Plamotamab: First Presentation of Subcutaneous Administration in a Phase 1 Dose Escalation Study in Heavily Pretreated R/R NHL Patients Who Had Prior CAR-T Cell Therapy
Authors: Riedell Peter A. , Patel Krish , Dunleavy Vanessa , Karimi Yasmin H. , Shah Nirav N. , Ribrag Vincent , Ysebaert Loic , Noel Robin , Brisou Gabriel , Kline Justin , Bohac Chet , Naranjo Carlos , Kanodia Jitendra , Woo Jacky , Chen Nancy , Michot Jean-Marie , Tessoulin Benoîtt , Ahmed Sairah 
Published: December 2024

Introduction: Plamotamab is a CD20 x CD3 bispecific antibody evaluated with intravenous (IV) and subcutaneous (SC) dosing separately in a multi-center, multi-stage Ph1 study (NCT02924402). Plamotamab administered IV with a step-up priming regimen was well tolerated and demonstrated clinical activity in heavily pretreated patients (pts) with relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL). ORR in the DLBCL/HGBCL was 52%, CR rate 24%; and post CAR-T was 50%. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event (TEAE; 70.5%; no Grade [Gr] 3 or 4 CRS) (Patel; ASH 2022). This abstract presents the first safety and efficacy results from the SC dose escalation.

Methods: Dose escalation in pts with CD20+ R/R malignancies was evaluated with a streamlined SC dosing regimen (prime/step-up/target doses) administered once weekly through Cycle 3 then every other week until disease progression or unacceptable toxicity. The primary objective was safety and tolerability; secondary objective was anti-tumor activity. Adverse events (AEs) were graded using CTCAE v4.03; ICANS and CRS using ASTCT Consensus Grading (Lee, 2019). Investigators assessed efficacy using Lugano Criteria. Data cut-off was 5Jun2024.

Results: Twenty-two pts enrolled in 4 escalating SC cohorts from 29Dec2022, through 22Nov2023: DLBCL (n=14); high-grade B-cell lymphoma HGBCL (n=5); other (n=3; T-cell rich lymphoma, mantle cell lymphoma, Waldenstrom macroglobulinemia). Median age: 67 years (range: 27-90); 73% male. At baseline 78% had stage III/IV disease. Median number prior lines of therapy was 4 (range: 2-10). 91% of pts had relapsed/progressed on the most recent therapy prior to enrollment, 82% of all pts and 93% of DLBCL pts having received prior CAR-T therapy.

TEAEs occurred in 96% of pts. CRS was the most common TEAE (68%, (Gr 1, 54%; Gr 2, 14%). The majority of CRS occurred after 1st dose (41%; 32% Gr.1) and decreased after the 3rd dose (30%; 100% Gr 1). In cohort 4 (n = 11), the majority of CRS occurred after 1st dose (64%), and 22% after 3rd dose (100% Gr 1). No Gr 3 CRS events were reported in any cohort. TEAEs of ≥25% incidence were consistent with the late line lymphoma population; fatigue (55%), anemia (36%), hyponatremia (32%), and AST increased, COVID-19, pyrexia (27%). Grade ≥3 AEs occurred in 73% of pts and in ≥10% of pts included lymphopenia (23%), neutropenia/ neutrophil count decreased (18%), anemia and hypoxia (14%). ICANS was observed in 9% of pts, with no Gr 3 events observed and no DLTs. Three pts (14%) discontinued plamotamab due to non-related AEs (hypoxia, acute respiratory distress, congestive heart failure). Based on a preliminary 2-compartment model, bioavailability was estimated to be ≈80%, terminal half-life = 17.9-days and Cmax was reduced &gt;5-fold post SC administration compared to IV in line with the favorable CRS profile observed.

Responses were seen in all 4 escalation cohorts. Among 17 evaluable pts (at least 1 dose and 1 on-study response assessment) with DLBCL, HGBCL, and T-cell rich lymphoma, the objective response (OR) rate was 53% (9/17 pts); CR rate was 24% (4/17 pts); and in DLBCL pts OR rate 43%; CR rate was 14%. In pts with prior CAR-T, OR rate was 82% (HGBCL/DLBCL/T-cell lymphoma [14/17 pts] and 39% [5/13pts] in DLBCL pts). The median duration of response in 9/17 pts was 5.5 months (min-max 2-11).

Conclusion: SC dosing of plamotamab was well tolerated and demonstrated activity in a heavily pretreated, post CAR-T cell population consistent with previously reported IV administration and comparable to other agents in this class. SC dosing had favorable PK with Cmax lower than IV administration, with lower incidence and severity of CRS after the 1st step-up dose. Plamotamab is an active and tolerable drug for further development in CD20+ disease.