Page 116 - Haematologica August 2018

M. Trnĕný et al. Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most fre- quent form of non-Hodgkin lymphoma, representing approximately 30-58% of cases.1 The majority of cases of DLBCL occur de novo, although some develop from indo- lent lymphoma.2 DLBCL is subclassified as germinal cen- ter B-cell-like (GCB) or activated B-cell-like (ABC) sub- types based on gene expression profiling. The ABC sub- type has a worse prognosis than the GCB subtype.3 In addition, concurrent deregulation of MYC and BCL2 has been associated with poor outcomes,4,5 however the prog- nostic significance of these rearrangements remains con- troversial.6-8
Standard first-line therapy for DLBCL is cyclophos- phamide, hydroxydaunorubicin, vincristine, and pred- nisone, combined with rituximab (R-CHOP). Five-year overall survival (OS) in patients treated with this regimen is over 70%.9,10 Dose-adjusted etoposide, prednisone, vin- cristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R), showed promise as an alternative first- line regimen to R-CHOP in a phase II study,11 but failed to demonstrate superior event-free survival or OS in a phase III trial which directly compared the two regimens.12 The majority of patients in the phase III study had good prog- nostic features, and therefore it is possible that DA- EPOCH-R may provide an advantage in patients with an adverse prognosis (such as MYC/BCL2 double-hit lym- phoma) or rare subtypes (such as primary mediastinal lymphoma). However, the phase III study was not designed to answer this question, and R-CHOP remains the standard of care for the majority of unselected patients with DLBCL.12-15 Salvage treatment with autologous stem cell transplantation (ASCT) is the most effective approach at first relapse. However, it can only be offered to young, fit patients, and long-term survival is only 40%.16 There are limited treatment options with unsatisfying results for patients relapsing after, or ineligible for, ASCT.17 New ther- apeutic strategies are essential for these patients.
Coltuximab ravtansine (SAR3419) is an anti-CD19 mon- oclonal antibody conjugated to a potent cytotoxic may- tansinoid, DM4, via an optimized, hindered, disulfide bond. The antibody selectively binds to the CD19 antigen present on the majority of B cells, resulting in internaliza- tion of the receptor-drug complex and intracellular release of DM4. DM4 is a potent inhibitor of tubulin polymeriza- tion and microtubule assembly, functioning by similar mechanisms to vincristine and vindesine.18,19
Coltuximab ravtansine has been evaluated in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lym- phoma. A first-in-human phase I study examined several dose levels in 3-weekly administrations. At the maximum tolerated dose (160 mg/m2) few clinical responses and high levels of treatment-related ocular toxicity were observed.20 A further phase I, dose-escalation study examined once- weekly dosing and a modified schedule consisting of 4 weekly doses followed by 4 doses given once every 2 weeks. Both schedules showed anti-lymphoma activity in approximately 30% of patients with either indolent or aggressive disease. The maximum tolerated dose was 55 mg/m2, and the modified dosing schedule was found to limit drug accumulation, reduce toxicity, and improve response rates.19
To confirm the clinical benefit observed in the phase I setting in a population with aggressive lymphoma, we
conducted a phase II, open-label, multicenter study evalu- ating coltuximab ravtansine monotherapy in transplant- ineligible patients with CD19-positive, R/R DLBCL.
Methods
Study design
In this phase II, open-label, single-arm study patients received 4 weekly doses of intravenous (iv) coltuximab ravtansine 55 mg/m2, followed by a 1-week rest period, then biweekly doses until disease progression (PD), unacceptable toxicity, or discontin- uation of treatment. One cycle was 4 weeks, except for cycle 1 (5 weeks). At the investigator’s discretion, patients received pre- medication consisting of iv diphenhydramine 50 mg and oral acetaminophen 650 mg 30-45 minutes before each infusion. Dose reductions were permitted (see Online Supplementary Methods).
Patients
Adult patients with de novo or transformed histologically con- firmed DLBCL and more than 30% of cells expressing CD19 (local assessment) were enrolled. Patients had relapsed (progression ≥6 months after completion of last line of therapy) or refractory (progression during or within 6 months of a prior therapy) disease and had previously received standard chemotherapy (including rit- uximab). Patients with primary refractory disease (refractory to first-line therapy) were ineligible. However, some primary refrac- tory patients were wrongly enrolled (see Results section). Full inclusion and exclusion criteria are included in the Online Supplementary Appendix.
All patients provided written informed consent. The protocol and subsequent amendments were approved by independent ethics committees and/or institutional review boards at each cen- ter. The study was conducted according to the Declaration of Helsinki.
Outcomes
The primary end point was overall response rate [ORR; propor- tion of patients achieving a partial response (PR) or complete response (CR) (International Working Group criteria21)]. Secondary end points included duration of response (DOR; time from first PR or CR until PD or death), progression-free survival (PFS; time from first study treatment until PD or death), OS (time from first study treatment until death), and safety. Assessment of biomarkers was an exploratory end point.
Assessments
Assessment of clinical response involved physical examination, bone marrow biopsy, and computerized tomography (CT) every 12 weeks until PD or treatment discontinuation. Positron-emis- sion tomography (PET) was performed at baseline and, if positive, repeated to confirm a CR. Patients with a negative CT but positive PET were classified as PR.
Adverse events (AEs) were classified using National Cancer Institute Common Terminology Criteria for Adverse Events (v.4.03). Pre-specified AEs of special interest were eye disorders, neuropathy, and infusion-related reactions (all drug hypersensi- tivity reactions and treatment-related AEs occurring on the day of infusion).
Details of biomarker assessments are included in the Online Supplementary Methods.
Statistical analysis
The predicted beneficial ORR was 40% or over. Assuming
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