August 2016, Vol. 5, No. 6
Targeting CD38 Leads to Responses in Relapsed/Refractory MM
Interim results from a phase 1b study indicate that the monoclonal antibody isatuximab in combination with lenalidomide and dexamethasone results in responses in more than 50% of patients with relapsed/refractory multiple myeloma (MM), including those refractory to immunomodulatory therapy.
Based on the positive findings from this trial, a global phase 3 clinical trial will be initiated soon, said Ravi Vij, MD, Professor of Medicine, Division of Oncology, Section of Bone Marrow Transplant, Washington University, St. Louis, MO.
Isatuximab is a humanized IgG1 monoclonal antibody that targets the CD38 protein with multiple modes of action. It exhibits tumor-killing activity through direct engagement with the tumor cell and also promotes immunomodulation. Preclinical data have demonstrated that the anti-MM activity of isatuximab was enhanced by adding lenalidomide.
In the trial, dose levels of isatuximab were explored. Previously, data were presented for cohorts receiving 3 mg/kg, 5 mg/kg, and 10 mg/kg every other week. Based on pharmacokinetic modeling, 2 new dosing schedules (expansion cohorts) were added: 10 mg/kg weekly followed by every other week (n = 12), and 20 mg/kg weekly and then every other week (n = 10). Lenalidomide 25 mg was given on days 1 to 21 of a 28-day cycle, and dexamethasone 40 mg was given on days 1, 8, 15, and 22.
The data Dr Vij presented were from 3 of the cohorts: a group that received 10 mg/kg (n = 24) and the 2 dose-expansion cohorts, for a total of 46 patients.
Patients who had received at least 2 prior treatments were enrolled. Patients in the 10-mg/kg dosing cohorts had received a median of 4 prior lines of therapy; patients in the 20-mg/kg cohort had received a median of 6.5 prior lines of therapy. Nearly all patients had undergone prior stem cell transplantation.
Sixty-six percent to 100% of patients in each dosing group entered the trial refractory to immunomodulatory therapy. “This represents probably one of the most heavily pretreated and lenalidomide-exposed groups that has been reported with an anti-CD38 antibody in combination with lenalidomide and dexamethasone,” said Dr Vij.
Sixteen of the 50 patients enrolled remain on study; 34 patients discontinued treatment, 24 because of disease progression. The median duration of dosing varied from 10.1 weeks in the 20-mg/kg isatuximab group to 35.9 weeks in the group that received 10 mg/kg weekly followed by every-other-week dosing. The 20-mg/kg cohort had the shortest duration of follow-up at a median of 14.7 weeks, compared with 29.1 weeks and 31.5 weeks in the 10-mg/kg groups.
There were 7 deaths in the expansion cohorts, 5 due to disease progression.
The cohort receiving 10 mg/kg every 2 weeks, which had the longest follow-up, had an objective response rate (ORR) of 63%. The other 2 expansion cohorts were more heavily pretreated, and each had response rates of 50%. The ORR for the entire expansion set was 57%. The median duration of response was 7.6 months. Depth of response was improved with longer treatment, said Dr Vij.
Among the 39 patients refractory to immunomodulatory therapy, the ORR was 54%, which was consistent across all 3 dosing groups for which data were presented.
Most toxicities were grade 1/2, the most common being diarrhea, fatigue, pyrexia, upper respiratory infection, dyspnea, and nausea. The drugs used in combination “did not seem to add to the toxicity profile,” he said. Infusion-related reactions, mostly grade 1/2, occurred in 60% of patients, predominantly during the first infusion.
Based on the findings, the investigators recommend proceeding with 10 mg/kg weekly followed by 10 mg/kg every other week for future combination studies.
Rafael Fonseca, MD, Deputy Director, Mayo Clinic Cancer Center, Scottsdale, AZ, said that CD38-targeted monoclonal antibodies in combination regimens “is likely the part of the path to cure in MM patients” as first-line therapy. “We need to decide which agents and in which order this is best used…and if they should be combined with other immune enhancers, potentially even other monoclonal antibodies.”
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