FDA Approves Bortezomib Regimen for Untreated MCL

The FDA has expanded the approval for bortezomib (Velcade) to include the frontline treatment of patients with mantle cell lymphoma.

Andrew Evens, DO

The FDA has approved bortezomib (Velcade) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) as a frontline treatment for patients with mantle cell lymphoma (MCL), according to an announcement made by Millennium/Takeda, the companies that manufacture the drug.

The decision was based on findings from the phase III LYM-3002 study that compared R-CHOP with VR-CAP in previously untreated patients with MCL. In the study, VR-CAP improved progression-free survival (PFS) by 37% compared with R-CHOP. Additionally, the complete response (CR) rate with VR-CAP was 44% compared with 34% with R-CHOP.

“Mantle cell lymphoma is a subtype of non-Hodgkin lymphoma that is usually a clinically aggressive malignancy, and it is a challenging disease to treat in part due to a relatively high risk of relapse,” Andrew Evens, DO, the director of the Tufts Cancer Center, said in a press release. “There are several new targeted drugs approved by the FDA for patients with relapsed or refractory disease, but up to this point, there had been none approved for the treatment of patients with previously untreated disease."

The open-label phase III study randomized 487 patients with previously untreated MCL who were ineligible for bone marrow transplant to R-CHOP (n = 244) or VR-CAP (n = 243). All patients had measurable stage II-IV MCL and an ECOG performance status between 0 and 2. The primary endpoint of the study was PFS by independent radiology review, with secondary outcome measures focused on time to progression and overall survival (OS).

On day 1 of each 21-day cycle, patients received rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2, and doxorubicin at 50 mg/m2. Prednisone was administered orally at 100 mg/m2 on day 1 to 5. In the VR-CAP arm, bortezomib was administered intravenously at 1.3 mg/m2 on day 1, 4, 8, and 11. In the R-CHOP arm, intravenous vincristine was administered at 1.4 mg/m2 on day 1.

At a median follow up of 40 months, the median PFS was 24.7 months with VR-CAP versus 14.4 months with R-CHOP (HR = 0.63; 95% CI, 0.50-0.79; P <.001). By investigator assessment, the median PFS was 30.7 versus 16.1 months for VR-CAP and R-CHOP, respectively (HR = 0.51; P <.001).

In data presented at the 2014 ASCO Annual Meeting, the objective response rate including unconfirmed CR with VR-CAP was 92% versus 90% with R-CHOP. The CR and unconfirmed CR rate by bone marrow and LDH was 53% versus 42% and the median duration of response was 42.1 versus 18 months, for VR-CAP and R-CHOP, respectively.

The 4-year OS rate was 64.4% with VR-CAP versus 53.9% with R-CHOP. The median was not reached for VR-CAP compared with 56.3 months with R-CHOP (HR = 0.80; P = .173). At the time of the analysis, 32% of OS events had occurred. The median time to next therapy was 24.8 versus 44.5 months, for VR-CAP and R-CHOP, respectively (HR = 0.50; P <.001).

"Velcade, when used in the VR-CAP regimen, Velcade, rituximab, cyclophosphamide, doxorubicin and prednisone, has demonstrated improved outcomes for patients, making it an important advance for the treatment of newly-diagnosed patients with mantle cell lymphoma,” Evans said.

The most common all-grade adverse with VR-CAP compared with R-CHOP, respectively, were neutropenia (85% vs 67%), leukopenia (44% vs 29%), thrombocytopenia (57% vs 6%), lymphopenia (28% vs 9%), and peripheral neuropathy (30% vs 29%). Infections were reported for 31% of patients in the VR-CAP arm and 23% of the patients in the R-CHOP arm including pneumonia (8% vs 5%).

Adverse reactions leading to discontinuation occurred in 8% of patients in the VR-CAP arm and 6% of patients in the R-CHOP arm. In the VR-CAP group, the most commonly reported adverse reaction leading to discontinuation was peripheral sensory neuropathy (1%).

“We are delighted Velcade has received approval in previously untreated mantle cell lymphoma. The Velcade-combination delivered an 11-month median advantage in progression-free survival as compared to a current standard of care," Dixie-Lee Esseltine, MD, the vice president of Oncology Clinical Research at Takeda, said in a statement. "Since 2006, Velcade has proven to be an important therapy for the treatment of relapsed or refractory mantle cell lymphoma, and it can now be used as an initial treatment for all patients with mantle cell lymphoma.”