and prognosis is poor. The safety and efficacy of mosunetuzumab, a full-length, fully humanized IgG1 CD20/CD3 bispecific antibody is currently being investigated in an ongoing open-label, multicenter, Phase I/Ib, dose-escalation and expansion trial in relapsed/refractory (R/R) B-cell lymphoma (GO29781; NCT02500407).
Objective(s): To present updated data from the R/R FL cohort.
Method(s): Pts received intravenous mosunetuzumab step-up doses in cycle (C) 1, days (D) 1 and 8, then the target dose on D15 and D1 of each subsequent 21-day cycle (Group B); treatment continued for <=17 cycles.
Result(s): As of January 21, 2020, mosunetuzumab 0.4/1.0/2.8 mg to 1/2/13.5 mg (C1D1/8/15 dose levels) was given to 62 pts with FL who received >=2 prior systemic therapies. Pts had a median age of 59 (27-85) years, median number of 3 (2-11) prior therapies; 33 pts (53%) were double refractory, 30 (48%) had progression of disease within 24 months of first-line treatment (POD24), and four (6%) received prior chimeric antigen receptor T-cell (CAR-T) therapy. Overall response rate (ORR) and CR rate were 68% and 50%, respectively. In high-risk pts, consistent CR rates were observed: 55% (18/33) in pts with double refractory disease, 53% (16/30) in pts who had POD24, 78% (7/9) in pts with PI3Ki refractory FL, and 50% (2/4) in those who received prior CAR-T therapy. Twenty-six pts with a CR (74%) remained in remission (median time on study: 14.4 months). In responders (n=42), median duration of response was 20.4 months (95% CI: 11.7-not reached), and median progression-free survival was 11.8 months (95% CI: 7.3-21.9). Adverse events (AEs) and serious AEs were reported in 60 (97%) and 22 pts (35%), respectively. The most common grade (Gr) >=3 AEs included hypophosphatemia (23%) and neutropenia (21%). Fourteen pts (23%) experienced CRS1; events were mostly Gr 1 or 2, reversible, and occurred largely during C1.
Conclusion(s): A high CR rate, durable responses, and a manageable safety profile were observed with mosunetuzumab monotherapy in heavily pre-treated pts with FL, including high-risk pts.
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Context: Mosunetuzumab (Mosun), a full-length, humanized, IgG1 CD20xCD3 bispecific antibody, showed promising efficacy/safety for R/R B-NHL (NCT02500407; Assouline, et al. ASH 2020). Mosun combined with the anti-CD79b antibody-drug conjugate Pola showed synergistic anti-lymphoma activity in a mouse xenograft model, supporting the Phase Ib/II, open-label, multicenter trial of Mosun-Pola for R/R B-NHL (GO40516, NCT03671018).
Objective(s): To present early clinical data from the Phase Ib cohort of GO40516.
Method(s): Patients with R/R follicular lymphoma (FL, grade 1-3a) or aggressive NHL (aNHL), including de novo diffuse large B-cell lymphoma (DLBCL), transformed FL (trFL), and grade 3b FL (FL3b), received Cycle (C)1 step-up doses of Mosun on Day (D)1 (1 mg) and D8 (2 mg), and target dose on C1D15, continuing from C2D1. Mosun was given every 21 days for eight cycles, continuing for <=17 cycles. Pola (1.8 mg/kg) was administered with Mosun on D1 of six cycles.
Result(s): As of November 17, 2020, 22 patients received Mosun-Pola (Mosun target doses: 9 mg, n=7; 20 mg, n=3; 40 mg, n=6; 60 mg [D1 dose 30 mg from C3 onward], n=6). Patients had DLBCL (n=12), FL (n=3), FL3b (n=3), and trFL (n=4). Median age: 70 (38-81) years; median 3 (1-10) prior lines of therapy; prior chimeric antigen receptor T-cell (CAR-T) therapy (n=7; 32%). Median follow-up duration: 9.6 (0.7-23.7) months. Most frequent treatment-related adverse events (AEs): neutropenia (45.4%), fatigue, nausea, and diarrhea (all 36.4%). Cytokine release syndrome was observed in two patients (9.1%; both grade 1 [Lee, et al. Biol Blood Marrow Transplant 2019]). One dose-limiting toxicity (grade 3 new-onset atrial fibrillation) was observed in the 40 mg cohort; maximum tolerated dose not exceeded. Most common grade >=3 AE: neutropenia (n=8; 36.4%). Two (9.3%) grade 5 AEs occurred (sudden cardiac death [n=1]); respiratory failure [n=1]); neither was deemed treatment-related. Complete responses were achieved with Mosun-Pola in patients with R/R aNHL (n=9; 47.4%), prior CAR-T therapy (n=2; 28.6%) and FL (n=3; 100%).
Conclusion(s): These data indicate that Mosun-Pola has an acceptable safety profile and shows promising efficacy in patients with predominantly aggressive R/R NHL. The Phase II expansion cohort in patients with R/R DLBCL is ongoing, with no requirement for mandatory hospitalization.
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