The New England Journal of Medicine (NEJM) published results from a LYM-3002 study on 5 March 2015, concluding that a bortezomib-based therapy was effective in patients with newly-diagnosed mantle-cell lymphoma, an incurable, aggressive haematological malignancy.
The proteasome inhibitor bortezomib was initially approved for the treatment of relapsed mantle-cell lymphoma in over 50 countries. The NEJM paper - whose main author was Tadeusz Robak M.D from the Copernicus Memorial hospital in Lodz, Poland – presented results of the phase III study that assessed the efficacy and safety of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) versus VR-CAP (same drugs as in R-CHOP regimen, but replacing vincristine with bortezomib) in 487 randomly assigned patients with newly-diagnosed mantle-cell lymphoma, in whom stem cell transplantation was not an option.
After a median follow-up of 40 months, the study met its primary end point by showing a 59% improvement in median progression-free survival with VR-CAP versus R-CHOP (hazard ratio, 0.63; P<0.001). Investigator assessment of the duration of progression-free survival consistently favoured VR-CAP, with a 96% improvement (hazard ratio, 0.51; P<0.001).
Most patients had tumour response. Rates of complete response were higher in the VR-CAP group (53%) than in the R-CHOP group (42%), according to the independent radiological assessment. The median time to response was 1.6 months in the R-CHOP group, versus 1.4 months in the VR-CAP group and the median duration of overall response was 36.5 months in the VR-CAP group versus 15.1 months in the R-CHOP group. Regarding other secondary end points, for R-CHOP versus VR-CAP, the median time to progression by independent assessment was 16.1 months versus 30.5 months (hazard ratio, 0.58).
The median overall survival was 56.3 months in the R-CHOP group and had not been reached in the VR-CAP group (hazard ratio, 0.80; P = 0.17). There was a between-group difference in 4-year survival of 10 percentage points (54% in the R-CHOP group vs. 64% in the VR-CAP group).158 patients (32%) died but overall survival data were not mature at the time the report was published.
Rates of adverse events of any grade and discontinuations due to adverse events were similar in the R-CHOP group and the VR-CAP group, including rates of drug-related adverse events (93% vs.96%) and discontinuations (6% vs. 8%). Haematologic toxic effects were the most common adverse events (thrombocytopenia, bleeding events, neutropenia/infections and peripheral neuropathy that was reversible in the majority of patients). Rates of individual serious adverse events were less than 5% in each group.
Investigators concluded that VR-CAP was more effective than R-CHOP in patients with newly diagnosed mantle-cell lymphoma, at the cost of increased haematological toxicity.
Rare malignancies perspective:
The investigators should be congratulated for conducting a well-performed clinical trial in rare malignancies setting. It is not often we see such positive results, especially in disease with poor prognosis. Bortezomib approval for disease relapse was based on findings from a previous phase II study. From replacing vincristine with bortezomib in this study, it was expected to improve efficacy in frontline treatment and to avoid overlapping peripheral neurotoxicity.
However, it took almost nine years from accrual of first patient to results publication. In the meantime, some important medical advances have occurred, one of them being subcutaneous administration of bortezomib, which offers improved safety, including the risk of peripheral neuropathy. Even more importantly, maintenance rituximab became a standard treatment approach. However, it was not used in this study, giving a hope that even better results could be achieved in patients with newly-diagnosed mantle-cell lymphoma. Although improved efficacy in this study was accompanied by higher rates of haematological toxicicity, there was no significant effect on the number of completed therapy cycles, median dose intensity for drugs common to both regimens, or treatment discontinuations or deaths related to adverse events.
Study supported by Janssen Research and Development and Millenium Pharmaceuticals.
Robak T., Huang H., Jin J., et al. N Engl J Med 2015; 372:944-953. DOI: 10.1056/NEJMoa1412096
See full study here.