Page 120 - Haematologica August 2018

M. Trnĕný et al.
7 patients (11%). Five patients (8%) reported peripheral neuropathy (PN) occurring during cycle 1 (n=3) or cycle 2 (n=2), including one case of grade 3 PN (unrelated to study treatment) in a patient with a history of the condition. Dose modifications were not required in any of the patients with PN, although none of these events had resolved at the time of analysis. A further 2 patients pre- sented with events compatible with optic neuropathy (grade 1); this diagnosis was not confirmed, but could not be confidently excluded. Neither of these patients required a dose modification and both events resolved within a median of 9 days (range 4-14). Overall, infusion- related reactions occurred in 10 patients (16%), and were most commonly gastrointestinal in nature (nausea 10%, vomiting 3%). Drug hypersensitivity was observed in one patient.
Dose modifications (dose omission, interruption, or cycle delay) due to AEs were required in 17 patients (28%), including 9 patients (15%) who experienced a grade 3-4 AE. Nine patients (15%) had at least one cycle delayed by >3 days, and 9 patients (15%) had one dose omitted. One patient (2%) required a dose interruption due to grade 1 hypotension, which was considered to be unrelated to treatment.
Of 8 patients (13%) who experienced AEs leading to death, 7 were due to PD. The other patient who died developed febrile neutropenia 34 days after the last dose of coltuximab ravtansine while receiving further anti- cancer therapy (gemcitabine-cisplatin); the investigator could not exclude the possibility that the event was due to a delayed effect of coltuximab ravtansine treatment.
Discussion
The results of this phase II trial indicate that treatment with coltuximab ravtansine as monotherapy is associated with moderate clinical responses in a proportion of DLBCL patients previously treated with rituximab-based chemotherapy, and has a favorable toxicity profile.
The responses described here are numerically higher than those reported in a phase II study of coltuximab rav- tansine in combination with rituximab [ORR 44% (90%CI: 30.6-57.9%) vs. 31% (90%CI: 22.0-41.6%), respectively].29 However, patients enrolled in the combina- tion study were limited to 3 cycles of treatment, whereas in the current study patients continued on therapy until disease progression or discontinuation due to an AE or investigator’s decision. Additionally, the patients in the combination therapy study could be described as a more refractory population (60% of patients had primary refrac- tory disease), whereas the primary analysis population for the current study excluded patients with primary refracto- ry disease. It should be noted that some patients with pri- mary refractory disease were wrongly included in this study due to a misclassification of their prior treatment history. The response rates described here are in line with other antibody-drug conjugates, when tested as monotherapy (44-56%)30,31 or in combination with ritux- imab (29-54%).32,33 Interestingly, the anti-CD30 antibody- drug conjugate brentuximab vedotin achieved an ORR of 44% among patients with R/R DLBCL, most of whom were refractory to their first (76%) and last (82%) line of therapy.30 The response rates were also similar to anti- CD19 monoclonal antibodies, such as MEDI-551,
Table 3. Adverse events (AEs) occurring in ≥10% of patients (safety population; n=61).
AE, n (%)
Any AE
Serious AEs
AE leading to dose modification* AE leading to discontinuation
Non-hematologic AEs Asthenia/fatigue Nausea
Diarrhea
Cough
Vomiting
Decreased appetite Disease progression Back pain Abdominal pain Dyspnea Constipation Peripheral edema
Laboratory abnormalities Hematologic AEs†
Anemia Lymphopenia Leukopenia Thrombocytopenia Neutropenia
Hepatic and renal abnormalities AST
Alkaline phosphatase‡ ALT
Creatinine
Bilirubin
All grades
61 (100%)
24 (39%) 17 (28%) 4 (7%)
18 (30%) 14 (23%) 12 (20%) 11 (18%) 8 (13%) 8 (13%) 8 (13%) 7 (11%) 7 (11%) 6 (10%) 6 (10%) 6 (10%)
53 (87%) 41 (67%) 39 (64%) 35 (57%) 32 (52%)
37 (61%) 26 (45%) 27 (44%) 19 (31%) 9 (15%)
Grade 3-4
23 (38%)
14 (23%) 9 (15%)
Grade 5
8 (13%)
8 (13%) –
0–
1 (2%) 1 (2%) 0
0
0
0
3 (5%) 1 (2%) 2 (3%) 1 (2%) 0
0
4 (7%) 13 (21%) 9 (15%) 6 (10%) 15 (25%)
2 (3%) 2 (3%) 2 (3%) 2 (3%) 1 (2%)
0
0
0
0
0
0
5 (8%) 0
0 0 0 0
– – – – –
– – – – –
1356
ALT: alanine aminotransferase; AST: aspartate aminotransferase. *Including dose omission, inter- ruption, and cycle delays. †Laboratory evaluations. ‡N=58.
MOR208, and blinatumomab, currently in phase II devel- opment for DLBCL.34-36 In comparison, in a recent multi- center, randomized study of the aza-anthracenedione pix- antrone in patients with aggressive B-cell lymphoma (DLBCL, transformed indolent lymphoma, or follicular lymphoma),37 the ORR was 26% (CR, 15%), with a medi- an PFS of 5.7 months (95%CI: 2.4-6.5).
The response rates among patients refractory to their first or last line of therapy were numerically lower than those observed among the relapsed patients included in the study (21.4% and 26.7% vs. 53.8%, respectively). However, given the limited numbers of patients in each group it is difficult to draw firm conclusions.
Biomarker analysis revealed no apparent correlation between cell of origin classification or MYC/BCL2 expres- sion and clinical response. In addition, none of the CD19 expression measures analyzed showed good predictive accuracy for distinguishing responders and non-respon- ders, and no significant optimal cut-off point for CD19 expression could be identified. This lack of correlation between CD19 expression and efficacy is counterintu- itive, but may represent an effect of coltuximab ravtansine on the tumor microenvironment that is important for lym- phoma cell growth and survival.38 Additional ad hoc analy- ses would be required to investigate this further. Interestingly, pre-clinical studies have also demonstrated
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