Gilles A. Salles, MD, PhD
Daratumumab (Darzalex) was associated with low overall response rates (ORRs) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and mantle cell lymphoma (MCL), missing the primary endpoint of a phase II trial published in Clinical Lymphoma, Myeloma & Leukemia
Results showed that the ORR was 6.7% in the DLBCL cohort, 12.5% in those with follicular lymphoma, and was not evaluable in the MCL cohort, leading investigators to terminate the trial.
“While the study did not show encouraging activity of single-agent daratumumab in patients with relapsed/refractory [non-Hodgkin lymphoma], daratumumab remains under active investigation in a number of diseases, including multiple myeloma and other hematologic cancers, myelodysplastic syndrome, and amyloid light-chain amyloidosis,” wrote first author Gilles Salles, MD, PhD, Hématologie, Hospices Civils de Lyon and Université de Lyon, Lyon, France, and coauthors wrote.
Prior preclinical data demonstrated encouraging activity in non-Hodgkin lymphoma (NHL) subtypes. In a human tumor xenograft model, in which 80% of tumor cells had high CD38 expression, the combination of daratumumab with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP plus rituximab (Rituxan; R-CHOP) led to complete tumor regression.2
Based on these findings, investigators conducted the proof-of-concept phase II trial to assess the clinical activity of single-agent daratumumab in relapsed/refractory NHL subtypes.
In the open-label, multicenter, two-stage, phase II study (NCT02413489), investigators screened 138 patients in 7 countries across 31 sites, with the final enrollment of patients with DLBCL (n = 15), follicular lymphoma (n = 16), and MCL (n = 5). To be eligible, patients had to have no evidence of transformation and an ECOG performance status of 0 or 1. For patients with DLBCL, prior high-dose therapy or autologous stem cell transplantation were not permitted. Those with relapsed/refractory follicular lymphoma must have received ≥2 prior systemic therapies, including one anti-CD20¬–containing combination regimen, and patients with relapsed/refractory MCL must have received ≥2 prior lines of therapy, including at least 1 cycle of BTK inhibition treatment.
Additional exclusion criteria were patients with known CNS lymphoma, anticancer therapy within 1 to 10 weeks before study start, 3-year history of cancer beyond NHL, and history of hepatitis C, or seropositive status for HIV or hepatitis B virus.
Patients who had any of these NHL subtypes with ≥50% CD38 expression, determined via immunohistochemistry, were eligible for stage I of the trial. In 28-day cycles, patients were treated with daratumumab weekly at 16 mg/kg intravenously for 2 cycles, biweekly for 4 cycles, and every 4 weeks thereafter. For the first and second infusion, the infusion rate was gradually increased from 50 mL/h to a maximum rate of 200 mL/h, and subsequent infusions were initially 100 mL/h and increased up to 200 mL/h.
The median age was 64 years (range, 43-82). The median time since initial diagnosis was 37.9 months, and the median number of prior therapies was 3 (range, 2-10). Moreover, all patients with follicular lymphoma previously received rituximab and all of those with MCL had received ibrutinib (Imbruvica).
The primary endpoint was ORR; secondary endpoints were pharmacokinetics and safety. Futility criteria were determined to be a ≤20% ORR for the DLBCL and MCL cohorts, and ≤40% ORR in the follicular lymphoma subgroup. If futility criteria were not met, then stage 2 was planned to further assess the CD38-targeted monoclonal antibody in larger populations of NHL subtypes.
However, as the futility criteria were met in the DLBCL and follicular lymphoma cohorts, and did not reach adequate recruitment in the MCL cohort, the study was terminated. Additionally, the investigators noted that there was a high screen failure rate, even in patients who were CD38 positive.
The pharmacokinetics of daratumumab were also similar to that of the agent in studies of multiple myeloma. Additionally, all patients discontinued therapy at the time of last follow-up; disease progression, which occurred in 80.6% if patients, was the most common reason for discontinuation.
Regarding safety, tolerability was consistent with what has been reported with daratumumab in prior studies. The most common treatment-emergent adverse events (TEAEs) were cough, abdominal pain, nausea, fatigue, and pyrexia. There were 9 patients who experienced grade 3/4 TEAEs that were considered to be related to daratumumab. Moreover, serious TEAEs occurred in 40.0%, 37.5%, and 60.0% of patients in the DLBCL, follicular lymphoma, and MCL cohorts, respectively.