ALBERT

Description: Background: MM inevitably relapses and becomes refractory to treatment, representing a patient (pt) population with unmet needs. Teclistamab (JNJ-64007957) is a bispecific BCMA x CD3 antibody that induces T cell-mediated cytotoxicity against BCMA-expressing MM cells. Previously presented results from an ongoing study of teclistamab in RRMM (NCT03145181) included a 67% objective response rate [ORR] for the 270 µg/kg dose administered intravenously (iv) (Usmani et al, ASCO 2020 Oral Presentation #100). Here we present updated results and newly available data for subcutaneous (sc) administration. Methods: Pts have MM that is RR to established therapies. The primary objective is to identify a recommended phase 2 dose(s) (RP2D). Multiple sc and iv doses ± step-up doses were explored. Adverse events (AEs) were graded per CTCAE v4.03 and cytokine release syndrome (CRS) per Lee et al 2014. Response was investigator-assessed using IMWG criteria; minimal residual disease (MRD) in bone marrow was assessed by next generation sequencing. Results: As of 20 Jul 2020, iv teclistamab (0.3-720 µg/kg) and sc teclistamab (20-3000 µg/kg) were received by 84 and 44 pts, respectively. Overall, median age was 64 y (24-82), median number of prior lines of therapies (LOT) was 6 (2-14), 95%/79% triple-class exposed/refractory, 70%/38% penta-drug exposed/refractory, and 91% refractory to last LOT. AEs in 〉20% of pts (both iv and sc combined) included anemia (55%), neutropenia (55%), thrombocytopenia (41%), and leukopenia (26%), as well as non-hematologic events of CRS (53%), pyrexia (28%), diarrhea (24%), cough (23%), fatigue (23%), nausea (22%), back pain (20%), and headache (20%). 39% of pts had treatment-related grade ≥3 AEs; neutropenia (23%) and anemia (9%) were most frequent. CRS occurred in 55% and 50% of pts with iv and sc dosing, respectively, tending to occur later (relative to the most recent dose) with sc administration (median time to onset of 1.0 day iv and 2.0 days sc). CRS events were all gr 1 (n=51) or 2 (n=17) and generally confined to initial doses. 5% of pts (all iv) had neurotoxicity (2% gr ≥3), and 12% had treatment-related infusion/injection related reaction (including 4 infusion reactions [all iv, 5%] and 11 injection related reactions [all sc, 25%], all gr 1/2). Gr 3 or higher infection-related AEs were reported in 15% of pts (3% treatment related). Four gr 5 AEs were reported (all iv and considered unrelated to treatment by investigator except for 1 case of pneumonia). Pharmacokinetic results showed that the half-life of teclistamab supports weekly iv dosing. Exposure increased in an approximately dose-proportional manner following weekly iv or sc treatment dosing. 1500 µg/kg sc dose had comparable Cmax to that of 270 µg/kg iv and higher trough levels than that of 720 µg/kg iv. Individual time to reach Cmax following sc dosing ranged from Day 3 - Day 8. Teclistamab treatment in both iv and sc cohorts led to pharmacodynamic changes supporting mechanism of action, including increases in T cell activation and circulating cytokine levels, such as IL-10, IL-2Ra and IL-6. 120 pts were evaluable for response, with the highest and most active dose levels of 270 µg/kg and 720 µg/kg weekly for iv and 720 µg/kg and 1500 µg/kg weekly for sc (of note, response data for 3000 µg/kg sc is not yet mature). Combining these 4 iv and sc dose levels, ORR was 30/47 (63.8%, including n=24 with very good partial response [VGPR] or better and n=9 with complete response [CR] or better). 1500 µg/kg sc was selected as a RP2D, and currently at this dose, 6 of 6 pts are in response (3 PR, 1 VGPR, 2 stringent CR) with progressive deepening of responses over time. Among 48 pts with responses across all iv and sc cohorts, median time to first response was 1 mo (range, 0.3-4.2) and median duration of response has not been reached, with 38 responding pts remaining on therapy 1.6 to 21.3+ months. Of MRD-evaluable pts who had a CR, 4/5 pts treated in the iv cohorts and 2/2 pts in the sc cohorts are MRD negative at 10-6. Conclusions: Teclistamab has a manageable safety profile, which includes low-grade CRS (with no gr ≥3 events) and low severe infection and neurotoxicity rates with both iv and sc administration. Deep and durable responses were observed with both iv and sc administration. The encouraging tolerability and efficacy of teclistamab support the planned phase 2 monotherapy (at 1500 µg/kg sc) trial and future combination studies. Disclosures Garfall: Tmunity: Consultancy, Other: Personal fees, Research Funding; Kite Pharma: Other: Personal fees; Amgen: Research Funding; Novartis: Research Funding; GSK: Consultancy; Janssen: Consultancy, Research Funding; Surface Oncology: Consultancy. Usmani:Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Research Funding; SkylineDX: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Celgene: Other; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Array Biopharma: Research Funding; Abbvie: Consultancy; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding. Mateos:Adaptive: Consultancy; Amgen: Consultancy; GlaxoSmithKline: Consultancy; Pharmamar: Consultancy; Janssen: Consultancy; Celgene: Consultancy; EDOMundipharma: Consultancy; AbbVie: Consultancy; Takeda: Consultancy. van de Donk:Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Ferrer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Oriol Rocafiguera:Amgen: Consultancy, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chari:Seattle Genetics: Consultancy, Research Funding; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Array BioPharma: Honoraria; The Binding Site: Honoraria; Sanofi Genzyme: Consultancy; Adaptive Biotechnology: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Research Funding; Antengene: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Secura Bio: Consultancy; Glaxo Smith Kline: Consultancy; Oncopeptides: Consultancy. Bhutani:Prothena: Other: Clinical Trial Funding to Institute; Janssen: Other: Clinical Trial Funding to Institute; Takeda: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Sanofi Genzyme: Consultancy; MedImmune: Other: Clinical Trial Funding to Institute. Pei:J&J: Current Employment, Current equity holder in publicly-traded company. Verona:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Girgis:Johnson & Johnson: Current Employment, Current equity holder in private company. Stephenson:Johnson & Johnson: Current Employment, Current equity holder in private company. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Banerjee:Janssen: Current Employment. Krishnan:BMS/Celgene: Consultancy, Other: Stock BMS, Speakers Bureau; Janssen: Consultancy; Takeda: Speakers Bureau; Z Predicta: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Sanofi: Consultancy; Sutro: Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy.

Description: Despite improved outcomes with current MM treatments, most patients (pts) will develop refractory disease, highlighting the need for novel treatments. GPRC5D is an orphan receptor whose transcript is highly expressed in primary MM cells but has generally limited expression elsewhere, making it an attractive therapeutic target. Talquetamab (JNJ-64407564) is a first-in-class bispecific antibody that binds to GPRC5D and CD3 to induce T cell-mediated killing of GPRC5D-expressing MM cells through the recruitment and activation of T cells. In preclinical models, talquetamab induced cell killing of primary MM cells and inhibited tumor formation and growth in MM mouse models. We present initial results from an ongoing phase 1 dose escalation study of talquetamab (NCT03399799). Eligible pts have measurable MM and progressed on or could not tolerate established therapies. Primary objectives are to characterize the safety of talquetamab and to identify a recommended phase 2 dose (RP2D). Escalating doses of intravenous (IV) or subcutaneous (SC) talquetamab ± step-up doses were assessed. Secondary objectives include characterizing the pharmacokinetics, pharmacodynamics, and preliminary efficacy. Adverse events (AEs) were graded per CTCAE, cytokine release syndrome (CRS) per Lee 2014. Response was assessed by the investigator according to IMWG criteria. As of 20 Jul 2020, 137 pts had received talquetamab; 102 by IV (0.5 - 180 µg/kg) and 35 by SC (5 - 800 µg/kg) dosing. Median age was 64 years (33 - 80; 31% were ≥70) and 22% had ISS stage III disease at study entry. Median number of prior therapies was 6 (2 - 20) over a median of 6.5 years (0.9 - 27) since diagnosis, 85% were refractory to last line of therapy, 79% triple-class refractory, 73% penta-drug exposed, and 31% penta-drug refractory. 13 (10%) pts had received selinexor and 21 (15%) had prior BCMA-directed therapy. Most frequently reported all grade AEs were anemia (50%), CRS (47%), neutropenia (45%), and lymphopenia (40%). Most common grade 3 - 4 AEs were lymphopenia (37%), anemia (27%), and neutropenia (25%). CRS was mostly grade 1 - 2 except for 5 pts with grade 3 CRS (˂8% of pts with CRS) that occurred with IV dosing; only grade 1 - 2 CRS was seen with SC dosing. CRS was generally confined to the first cycle with median time to onset of 1 day (1 - 3) for IV and 2 days (1 - 5) for SC dosing. Treatment-related neurotoxicity was reported in 7 (5%) pts (all resolved/resolving; median duration of 2 days [1 - 9]): 4 had grade 1 - 2 events and 3 had grade 3 events of delirium (n=1), decreased level of consciousness (n=1), or confusion (n=1). Six of 7 pts had neurotoxicity that occurred in the context of CRS, including all 3 grade 3 events. Infections were reported in 37% of pts (8% grade 3 - 4). Infusion related reactions (IV; 15%) and injection site reactions (SC; 14%) were grade 1 - 2 and generally occurred in cycle 1. Two dose-limiting toxicities were observed: clinically asymptomatic grade 4 increased lipase in the setting of a pancreatic plasmacytoma (7.5 µg/kg IV) and grade 3 maculopapular rash (135 µg/kg SC). The maximum tolerated dose (MTD) has not been defined. The half-life of talquetamab supports weekly IV dosing. Exposure increased in an approximately dose-proportional manner following the first IV dose (1.5 - 60 µg/kg). SC dosing resulted in lower Cmax with trough levels comparable to IV dosing at a similar dose. IV and SC dosing of talquetamab led to comparable increases in T cell activation and cytokines (e.g., IL-10, IL-2Rα, IL-6). Cytokine production was modulated with step-up dosing while T cell activation was maintained. Overall response rate (ORR) for IV doses of 20 - 180 µg/kg was 78% (14/18; 2 pending confirmation); 6/6 responded at the 60 µg/kg IV dose. ORR for SC doses of 135 - 405 µg/kg was 67% (8/12); 3/4 responded at the 405 µg/kg SC dose. Responses were noted starting at 1.0 µg/kg, were rapid at a median of 1 month (0.2 - 3), and durable with median not reached in 36/46 (4 pts with response 15+ months; longest at 23+ months). Data at higher doses are immature, and results will be updated at the meeting. GPRC5D is a novel target for MM and in the first clinical report of this first-in-class agent, encouraging clinical activity with manageable safety was observed with talquetamab in heavily pretreated pts with RRMM. A MTD has not been defined and dose escalation continues, with the study nearing a RP2D. The encouraging clinical activity supports monotherapy development and combination approaches. Disclosures Chari: Novartis: Honoraria; Array BioPharma: Honoraria; The Binding Site: Honoraria; Bristol Myers Squibb: Consultancy; Adaptive Biotechnology: Honoraria; Pharmacyclics: Research Funding; Karyopharm: Consultancy; Sanofi Genzyme: Consultancy; Seattle Genetics: Consultancy, Research Funding; Oncopeptides: Consultancy; Takeda: Consultancy, Research Funding; Antengene: Consultancy; Glaxo Smith Kline: Consultancy; Secura Bio: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Berdeja:Takeda: Consultancy, Research Funding; Servier: Consultancy; Teva: Research Funding; Prothena: Consultancy; Poseida: Research Funding; Lilly: Research Funding; Novartis: Research Funding; Acetylon: Research Funding; BMS: Consultancy, Research Funding; CURIS: Research Funding; Karyopharm: Consultancy; Bluebird: Research Funding; EMD Sorono: Research Funding; Bioclinica: Consultancy; Kesios: Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Abbvie: Research Funding; Constellation: Research Funding; Cellularity: Research Funding; Vivolux: Research Funding; Legend: Consultancy; Glenmark: Research Funding; Celgene: Consultancy, Research Funding. Oriol:Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. van de Donk:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rodriguez:Oncopeptides: Consultancy; Sanofi: Consultancy; Abbvie: Consultancy; Kite: Consultancy; GSK: Consultancy; Janssen: Consultancy, Honoraria; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees. Askari:Hospital Universitario Fundacion Jimenez Diaz: Consultancy, Current Employment. Mateos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Pharmamar: Consultancy; Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; EDOMundipharma: Consultancy; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Minnema:Janssen Cilag: Honoraria; Celgene Corporation: Honoraria, Research Funding; Gilead: Honoraria; Amgen: Honoraria; Servier: Honoraria. Verona:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Girgis:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Prior:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Hilder:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Russell:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Krishnan:Takeda: Speakers Bureau; Sanofi: Consultancy; Sutro: Membership on an entity's Board of Directors or advisory committees; Z Predicta: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Regeneron: Consultancy; Amgen: Speakers Bureau; BMS/Celgene: Consultancy, Other: Stock BMS, Speakers Bureau.

Description: Introduction: New targets and treatment modalities are needed for multiple myeloma (MM). Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed on B cells and plasma cells, and is found on myeloma cells with near 100% prevalence. BFCR4350A, a humanized immunoglobulin G-based T-cell-engaging bispecific antibody (bsAb), targets the most membrane-proximal domain of FcRH5 on myeloma cells and CD3 on T cells. Dual binding facilitates efficient immunological synapse formation, resulting in T-cell activation and potent killing of myeloma cells (Li et al. Cancer Cell 2017). GO39775 (NCT03275103) is an ongoing, multicenter Phase I trial evaluating the safety, activity, pharmacodynamics, and pharmacokinetics of BFCR4350A monotherapy in pts with relapsed/refractory (R/R) MM. We present dose-escalation data from the single step-up dosing cohort (Arm A). Methods: All pts have R/R MM for which no established therapy is available, appropriate, or tolerated. Prior exposure to CAR-T cells, T-cell engaging bsAbs, and antibody-drug conjugates (ADCs), including those targeting BCMA, is allowed. In dose-escalation, pts receive BFCR4350A by IV infusion in 21-day cycles (Q3W). In Arm A, a single step-up dose is used in Cycle (C) 1 to mitigate the risk for cytokine release syndrome (CRS), with the step dose (0.05-3.6mg) given on C1 Day (D) 1 and the target dose (0.15-132mg) given on C1D8, and on D1 of each subsequent cycle. Results: At cut-off (April 13, 2020), 51 pts (median age: 62.0 years [range: 33-80]; high-risk [HR] cytogenetics [1q21, t(4;14), t(14;16), or del(17p)]: 28 pts) had been enrolled into Arm A. Median number of prior lines of therapy was 6 (range: 2-15). Prior treatments included: proteasome inhibitors (PIs), 100% (94.1% refractory); immunomodulatory drugs (IMiDs), 100% (98.0% refractory); anti-CD38 mAbs, 78.4% (92.5% refractory); autologous stem cell transplant, 86.3%. Overall, 66.7% of pts were triple-class refractory (≥1 PI, ≥1 IMiD, and ≥1 anti-CD38 mAb), and 94.1% of pts were refractory to their last therapy. At cut-off, 46/51 pts were evaluable for efficacy. Responses were observed at the 3.6/20mg dose level and above, in 15/29 pts (51.7%) (Table). Responses included 3 stringent CRs, 3 CRs, 4 VGPRs, and 5 PRs (Table). At the 3.6/20mg dose level and above, responses were observed in pts with HR cytogenetics (9/17), triple-class refractory disease (10/20), and prior exposure to anti-CD38 mAbs (11/22), CAR-Ts (2/3), or ADCs (2/2). Duration of response data are evolving, with 6/15 pts in response for 〉6 months at cut-off. Median follow-up for safety was 6.2 months (range: 0.2-26.3 months). Almost all pts (49/51) had ≥1 treatment-related AE. The most common treatment-related AE was CRS (Lee et al. 2014 criteria; 38/51 pts, 74.5%). CRS was Grade (Gr) 1 in 20 pts (39.2%), Gr 2 in 17 pts (33.3%), and Gr 3 in 1 pt (2%) (due to Gr 4 transaminase elevation). CRS was most common in C1 (38 pts) and was uncommon or absent in subsequent cycles (4 pts). Most CRS events (49/58, 84.5%) resolved within 2 days. 18/38 (47.3%) pts with CRS received tocilizumab and/or steroids. Other treatment-related AEs in ≥5 pts were neutropenia and lymphocyte count decreased (6 pts each, 11.8%), aspartate aminotransferase increased and platelet count decreased (5 pts each, 9.8%). Treatment-related Gr 3-4 AEs (20 pts, 39.2%) in ≥3 pts were lymphocyte count decreased (6 pts, 11.8%), neutropenia (5 pts, 9.8%), anemia and platelet count decreased (3 pts each, 5.9%). No treatment-related Gr 5 (fatal) AEs were observed. Treatment-related AEs leading to withdrawal of treatment were uncommon (1 pt, 2.0%). One DLT (Gr 3 pneumonia) was observed in the 3.6/90mg cohort, but the MTD was not reached. BFCR4350A PK was linear across the active dose levels tested and the estimated half-life was supportive of the Q3W dosing regimen. Conclusions: BFCR4350A monotherapy demonstrates promising activity in heavily pre-treated R/R MM, with deep and durable responses observed in pts with HR cytogenetics, triple-class refractory disease, and/or prior exposure to anti-CD38 mAbs, CAR-Ts, or ADCs. Toxicity was manageable, with C1 single step-up dosing effectively mitigating the risk for severe CRS and allowing escalation to clinically active doses. Updated data will be presented. Disclosures Cohen: Novartis: Other: Patents/Intellectual property licensed, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Haemalogix: Consultancy; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Krishnan:Sutro: Membership on an entity's Board of Directors or advisory committees; Z Predicta: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Regeneron: Consultancy; Takeda: Speakers Bureau; Amgen: Speakers Bureau; BMS/Celgene: Consultancy, Other: Stock BMS, Speakers Bureau; Sanofi: Consultancy. Fonseca:Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Merck: Consultancy; Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Forsberg:Celgene: Speakers Bureau; Genentech, Inc., Sanofi, Karyopharm, Abbvie: Research Funding. Spencer:AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy; Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding; AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria; Celgene, Janssen and Takeda: Speakers Bureau. Berdeja:BMS: Consultancy, Research Funding; Glenmark: Research Funding; Genentech, Inc.: Research Funding; Bioclinica: Consultancy; Teva: Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Cellularity: Research Funding; Acetylon: Research Funding; CURIS: Research Funding; Legend: Consultancy; Lilly: Research Funding; Constellation: Research Funding; EMD Sorono: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy; Poseida: Research Funding; Amgen: Consultancy, Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; Bluebird: Research Funding; Karyopharm: Consultancy; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Kesios: Research Funding. Li:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment. Choeurng:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Vaze:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Samineni:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Sumiyoshi:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Cooper:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Fine:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Trudel:Janssen: Honoraria, Research Funding; Sanofi: Honoraria; GSK: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Karyopharm: Honoraria; AstraZeneca: Honoraria; BMS: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Honoraria. OffLabel Disclosure: BFCR4350A is a humanized IgG-based T-cell-engaging bispecific antibody that targets the most membrane-proximal domain of FcRH5 on myeloma cells and CD3 on T cells. Dual binding facilitates efficient immunological synapse formation, resulting in T-cell activation and killing of myeloma cells. BFCR4350A is an investigational agent.

Description: Background:Lenalidomide(Len) maintenance following autologous transplantation(ASCT) for multiple myeloma has improved progression free survival (PFS)and overall survival compared with placebo. Optimal duration of maintenance is unknown with considerable inter-trial variability. Depth of remission correlates with PFS, with patients (pts) in a minimal residual disease negative state (MRD) to a sensitivity of 10 -5 having a better PFS. Therefore, Len combinations that lead to higher MRD negativity rates are under study. The anti CD38 antibody Daratumumab in combination with lenalidomide in newly diagnosed MM pts showed a higher MRD negativity rates in the MAIA trial (NEJM2019). SWOGS1803 is testing this regimen as maintenance following ASCT while also assessing the optimal duration of maintenance in patients who achieve MRD negativity. Methods:Pts 18-75 years, with MM within 12 months of induction and without progression from diagnosis are eligible. Prior daratumumab therapy is allowed. Enrollment may be before or after ASCT with transplant being within 18 months from initial registration. Within 180 days from ASCT pts will undergo first randomization to Len or Len plus subcutaneous daratumumab/rHuPH20 maintenance (Len Dara). MRD will be assessed prior to start of maintenance and then annually. Randomized treatment will continue for two years at which time repeat MRD will be assessed for pts in VGPR or better. Pts who are MRD negative will undergo second randomization to either continue maintenance on their assigned arm or discontinue maintenance. The continued maintenance arm will stay on therapy for 7 years or until disease progression or unacceptable toxicity.(see schema) The primary objective of the trial is to compare OS between the two treatment arms (Len vs. LenDara). Secondary objectives include comparisons of overall response rate, PFS, and MRD negativity rate between the treatment arms. The objectives of the second randomization are to compare OS of MRD negative pts who continue maintenance on each arm vs. those who discontinue. An early read out of the trial will be the 24 month MRD analysis after all pts have been accrued. A total of 1100 pts will be accrued to initial step 1 to allow for a 5% drop out and allow 950 pts for the second randomization. As of Aug 1, 171 pts are enrolled for screening among whom 133 have been randomized. Figure 1 Disclosures Krishnan: BMS/Celgene: Consultancy, Other: Stock BMS, Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Consultancy; Sutro: Membership on an entity's Board of Directors or advisory committees; Z Predicta: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Regeneron: Consultancy. Hari:Incyte Corporation: Consultancy; Takeda: Consultancy; BMS: Consultancy; Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy. Orlowski:STATinMED Research: Consultancy; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Background: CD74 is highly expressed on B cell malignancies, including non-Hodgkin's lymphoma (NHL). STRO-001, a novel CD74-targeting ADC was generated using cell-free protein synthesis and site-specific conjugation platform technologies. STRO-001 contains a potent maytansinoid warhead conjugated to two specific sites (drug-antibody ratio of 2) using a stable non-cleavable linker. This first-in-human Phase 1, open-label, multicenter, dose escalation study was designed to evaluate the safety, tolerability, and preliminary anti-tumor activity of STRO-001 in adults with B-cell malignancies (NHL and multiple myeloma). Herein we report preliminary results from the B-cell NHL cohort. Methods: Patients with advanced, relapsed/refractory NHL are eligible for enrollment. STRO-001 is administered as a 60-minute IV infusion. STRO-001 was initially administered on Days 1 and 15 of a 28-day cycle. Starting at 0.91 mg/kg, STRO-001 was administered on Day 1 of a 3-week cycle. Treatment is administered until disease progression or unacceptable toxicity. The study employed a modified 3+3 design with an accelerated dose titration (N=1 per cohort until set specified AEs are observed) for initial dosing cohorts. Results: 18 patients with NHL have been treated at 9 dose levels: .05, .075, .15, .27, .43, .65, .91, 1.27 and 1.78 mg/kg. NHL subtypes include: 6 diffuse large B-cell lymphoma (DLBCL), 5 follicular lymphoma (FL), 2 mantle cell lymphoma (MCL), 2 marginal zone lymphoma, 1 Burkitt's lymphoma, 1 composite DLBCL/FL and 1 composite DLBCL/CLL. Median age is 64.5 (range 21-82). Median ECOG performance status is 1 (range 0-2). Median number of prior therapies is 4 (range 1-12). Three patients received prior CAR-T therapy. Median number of STRO-001 doses administered is 2 (range 1-12). 17 patients have completed at least one cycle of STRO-001 and are evaluable for safety and toxicity for dose escalation recommendation. One patient at the 1.78 mg/kg dose level is currently completing Cycle 1 and not yet evaluable for DLT assessment. Most AEs are grade 1 or 2 (90%) with the most common grade 1-2 TEAEs of chills, fatigue, nausea, anemia, headache, pyrexia, infusion reaction, decreased appetite, and abdominal pain occurring in ≥ 20% of patients. There was one DLT in the NHL cohort, a grade 3 thromboembolic event at the 0.91 mg/kg dose level. 16 patients are evaluable for response. The preliminary clinical benefit/disease control rate for all patients is 25% (4/16) including 1 patient with complete response (CR) 2 with partial response (PR) and 1 with stable disease (Table). One patient with DLBCL treated at .075 mg/kg achieved a CR after 2 cycles (4 doses) and progressed after 12 doses (on study 24 weeks). A DLBCL patient treated at 0.65 mg/kg achieved a PR at Cycle 3 and progressed after 8 doses (on study 15 weeks). A DLBCL patient treated at 1.27 mg/kg who achieved a PR has received 10 cycles and remains on study after 27 weeks. Preliminary PK analysis of ADC shows exposure increased (Cmax from 0.39 to 19 µg/mL) and (AUC0-tlast from 0.6 to 71 h*µg/mL) as dose increased from 0.05 to 0.91 mg/kg. Summary/Conclusion: STRO-001 is the first ADC generated with novel cell-free protein synthesis technology and site-specific conjugation to be tested in the clinic. STRO-001 has been well-tolerated. No ocular or neuropathy toxicity signals have been observed and the MTD has not been reached. Preliminary anti-tumor activity has been observed in this heavily pre-treated patient population, including two DLBCL patients who had previously progressed after a CAR-T (Table). The study continues to enroll patients in dose escalation. Next planned dose levels are 2.5 mg/kg and 3.5 mg/kg. This study is registered with clinicaltrials.gov identifier NCT03424603. Table Disclosures Shah: Verastim: Consultancy; Kite Pharma: Consultancy, Honoraria; Lily: Consultancy, Honoraria; Cell Vault: Research Funding; TG Therapeutics: Consultancy; Miltenyi Biotec: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Incyte: Consultancy. Popplewell:Pfizer: Research Funding; Novartis: Research Funding; Roche: Research Funding. Andreadis:Gilead/Kite: Consultancy; Merck: Research Funding; Incyte: Consultancy; Karyopharm: Honoraria; Jazz Pharmaceuticals: Honoraria; Genentech: Consultancy, Current equity holder in publicly-traded company; BMS/Celgene/Juno: Honoraria, Research Funding; Novartis: Research Funding. Melear:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau. Spira:Cardiff Oncology: Research Funding; Takeda: Consultancy; Novartis: Consultancy; Merck: Consultancy; BMS: Consultancy; Incyte: Consultancy; Janssen: Consultancy; ADCT: Research Funding. Manda:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Burke:Roche: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Astra Zeneca: Consultancy; Verastem: Consultancy; Morphosys: Consultancy; Adaptive: Consultancy; Epizyme: Consultancy; Kura: Consultancy; Celgene: Consultancy; Adaptive Biotechnologies: Consultancy; Bristol Myers Squibb: Consultancy; Gilead: Consultancy; Seattle Genetics: Speakers Bureau. Sharman:TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; BeiGene: Research Funding. Krishnan:Sanofi: Consultancy; Sutro: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Takeda: Speakers Bureau; BMS/Celgene: Consultancy, Other: Stock BMS, Speakers Bureau; Janssen: Consultancy; Regeneron: Consultancy; Z Predicta: Membership on an entity's Board of Directors or advisory committees. Shah:BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Kuriakose:Sutro Biopharma: Current Employment. Berman:Sutro Biopharma: Current Employment. Matheny:Sutro Biopharma: Current Employment. Leonard:Miltenyi: Consultancy; BMS/Celgene: Consultancy; Regeneron: Consultancy; Karyopharm: Consultancy; GenMab: Consultancy; Sutro: Consultancy; Roche/Genentech: Consultancy; Epizyme: Consultancy; Bayer: Consultancy; Gilead/Kite: Consultancy; ADC Therapeutics: Consultancy; MEI Pharma: Consultancy; AstraZeneca: Consultancy. Molina:Sutro Biopharma: Current Employment.