Thomas G. Martin, MD
The CD38-specific monoclonal antibody SAR650984 demonstrated encouraging efficacy as a monotherapy and in combination with dexamethasone and lenalidomide without reaching a maximum tolerated dose in patients with heavily pretreated multiple myeloma, according to results from two early-phase clinical trials presented at the 2014 ASCO Annual Meeting.
"There's a handful of evidence to move forward with this combination. First, these drugs all have shown single-agent activity. Second, lenalidomide may increase serum IL-2 levels, and thus promote NK cell activity and enhance ADCC [antibody dependent cellular cytotoxicity]. And there's also data from xenograft models," Thomas G. Martin, MD, the associate director of the myeloma program at the University of California, San Francisco, explained during his presentation.
Single-agent SAR650984 was administered intravenously to 35 patients with relapsed/refractory multiple myeloma across a variety of doses ranging from 0.3 to 20 mg/kg, in a phase I study. Patients had a median age of 64 years and had received a median of 6 prior therapies, including immunomodulatory agents and proteasome inhibitors.
Across all doses, the overall response rate (ORR) was 24% with a stable disease (SD) rate of 41%. In patients receiving a dose ≥10mg/kg (n = 18), the ORR was 33% with a 39% SD rate.
The most common all-grade adverse events (AEs) were fatigue (48.6%), nausea (34.3%), pyrexia (28.6%), anemia (28.6%), cough (25.7%), headache (25.7%), upper respiratory infection and chills (22.9%), dyspnea (20%), constipation (17.1%), and diarrhea and vomiting (14.3%). The most common, greater than grade 3 AE was pneumonia (9%).
In a separate phase Ib study, 13 patients with relapsed/refractory multiple myeloma were treated with SAR650984 at either 3, 5, or 10 mg/kg every 2 weeks. Lenalidomide was administered at 25 mg on days 1 through 21, and dexamethasone was administered at 40 mg once per week in a 28-day cycle.
The ORR across all doses was 58%, which was comprised of 1 partial response (PR) at the 3-mg/kg dose, 1 PR and 1 very good PR (VGPR) in the 5-mg/kg arm, and 1 PR and 3 VGPRs in the 10-mg/kg cohort.
Based on these findings, an expansion cohort was opened that enrolled an additional 18 patients who received treatment with the 10-mg/kg dose of SAR650984. Altogether, in patients treated with the 10-mg/kg dose (n = 24), the ORR was 63% (25% VGPR, 38% PR). When considering minimal responses, the clinical benefit rate was 67%.
In an analysis of response rates based on prior therapy, it was found that patients refractory to lenalidomide (n = 25) had an ORR of 48% (20% VGPR, 28% PR). Those refractory to bortezomib (n = 16) had an ORR of 44% (25% VGPR, 19% PR) and those refractory to pomalidomide (n = 9) had an ORR of 33% (11% VGPR, 22% PR). Strikingly, in 6 patients that were nonrefractory to lenalidomide, the ORR was 100% (33% VGPR, 67% PR).
The most frequent AEs included nausea (19%), cough (19%), fatigue, muscle spasm, and infection (n = 16% each). Greater than grade 3 neutropenia occurred in 13% of patients and thrombocytopenia was apparent in 10%. One patient discontinued therapy after the first treatment due to a grade 3 infusion reaction.
"This appears to be a very exciting and interesting mode of therapy with single-agent activity in about a third of patients and with lenalidomide and dexamethasone in combination it was about two-thirds clinical benefit, even in previously lenalidomide exposed patients," Angela Dispenzieri, MD, a professor of medicine in the division of hematology at the Mayo Clinic, said in an interview with OncLive
. "Very exciting to see myeloma finally getting access to effective antibodies."
The encouraging findings demonstrated by SAR650984 add to impressive results seen with other monoclonal antibodies being explored as treatments for patients with multiple myeloma, including the FDA breakthrough designated therapies elotuzumab and daratumumab. Taken together, monoclonal antibodies hold the potential to revolutionize treatment for patients with this disease.
"The hope is that if we have our own antibody [in multiple myeloma], that it could be used in frail patients perhaps as a single-agent or more importantly in combination," Dispenzieri said. "Because of the low toxicity and the fact that there's not huge hematologic toxicity, we have the opportunity to mix it with cytotoxic drugs or other immunomodulators or proteasome inhibitors, etcetera. It's a new class, and that's really important."
Martin TG, Hsu K, Strickland SA, et al. A phase I trial of SAR650984, a CD38 monoclonal antibody, in relapsed or refractory multiple myeloma. J Clin Oncol. 2014;32:5s (suppl; abstr 8532).
Martin TG, Hsu K, Charpentie E, et al. A phase Ib dose escalation trial of SAR650984 (Anti-CD-38 mAb) in combination with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma. J Clin Oncol. 2014;32:5s (suppl; abstr 8512).
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