This study confirms and extends prior clinical observations of the anti-CD40 antibody dacetuzumab administered to patients with non-Hodgkin lymphoma . Overall, the safety profile for dacetuzumab was acceptable and manageable in this patient population. Consistent with prior experience and the known cellular target of dacetuzumab, there was evidence of dacetuzumab-related B-cell depletion. Baseline lymphopenia likely reflects, in large part, extensive prior treatment of the study patients with multiple myelosuppressive regimens and rituximab. Total lymphocyte depletion > Grade 3 was identified in 18% of patients, but did not result in high rates of clinical infections. A notable exception was a single case of bacterial orbital cellulitis requiring enucleation after ocular inflammation. Noninfectious ocular inflammation has been potentially attributed to reports of CD40 expression on conjunctival tissue, and mild conjunctival symptoms reported 12-21% of patients in phase I trials with dacetuzumab [10, 14, 16]. Consistent with prior phase I experience, mild symptoms related to CRS were noted, easily managed with premedications and did not compromise the ability to administer dacetuzumab. The rate of elevated asymptomatic hepatic transaminase values was also consistent with prior clinical experience. The observed dacetuzumab serum concentrations and the absence of host antibody responses also mirrored prior clinical experience.
In this study, restricted to a heavily pretreated DLBCL population, a 9% objective response rate was observed with a disease control rate of 37% (CR + PR + SD). In a retrospective pathology review, 1 patient with a PR was found to have Grade 2 follicular lymphoma. Therefore, the ORR for confirmed DLBCL patients in this study was 7%. This trial confirms the limited single-agent antitumor activity of dacetuzumab in aggressive NHL reported in the phase I trial . Though infrequent, the individual responses seen in the present trial were robust. Most notable was a durable CR that was attained in a case of multifocal primary cutaneous DLBCL leg type, a distinct DLBCL subtype with characteristic molecular features and an unfavorable prognosis [17, 18], that had relapsed shortly after failure of aggressive salvage therapy. Moreover, at a subsequent relapse, the patient’s disease again responded nearly completely to re-treatment with dacetuzumab. A second CR was obtained in a patient who had previously failed therapy with multiple regimens, including ASCT. The individual responses observed suggest that selected patients with DLBCL could benefit from treatment with dacetuzumab.
DLBCL is a notably heterogeneous group of lymphomas with different pathogeneses, driver mutations, and pathway dependencies. CD40-targeting is a precise therapeutic approach. It is not surprising that only a subset of unselected patients with DLBCL benefited from treatment with dacetuzumab. Predictive biomarkers may allow enriching the patient population likely to respond. However, predetermined correlative studies in the present trial did not identify factors that could predict clinical benefit. Specifically, the uniformity and intensity of CD40 expression, DLBCL subtype, and FcγR polymorphism did not correlate with response or stable disease.
In contrast, Burington et al.  examined the activation status of the CD40 pathway, and identified and validated an associated 15-gene qRT-PCR signature generated from preclinical models of NHL. The 15-gene signature predicted outcomes following CD40 pathway stimulation and suggested that CD40 activation status was a significant factor predicting response. It was applied to patient samples from two separate dacetuzumab monotherapy studies. Data from 28 of the 39 patient samples used in the training set for the clinical exploratory work were collected as part of the present phase II trial. A low baseline CD40 pathway activity correlated with high sensitivity to dacetuzumab and a high baseline CD40 pathway activity correlated with resistance to dacetuzumab . The mechanism of resistance to dacetuzumab might be the selective activation of the noncanonical NF-κB signaling pathway in constitutively active CD40 receptors that could promote cell survival by shifting the balance to an anti-apoptotic response . A limitation of this signature is that it only relates to the CD40 signaling mechanism of action of SGN-40 and does not take into account other potential mechanisms, such as effector functions (e.g., ADCC) or activation of immune cells (APCs). Therefore, additional work is needed to identify which patient-specific characteristics may be associated with response to dacetuzumab.
Preclinical studies with dacetuzumab have shown synergy when combined with rituximab or combination chemotherapy in animal models [21, 22]. This has led to additional trials of dacetuzumab in combination with standard agents. Activity in relapsed DLBCL was reported in a single-arm Phase Ib trial of dacetuzumab in combination with rituximab and gemcitabine, showing an ORR of 47% (14 of 30 patients) in relapsed or refractory DLBCL . Separately, a randomized phase IIb trial of rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) with or without dacetuzumab was conducted in patients who previously failed R-CHOP. Although the trial was stopped early due to failure to increase the CR rate, extended follow-up demonstrated a trend toward increased survival for those patients who were randomized to receive dacetuzumab . These studies suggest that dacetuzumab may be beneficial when combined with active regimens. However, the selection criteria to identify these patients have not been identified. Any future development of dacetuzumab should evaluate the multiple potential mechanisms of action that have been documented preclinically, including ADCC, ADCP, induction of apoptosis by signaling through CD40 on malignant cells, and immunomodulation by activation of CD40-expressing immune cells.