Velcade: A Progress Report in Various Cancers

Velcade (bortezomib), developed by Millenium Pharmaceuticals, is a proteasome inhibitor that is currently approved for the treatment of multiple myeloma and relapsed mantle cell lymphoma.¹ Several abstracts were presented at the annual meeting of the American Society of Clinical Oncology this year for its use in other indications.

Bortezomib and rituximab in the treatment iNHL.

This study was designed to assess the tolerability of bortezomib and rituximab in patients with high tumor burden (HTB) non-Hodgkina’s lymphoma (NHL). Treatment in this multicenter phase 2 study consisted of 3 induction cycles of bortezomib and rituximab, followed by an abbreviated consolidation. All outcomes were analyzed by intent-to-treat. All 42 patients enrolled in the trial were evaluable. The therapy was well tolerated with few grade 3/4 toxicities and minimal neurotoxicity. Grade 3 adverse events (AE) included fever, infusion reaction, infection, cardiac, fatigue, diarrhea, hypokalemia, and bowel obstruction; the only grade 4 AEs were neutropenia and thrombocytopenia. Overall response rate (ORR) at end of therapy was 70%, with a 40% complete remission (CR) rate (follicular lymphoma (FL): ORR 76%, CR 44%). At 50 month median follow-up, 4-year progression-free survival (PFS) was 44%, with 4-year overall survival (OS) of 87% (FL: 44% and 97%, respectively). Interestingly, 4-year OS was superior for FL compared with non-FL histologies (97% vs 43%, respectively, P=0.003). Altogether, bortezomib/rituximab is a targeted therapeutic regimen that was very well tolerated and resulted in long-term survival rates comparable with prior HTB FL rituximab/chemotherapy series.

Replacing vincristine with bortezomib in R-CHOP regimen in treating mantel cell lymphoma

R-CHOP is standard therapy for newly diagnosed, BMT-ineligible mantle cell lymphoma patients (MCL). Bortezomib is approved in the Unites States for relapsed MCL. This study evaluated whether replacing vincristine with bortezomib in R-CHOP improves outcomes in newly diagnosed, BMT-ineligible MCL patients. Adults with treatment-naive, measurable stage II—IV MCL and ECOG PS 0–2 were randomized to VR-CAP or R-CHOP. Primary endpoint was PFS and secondary endpoints included time to progression, time to next treatment, OS, response by modified IWRC criteria, and safety. 487 patients were randomized between R-CHOP (244), and VR-CAP (244) arms. Patients received a median of 6 cycles. After 40 months median follow-up (298 PFS events), median PFS by IRC was 14.4 months (R-CHOP) vs 24.7 months (VR-CAP). Rates of grade ≥3 AEs were 85% (R-CHOP) vs 93% (VR-CAP), serious AEs were 30% vs 38%, discontinuations due to AEs 7% vs 9%, and on-treatment drug-related deaths 3% vs 2%. This trial showed that VR-CAP significantly prolonged PFS and consistently improved secondary efficacy endpoints vs R-CHOP in newly diagnosed, BMT-ineligible MCL patients, with additional but manageable toxicity.

Phase 3 trial for myeloma comparing different iMiDs

Treatment with immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) has dramatically increased response rates and survival for myeloma patients over the last decade, with triple drug combinations proving more effective than double or single agents. This trial, Myeloma XI, was a phase 3 randomized trial for newly diagnosed patients of all ages, which compared induction treatment with cyclophosphamide/lenalidomide/dexamethasone (CRD) to cyclophosphamide/thalidomide/dexamethasone (CTD) given to maximum response or intolerance. To evaluate the role of pre-transplant consolidation with a proteasome inhibitor, we randomized patients achieving less than a very good partial response (VGPR) to additional cyclophosphamide/bortezomib/dexamethasone (CVD) vs nothing. Fit patients went on to receive melphalan+ASCT. Of the 1939 patients analyzed, 1104 were on the intensive pathway arm (540 CRD vs 564 CTD) and 835 were on the non-intensive arm (411 CRDa vs 424 CTDa). 274 patients received additional bortezomib. The pre-planned ITT analysis of combined CR+VGPR rates shows a significant difference between CRD and CTD treatment on multivariate analysis in favour of CRD with odds ratio 1.27 (95% CI 1.06-1.52, p = 0.009). Additional bortezomib therapy for those with a suboptimal response upgraded response in 51%, demonstrating that PI therapy can be effective in patients intrinsically resistant to IMiDs. Treatment with both IMiDs was well tolerated. The trial demonstrated an important difference in response between the IMiDs thalidomide and lenalidomide, however further follow up is required to see whether this translates into prolonged PFS and OS.

References

1. How Velcade (bortezomib) works. Velcade website. http://www.velcade.com/Understanding-velcade/About-velcade. Accessed June 1, 2014.