A Phase 3 Trial Comparing Bortezomib Plus Rituximab with Rituximab Alone In Patients with Relapsed, Rituximab-Naive or -Sensitive, Follicular Lymphoma

Follicular lymphoma (FL) is an incurable B-cell non-Hodgkin's lymphoma (NHL) representing ∼20% of all NHL. Rituximab (R) is approved for the treatment of CD20+ relapsed/refractory FL, and single-agent bortezomib (Vc; VELCADE^®) has shown activity in heavily pretreated patients. Vc and R show additive activity in preclinical models, and the combination was active and well tolerated in a phase 2 study. This randomized, open-label, multi-center, international, phase 3 clinical trial (LYM3001) compared the efficacy and safety of Vc plus R (Vc-R) vs R alone in patients with relapsed or refractory, R-naive or R-sensitive FL.

Patients with grade 1/2 measurable FL who had relapsed/progressed following prior therapy (time to progression [TTP] ≥6 months if prior R-containing therapy), ECOG performance status ≤2, and no peripheral neuropathy grade ≥2 were randomized (1:1) to receive 5-week cycles of Vc-R (Vc 1.6 mg/m², d 1, 8, 15, 22, cycles 1–5, plus R 375 mg/m², d 1, 8, 15, 22 in cycle 1 and d 1 only in cycles 2–5) or R alone (administered according to the same schedule as for the Vc-R arm). In both groups, treatment was administered for five cycles or until progression or unacceptable treatment-related toxicity. Randomization was stratified by FLIPI score (0–1 vs 2 vs ≥3), prior R therapy (yes vs no), time since last dose of anti-FL therapy (≤1 vs >1 year), and region (US vs EU vs rest of world). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), complete response (CR) rate, TTP, and safety/tolerability. Response and progression were assessed by independent radiology committee (IRC) using the modified International Workshop Response Criteria. Planned sample size was 670 patients to provide 90% power (α=0.05, 2-sided) to detect a 33% improvement in median PFS with Vc-R vs R (i.e. 13.3 vs 10 months).

Between April 2006 and August 2008, 676 patients (intent-to-treat [ITT] population) were enrolled from 164 centers in 29 countries across Europe, the Americas, and Asia. Baseline characteristics were well balanced between the two arms; median age was 57 years (range 21–84), 54% were female, 75% were Caucasian and 21% were Asian. The majority of patients (93%) had an ECOG performance status of 0 or 1, 51% and 48% had grade 1 and 2 FL, respectively, and 41%, 35%, and 23% had high, intermediate, and low FLIPI score, respectively; 83% had Ann Arbor Stage III or IV, and 38% had bone marrow involvement at baseline. 33% of patients had received 3 or more prior lines of therapy (range 1–6+); 44% had received prior R therapy. The most common prior regimens were CHOP (38%), CVP (25%), single-agent R (17%), R-CHOP (12%), and R-CVP (11%). At a median follow-up of 33.9 months, a total of 440 PFS events were observed by IRC in the ITT population, 212 in the Vc-R arm and 228 events in the R arm. Median PFS improved from 334 days (95% CI: 278, 365) with R alone to 389 days (95% CI: 351, 456) with Vc-R; the hazard ratio was 0.822 (95% CI: 0.681, 0.991). This improvement is statistically significant with a 2-sided P-value of 0.039. The ORR was 63% with Vc-R vs 49% with R (P<0.001), including 25% and 18% verified CR rates, respectively (P=0.035). The durable response rate (>6 months) was 50% with Vc-R vs 38% with R (P=0.002). The median time to subsequent antilymphoma treatment was significantly improved in the Vc-R vs R arm (700 vs 537 days, P=0.027). Median OS was not reached in either group. Patients received a median 25 weeks treatment in both the Vc-R and R groups (range 5–40 and 5–35 in the Vc-R and R groups, respectively). Adverse events (AEs) were reported for 95% of Vc-R and 78% of R patients. The most common AEs were diarrhea (52% Vc-R, 8% R), nausea (29% Vc-R, 7% R), and pyrexia (25% Vc-R, 10% R). Most AEs were grade 1 or 2. Grade ≥3 AEs were reported in 46% of Vc-R and 21% of R patients; the most common grade ≥3 AEs were neutropenia (11% vs 4%) and diarrhea (7% vs 0%). Peripheral sensory neuropathy was reported in 17% of patients in the Vc-R arm vs 1% in the R arm; 3% vs 0% grade ≥3. 18% and 11% of Vc-R and R patients, respectively, had serious AEs, only 4% and 1% of patients discontinued due to drug-related AEs, and there were 9 and 4 on-treatment deaths, respectively.

The addition of weekly Vc to R therapy in patients with relapsed FL was associated with statistically significant improvements in PFS, response rate, and time to next antilymphoma treatment, with acceptable additional toxicity.

Coiffier:Johnson & Johnson: Honoraria. Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Mayer:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rule:Johnson & Johnson: Consultancy, Speakers Bureau; Roche: Consultancy. Walewski:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Investigators fee. Crump:Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy. Shpilberg:Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hermann:Millennium Pharmaceuticals: Research Funding. Parasuraman:Millennium Pharmaceuticals: Employment, Equity Ownership. Zhu:Johnson & Johnson: Employment. Enny:Johnson & Johnson: Employment, Equity Ownership. Theocharous:Johnson & Johnson: Employment. van de Velde:Johnson & Johson: Employment, Equity Ownership. Elsayed:Johnson & Johnson: Employment, Equity Ownership.