Résumé
Rituximab-based chemoimmunotherapy is standard treatment for non-Hodgkin’s lymphoma (NHL), but some patients relapse or do not respond to treatment. GA101, the first glycoengineered, humanized, anti-CD20 monoclonal antibody, was developed to induce increased direct cell death and antibody-dependent cellular cytotoxicity relative to rituximab. Phase 1 and 2 studies of patients with NHL have shown that GA101 monotherapy has promising activity. The phase 1b GAUDI study (NCT00825149, BO21000) evaluated the safety and efficacy of induction treatment with GA101 plus chemotherapy in patients with relapsed/refractory follicular lymphoma (FL). GA101 was partnered with cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP) or with fludarabine and cyclophosphamide (G-FC). The end-of-induction overall response rate was 96% for G-CHOP and 93% for G-FC (Radford et al. Blood. 2013). Here we report results from the cohort of patients who received GA101 maintenance monotherapy after responding to induction treatment.
During induction, patients with relapsed/refractory FL received G-CHOP (every 3 weeks, 6–8 cycles) or G-FC (every 4 weeks, 4–6 cycles). Chemotherapy backbone was selected by the investigator on the basis of patient characteristics and treatment history. Patients were randomized to either high-dose GA101 (1600 mg on days 1 and 8 of cycle 1, 800 mg on day 1 of subsequent cycles) or to low-dose GA101 (400 mg on days 1 and 8 of cycle 1 and day 1 of subsequent cycles). Patients with complete response (CR) or partial response after induction were eligible to receive GA101 monotherapy (at the same dose used for induction) as maintenance treatment every 3 months for 2 years or until disease progression. Patients who completed maintenance therapy were followed for 2 years after the last GA101 dose or until progression/initiation of a new antilymphoma treatment. The primary end point was safety. Progression-free survival (PFS) was a secondary end point.
Median observation time from study start in the G-CHOP and G-FC cohorts was 31.8 and 37.5 months, respectively. In the G-CHOP cohort, 82% (23/28) and 65% (15/23) of patients started and completed maintenance therapy, respectively. There were 7 discontinuations due to stable disease (SD) or progressive disease (PD) and 1 due to an adverse event (AE; hepatosplenic T-cell lymphoma). In the G-FC cohort, 61% (17/28) and 53% (9/17) of patients started and completed maintenance therapy, respectively. There were 4 discontinuations due to AEs (pancytopenia/septicemia, n=1; diarrhea/weight loss, n=1; neutropenia, n=2), 2 due to SD or PD, 1 due to administrative/other (patient moved away), and 1 due to death (chronic obstructive pulmonary disease, which was considered unrelated to GA101). During the maintenance period, 3 and 6 patients in the G-CHOP and G-FC cohorts, respectively, experienced a serious AE. No grade ≥3 AEs occurred in >1 patient in the G-CHOP cohort; in the G-FC cohort, the most common grade ≥3 AE was neutropenia (n=3). The proportion of patients with CR as a best overall response increased between the end of induction and the end of maintenance in the G-CHOP (39% [9/23] to 52% [12/23]) and G-FC cohorts (59% [10/17] to 82% [14/17]). Median PFS was not reached for G-CHOP; median PFS in the G-FC cohort was 46.0 months (95% CI: 24.4–46.0 months). Pharmacokinetic data will be presented.
In this phase 1b study, maintenance treatment with GA101 monotherapy was well tolerated and CR rates increased compared with the end of the induction phase. This suggests that GA101 could be used to sustain and extend the clinical response achieved after induction with GA101 plus chemotherapy in patients with relapsed/refractory FL. The majority of responders completed maintenance treatment. No new safety signals emerged during maintenance treatment with GA101 monotherapy. In summary, data from the GAUDI study show that GA101 maintenance monotherapy is well tolerated and confers clinical benefit after induction with GA101 plus chemotherapy.