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

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 C_max was reduced >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 C_max 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.