Preliminary Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Subcutaneously (SC) Administered PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: Lesokhin Alexander M. , Levy Moshe Y. , Dalovisio Andrew P. , Bahlis Nizar J. , Solh Melhem , Sebag Michael , Jakubowiak Andrzej , Jethava Yogesh S. , Costello Caitlin L. , Chu Michael P. , Savona Michael R. , Gasparetto Cristina , Trudel Suzanne , Chou Jeffrey , Udata Chandrasekhar , Basu Cynthia , Krupka Heike I. , Raje Noopur S. 
Published: February 2021

Introduction: PF-06863135 (PF-3135) is a full-length, humanized, bispecific monoclonal antibody (mAb, IgG2a) targeting BCMA, which is highly expressed on multiple myeloma cells, and CD3 expressed on T cells. Intravenous (IV) dosing of PF-3135 has been previously evaluated at 0.1 - 50 μg/kg weekly with preliminary evidence of anti-myeloma activity in RRMM, without reaching the maximum tolerated dose (MTD). SC dose escalation was subsequently initiated given the potential to reduce the maximum concentration (Cmax), which is believed to be associated with cytokine release syndrome (CRS) and inflammatory response, with the intent of achieving a more favorable therapeutic window.
Methods: Patients with RRMM previously treated with immunomodulatory drugs, proteasome inhibitors, and anti-CD38 mAb received SC dosages of PF-3135 at 80, 130, 215, and 360 μg/kg weekly. A modified toxicity probability interval method was used for dose escalation, with dose-limiting toxicities (DLTs) monitored in the first cycle (21 days). AEs were graded by CTCAE criteria except CRS, which was graded by Lee et al. 2014 criteria. Responses were assessed at the end of each cycle by the International Myeloma Working Group (IMWG) criteria. Peripheral blood was evaluated for soluble BCMA, cytokines, and immunophenotyping. PF-3135 pharmacokinetics and immunogenicity were also characterized.
Results: As of April 15, 2020, 18 patients had received PF-3135 SC at 80 (n=6), 130 (n=4), 215 (n=4) and 360 (n=4) μg/kg weekly. The median number of prior anticancer treatment regimens was 7; all patients had received prior daratumumab therapy; 4 (22%) patients had received prior BCMA-targeted antibody-drug conjugate or chimeric antigen receptor T-cell therapy. All patients completed the DLT-monitoring period and none were observed. At cut-off date, dose escalation was ongoing with MTD not reached. All patients experienced treatment-emergent AEs (TEAEs); the most common were CRS reported in 11 (61%) patients, anemia in 9 (50%), thrombocytopenia in 7 (39%), and injection site reaction and lymphopenia in 6 (33% each). Grade (G) 3-4 TEAEs were observed in 12 (67%) patients, including G3 anemia in 8 (44%), G3 thrombocytopenia, lymphopenia, neutropenia, hypoalbuminemia, and bone pain in 2 (11% each), G4 lymphopenia in 4 (22%), G4 thrombocytopenia in 3 (17%), and G4 neutropenia in 2 (11%) patients. G5 TEAEs occurring in 3 (17%) patients (80 μg/kg group) were considered not treatment-related (disease progression [n=2] and sepsis [n=1]). CRS, the most common treatment-related AE, was observed across all dose levels in 11 patients (61% overall; 50% at 80 and 130 µg/kg; 75% at 215 and 360 µg/kg). Of these, 9 (50%) patients experienced G1 CRS and 2 (11%) had G2 CRS. CRS began within the first 2 days of treatment, with a median duration of 2 days (range 0-4). Per IMWG criteria, the objective response rate was 33% in the overall SC-dosed population and 75% at the top 2 dose levels (215 and 360 μg/kg). Two patients each achieved a best response of partial response (PR), very good PR (VGPR), and stringent complete response (sCR). Seven patients had best response of stable disease. Exposure to PF-3135 increased with dose in an approximately dose-proportional manner. SC administration resulted in a lower dose-normalized Cmax relative to IV administration and a prolonged absorption phase, with median time to Cmax ranging from 3 to 7 days. Consistent with the observed CRS, cytokine increases were the highest following the first dose and diminished significantly at subsequent doses. Levels of free, soluble BCMA decreased with increasing doses and demonstrated sustained decreases throughout each dose interval.
Conclusions: AEs were generally manageable; CRS reported in the majority of patients was grade 1-2. Responses were achieved with SC dosing of PF-3135 in 6 of 8 (75%) patients at the 2 highest dose levels evaluated. Compared to IV, SC dosing did modulate the Cmax, so higher doses could be administered without observing increased severity of CRS. SC dose escalation is ongoing and additional results, including biomarkers and data from higher dose cohorts, will be presented.
Clinicaltrials.gov identifier: NCT03269136.
Funding: Pfizer.

Disclosures
Lesokhin: Janssen: Research Funding; Genentech: Research Funding; Takeda: Consultancy, Honoraria; Juno: Consultancy, Honoraria; GenMab: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Serametrix Inc.: Patents & Royalties. Levy:Baylor University Med Center: Current Employment; Seattle Genetics: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Research Funding, Speakers Bureau. Bahlis:Sanofi: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Solh:Amgen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Partner Therapeutics: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Costello:Takeda: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Poseida Therapeutics: Research Funding; Janssen: Research Funding. Chu:BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Teva: Consultancy, Honoraria. Savona:Boehringer Ingelheim: Patents & Royalties; Ryvu: Consultancy; Astex: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Karyopharm: Consultancy, Current equity holder in publicly-traded company; Gilead: Consultancy; AbbVie: Consultancy; BMS: Consultancy; TG Therapeutics: Consultancy, Research Funding. Trudel:Sanofi: Honoraria; Takeda: Honoraria; Amgen: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; AstraZeneca: Honoraria; Karyopharm: Honoraria. Chou:Pfizer: Current Employment, Current equity holder in publicly-traded company. Udata:Pfizer: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Basu:Pfizer: Current Employment, Current equity holder in publicly-traded company. Krupka:Pfizer: Current Employment, Current equity holder in publicly-traded company. Raje:Immuneel: Membership on an entity's Board of Directors or advisory committees; Caribou: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Astrazeneca: Consultancy; Takeda: Consultancy; Bluebird, Bio: Consultancy, Research Funding; Karyopharm: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy.

OffLabel Disclosure:
BCMA/CD3 bi-specific antibody in development for the treatment of patients with relapsed/refractory multiple myeloma