Page 118 - Haematologica August 2018

M. Trnĕný et al.
(n=4)] (Table 2). Seven patients (7 of 41; 17.1%) had stable disease, and the remaining patients (16 of 41; 39.0%) had progressive disease. Higher response rates were observed among patients with relapsed DLBCL (14 of 26; 53.8%, 90%CI: 36.2-70.8%) compared with patients refractory to their last regimen (4 of 15; 26.7%, 90%CI: 9.7-51.1%). A higher ORR (56.3%) was also observed in patients who received only one prior therapeutic regimen (n=16). At the time of analysis, 6 patients with relapsed disease were still responding to therapy (3 CRs and 3 PRs).
Table 1. Baseline characteristics (safety population; n=61).
Overall response rate was also assessed in 14 patients with primary refractory disease (sole important deviation affecting efficacy) who were excluded from the PP popu- lation. Among these patients, the ORR was 21.4% (3 of 14; 90%CI: 6.1-46.6%), with the majority having PD (9 of 14; 64.3%) and only one patient achieving CR.
Figure 2 shows the DOR in individual patients in the PP population according to initial responses. The median DOR was 4.7 (range 0-8.8) months. Of 18 patients who responded to coltuximab ravtansine treatment (PR or bet- ter), 4 achieved a DOR of >6 months (one of 4 patients with refractory disease and 3 of 14 patients with relapsed disease). At the time of analysis, 34 of 41 patients (82.9%) in the PP population had experienced PD and the median PFS was 4.4 (90%CI: 3.02-5.78) months. Forty-one of the 61 patients in the safety population had died at the analy- sis cut-off date. Estimated median OS was 9.2 (90%CI: 6.57-12.09) months (Figure 3).
CD19 was locally assessed in all patients (n=41) during enrollment, and centrally assessed in 37 of 41 PP patients (90.2%) during biomarker analysis. Overall, 35 patients had 30% or more CD19-positive cells (range 30-100%). Variable levels of expression were recorded, with 11, 16, and 8 samples having a mean intensity of 1+, 2+, and 3+, respectively. The median H-score (see Online Supplementary Methods) was 162 (range 0-270). There was no relationship between levels of expression of CD19 and response; some patients with high CD19 expression had PD as their best response whereas some patients with lower expression experienced a PR (Online Supplementary Figure S1). Two patients with absent CD19 staining had progressive disease. For each measure of CD19 expres- sion, the receiver operating characteristic curve AUC val- ues varied between 0.42 and 0.65, indicating that none of the CD19 expression measures showed good predictive accuracy for distinguishing between responders and non- responders (Online Supplementary Table S1). No significant optimal cut-off point for CD19 expression was identified. In addition, there was no apparent correlation between cell of origin classification or MYC/BCL2 expression and response rate (data not shown).
All 61 patients in the safety population (Table 3) experi- enced at least one AE, including 33 of 61 patients (54%) who experienced at least one treatment-related AE. Grade 3-4 AEs were reported in 23 of 61 patients (38%), the most frequent being hepatotoxicity (2 of 61, 3%) and abdomi- nal pain (2 of 61, 3%). Serious AEs (SAEs) were reported in 24 of 61 patients (39%). Six SAEs (occurring in
Table 2. Summary of best response to treatment by subgroup based on International Working Group criteria.
Variable
Median age (range), years
Age group, years <65
65–75
>75
Sex Male Female
Histology (investigator determined) De novo DLBCL
Transformed DLBCL
Cell of origin classification* ABC
GCB Unclassified
ECOG performance status† 0
1
2
Ann Arbor stage I
II III IV
International Prognostic Index score Low
Low intermediate High intermediate High
Lactate dehydrogenase >ULN† Extranodal involvement
Bulky disease‡
Prior transplant for DLBCL
Disease status at study entry§ Primary refractory Refractory to last regimen Relapsed
Number of prior regimens for DLBCL 0
1 2 3 >3
Prior regimen for non-DLBCL lymphoma¶
Value, n (%)
69 (30–88)
17 (27.9%) 26 (42.6%) 18 (29.5%)
31 (50.8%) 30 (49.2%)
50 (82.0%)
11 (18.0%)
16 (43.2%) 17 (45.9%) 4 (10.8%)
27 (45.0%) 26 (43.3%) 7 (11.7%)
4 (6.6%) 11 (18.0%) 15 (24.6%) 31 (50.8%)
12 (19.7%) 11 (18.0%) 25 (41.0%) 13 (21.3%)
41 (68.3%) 36 (59.0%) 28 (45.9%) 12 (19.7%)
16 (26.7%) 16 (26.7%) 28 (46.7%)
1 (1.6%) 25 (41.0%) 17 (27.9%) 9 (14.8%) 9 (14.8%)
9 (81.8%)
Response, n (%)
ORR
90% CI* CR
PR
SD
PD
All (n=41)
18 (43.9%)
30.6–57.9
6 (14.6%) 12 (29.3%) 7 (17.1%) 16 (39.0%)
Refractory to last regimen (n=15)
4 (26.7%)
9.7–51.1
1 (6.7%) 3 (20.0%) 3 (20.0%) 8 (53.3%)
Relapsed (n=26)
14 (53.8%)
36.2–70.8
5 (19.2%)
9 (34.6%)
4 (15.4%)
8 (30.8%)
Primary refractory (n=14)
3 (21.4%)
6.1–46.6
1 (7.1%) 2 (14.3%) 2 (14.3%) 9 (64.3%)
1354
Data are number (n) (%) unless otherwise stated. ABC: activated B-cell-like; DLBCL: diffuse large B-cell lymphoma; ECOG: Eastern Cooperative Oncology Group; GCB: ger- minal center B-cell-like;ULN:upper limit of normal.*N=37.†N=60.‡Longest diameter of lesion >5 cm for at least 1 location.§N=60 (1 patient had received no prior regimen for DLBCL). ¶N=11 (patients with transformed DLBCL).
n: number; CI: confidence interval; CR: complete response; ORR: overall response rate; PD: pro- gressive disease; PR: partial response; SD: stable disease. *Estimated by Clopper–Pearson exact method.
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