KappaMab is a chimeric IgG1 monoclonal antibody specific for Kappa Myeloma antigen (KMA), a tumour specific cell antigen exclusively expressed on the surface of kappa restricted MM cells. Early safety and efficacy signals seen with single-agent treatment in phase I/II studies in conjunction with observations that IMiD®-treatment upregulates the KMA target and enhances effector cell cytotoxicity, provide rationale for this proof-of principal immune-oncology (IO) approach in a minimally pre-treated MM population.
To establish the clinical benefit rate (CBR) of KappaMab alone (Stage 1) and in combination with lenalidomide (LEN) and low dose dexamethasone (DEX) (Stage 2). Secondary aims: to determine the safety of KappaMab in combination with LEN and DEX, in particular, the incidence of immunological adverse events (AEs); and to evaluate the kinetics of response and loss of response (time to response [TTOR], time to disease progression [PFS], overall survival [OS]).
Investigator initiated, phase IIb, multi-centre, open label sequential cohort study comparing KappaMab alone to KappaMab in combination with LEN and DEX in RR MM (funded by the Victorian Cancer Agency, Australia). Key inclusion criteria were kappa-restricted myeloma, 1–3 prior lines of therapy but no prior LEN. In Stage 1 (n = 30), patients received KappaMab (10 mg/kg IV infusion) weekly for 8/52 (induction), then every 4/52 (maintenance). [One cycle = 28d] For patients in Stage 2 (n = 30), KappaMab dosing was as per stage 1 with the addition of LEN (25 mg D1–21) and DEX 40 mg weekly. In cycle 1 of Stage 2, LEN and DEX commenced 1/52 prior to KappaMab. [Cycle 1 was of 35 days duration: LEN 25 mg D1–28 and DEX 40 mg weekly (D1, 8, 15, 22, 29)]. Treatment continued until toxicity/progression. This is a planned interim analysis of the primary endpoint (CBR).
40 patients have commenced therapy. Following review by the DMC, recruitment to Stage 1 was terminated early (n = 19). 21 of a planned 40 patients for Stage 2 have commenced treatment. Cut-off date for analysis: 15/2/2019. 13 patients remain on study (Stage 1 = 1, Stage 2 = 12). 19 have progressed (Stage 1 = 14, Stage 2 = 5), 6 withdrew consent (3 each stage), 1 other and 4 patients have died (Stage 1 = 2, Stage 2 = 2).
Observed CBR in Stage 1 was 5.3% (1/19, PR = 1) compared to 66.7% in stage 2 (14/21, VGPR = 2, PR = 11, MR = 1). (Response assessments are continuing and will be updated at the June meeting). Proof of concept (PoC) criteria were not met for Stage 1, but were met for Stage 2: observed CBR ≥ 55%, and the posterior probability (PP) that the true CBR exceeds 35% was > 0.95 (PP = 0.998). ORR for Stage 1 was 5.3% (1/19) compared to 61.9% (13/21) for Stage 2. TTOR was not reached in Stage 1, and was 1.8m in Stage 2 (95% CI: 1.2 – 2.3m). Median PFS for stage 1 was 1.97m (95% CI: 1.67 - 4.63m), compared to 8.2m for patients in Stage 2 (95% CI 3.9 – 8.2m) (p = 0.004). Median OS for stage 1 was 16.4m (95% CI 4m and above), median OS for Stage 2 not reached (p = 0.682).
AEs of interest: 3/19 patients in Stage 1 had infusion reactions (grade 1 = 1, grade 2 = 2), compared to 4/21 patients in Stage 2 (grade 2 = 4). There were no haematologic toxicities reported in Stage 1, in comparison to anaemia 2/21, neutropenia 3/21 (grade 3 = 3), thrombocytopenia 4/21 (grade 3 = 1, grade 4 = 2) reported in Stage 2.
PoC for efficacy was met for KappaMab when combined with LEN and DEX, and the combination is well tolerated. This novel IO combination may represent a promising new therapeutic option for MM patients. This study is ongoing.