Background: Treatments are limited and outcomes
poor in rituximab-refractory (Rit-Ref) iNHL. Bendamustine (B) has a
9 mo median PFS and 10 mo response duration in ph II trials.
Obinutuzumab (GA101/Gazyva [G]) is a glycoengineered type II aCD20
mAb with activity and acceptable safety in Rit-Ref NHL.
Methods: GADOLIN (NCT01059630) is a ph III open
label study in pts with CD20+ Rit-Ref iNHL. In the B arm, pts
received B 120 mg/m
2 (d1+2, c1–6) alone; GB arm pts
received B 90 mg/m
2 (d1+2, c1–6) with G 1000 mg (d1, 8,
15 c1, d1 c2–6) for up to six 28d cycles. Non-PD GB pts then
received G monotherapy every 2 mo for up to 2 yrs. Primary endpoint
was PFS assessed by an independent radiology facility (IRF), with
80% power to detect 43% improvement in median PFS.
Results: In the protocol specified interim
analysis, 396 pts were randomized to receive B (n = 202 [198
treated]) or GB (n = 194). The IDMC recommended to unblind the
study as the primary endpoint had been reached (4 Feb 2015).
Baseline characteristics were balanced between arms. Median age was
63 yrs and pts had a median of 2 prior therapies. Median
observation time was 20 mo (B) and 22 mo (GB). IRF-assessed median
PFS was 14.9 mo (B) and not reached (NR) for GB (HR 0.55, 95% CI
0.4–0.74; p = 0.00011). Median investigator-assessed PFS was 14 mo
for B and 29 mo for GB (HR 0.52, 95% CI 0.39–0.70; p < 0.0001).
There were no significant differences in IRF-assessed ORR (63.0% B
vs 69.1% GB) or CR (12.2% B vs 11.2% GB) at end of induction, in
IRF-assessed best overall response up to 12 mo from start of
treatment (76.6% B vs 78.6% GB), or in preliminary OS (median OS NR
in either arm). In the treatment period, there were fewer Grade ≥ 3
adverse events with B than GB (62.1% B vs 68% GB), notably
neutropenia (26.3% B vs 33.0% GB) and infusion-related reactions
(3.5% B vs 8.8% GB), but more Grade ≥ 3 thrombocytopenia (16.2% B
vs 10.8% GB), anemia (10.1% B vs 7.7% GB) and pneumonia (5.6% B vs
2.6% GB).
Conclusions: G combined with B (90
mg/m
2) followed by G maintenance significantly improved
PFS vs B alone (120 mg/m
2) in Rit-Ref iNHL. The
clinically meaningful PFS improvement with GB is the first
randomized evidence of benefit for a novel aCD20 mAb in Rit-Ref
iNHL. Clinical trial information:
NCT01059630