BFCR4350A, or cevostamab (RG 6160), is a bispecific T-cell engager (BiTE) antibody that targets both Fc receptor–like protein 5 (FcRH5) on myeloma cells and CD3 on T-cells, resulting in T-cell–mediated cytotoxicity against FcRH5-expressing myeloma cells. GO39775, an ongoing, multicenter, phase 1 trial, is assessing the safety, activity, pharmacodynamics, and pharmacokinetics of BFCR4350A monotherapy in relapsed/refractory multiple myeloma (RRMM). Dose-escalation data from the single step-up dosing cohort are available.
Patients enrolled in the study had exhausted available therapy options; prior exposure to chimeric antigen receptor (CAR) T-cells, BiTE antibodies, and antibody–drug conjugates (ADCs) was allowed. For the dose-escalation phase, patients received intravenous infusion of BFCR4350A in 21-day cycles (every 3 weeks). To decrease the risk for cytokine release syndrome (CRS), a single step-up dose was used in cycle 1, with the step dose (0.05 mg-3.6 mg) administered on cycle 1 day 1 and the target dose (0.15 mg-132 mg) administered on cycle 1 day 8, and on day 1 of each cycle thereafter.
Through August 18, 2020, 53 patients had been enrolled. The median age was 62 years; patients received a median of 6 prior lines of therapy, including proteasome inhibitors (100%), immunomodulatory drugs (100%), anti-CD38 monoclonal antibodies (mAbs; 81.0%), and anti–B-cell maturation antigen (BCMA) therapy (21.0%). A total of 72.0% of patients were triple-class refractory (proteasome inhibitors, immunomodulatory drugs, anti-CD38 mAbs), and 94.0% were refractory to their last therapy. Twenty-eight of the 53 patients had high-risk cytogenetics, defined as 1q21, t(4;14), t(14;16), or del(17p).
Efficacy data were available for 51 of 53 patients at data cutoff. The overall response rate at the ≥3.6/20-mg dose level was 53.0% (18/34), which included 12% of patients with stringent complete response, 6% with complete response, 15% with very good partial response, and 21% with partial response. Also at this dose level, responses were observed in 7 of 17 (41%) with penta-class refractory disease and 5 of 8 (63%) with prior exposure to anti-BCMA therapies. Although data are still being collected, 8 patients were in response for a period of ≥6 months as of data cutoff.
With a median safety follow-up of 10.3 months, CRS was the most common treatment-related adverse event (TRAE), occurring in 76.0% (40/53) of patients. The majority of CRS events were grade 1/2 (34.0%/40.0%); grade 3 CRS was observed in 1 patient, resulting from a grade 4 transaminase elevation. CRS tended to occur in cycle 1 and resolved within 2 days. A total of 22 patients who experienced CRS received tocilizumab and/or steroids. Other observed TRAEs included neutropenia (9 patients), lymphocyte count decreases (8 patients), aspartate aminotransferase increases (8 patients), platelet count decreases (17 patients), and anemia (15 patients). Grade 3/4 TRAEs occurring in ≥3 patients were lymphocyte count decreases (8 patients), neutropenia (8 patients), anemia (10 patients), hypophosphatemia (5 patients), and platelet count decreases (13 patients). No deaths occurred in the trial. Five patients were withdrawn from the study because of TRAEs. Although 1 dose-limiting toxicity (grade 3 pneumonia) occurred in the 3.6/90-mg cohort, the maximum tolerated dose was not reached. A linear dose-response curve was observed for BFCR4350A across the active dose levels tested, and dosing every 3 weeks is supported by the estimated half-life.
Preliminary results from this phase 1 study show promising efficacy and manageable toxicity for BFCR4350A (cevostamab) when used as monotherapy in heavily pretreated RRMM. Indeed, deep and durable responses were observed for patients lacking other therapeutic options, including those with high-risk cytogenetics, triple-class refractory disease, and/or prior exposure to anti-CD38 mAbs, CAR T-cell products, or ADCs. The risk for severe CRS was effectively decreased by Cycle 1 single step-up dosing.
Reference
Abstract 292. ASH 2020. December 5, 2020. Initial Clinical Activity and Safety of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Relapsed/Refractory Multiple Myeloma.