VR-CAP Regimen Improves Survival Over R-CHOP in Mantle Cell Lymphoma

Using the VR-CAP regimen instead of R-CHOP significantly improved median overall survival in previously untreated newly diagnosed patients with mantle cell lymphoma who were not eligible for transplant, according to results from the long-term follow-up phase of a randomized, open-label, phase III trial.

Tadeusz Robak, MD

Using the VR-CAP regimen instead of R-CHOP significantly improved median overall survival (OS) in previously untreated newly diagnosed patients with mantle cell lymphoma (MCL) who were not eligible for transplant, according to results from the long-term follow-up phase of a randomized, open-label, phase III trial.1

“Compared with R-CHOP, VR-CAP was associated with significantly longer survival, and had a manageable and expected safety profile,” the authors, led by Tadeusz Robak, MD, Medical University of Lodz in Lodz, Poland, wrote inLancet Oncology. “Although hematological toxicities were more common and more severe with VR-CAP than with R-CHOP at the primary analysis, overall the safety profile of VR-CAP was acceptable at the final analysis. Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma.”

The LYM-3002 study was designed to assess whether the benefits noted with bortezomib in patients with relapsed or refractory MCL could be translated into the frontline setting and achieve durable responses to prolong progression-free survival (PFS). The trial compared the efficacy and safety of frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with untreated, newly diagnosed, MCL.

To meet LYM-3002’s inclusion criteria, patients were required to have confirmed stage II—IV previously untreated MCL with an ECOG performance status score of 2 or less, and to be ineligible for stem cell transplantation. The investigators randomized 1:1 a total of 487 participants to receive 21-day cycles of either VR-CAP or R-CHOP. The VR-CAP regimen consisted of intravenous rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², and bortezomib 1.3 mg/m², plus oral prednisone 100 mg/m². Patients in the R-CHOP group received intravenous vincristine 1.4 mg/m² (2 mg maximum), rituximab 375 mg/m², cyclophosphamide 750 mg/m², and doxorubicin 50 mg/m², plus oral prednisone 100 mg/m². Patients who responded to 6 cycles then received 2 additional cycles of their assigned regimen.

PFS was the primary endpoint of LYM-3002, which was conducted at 128 institutions in 28 countries in Asia, Europe, North America, and South America. The primary results showed a significantly longer median progression-free survival in participants who received VR-CAP compared with those who received R-CHOP (24.7 vs 14.4 months; HR, 0.63; 95% CI, 0.50-0.79;P<.001).

The new analysis reports final OS in the intention-to-treat population as its primary endpoint, as well as safety outcomes for patients in the long-term follow-up phase.

The authors included 268 patients in the follow-up analysis:140 in the VR-CAP group and 128 in the R-CHOP group. This total included patients with data that became available after the primary analysis clinical cutoff date of Dec 2, 2013. After median follow-up of 82.0 months (range, 74.1—94.2), median OS in the VR-CAP group was 90.7 months.This was significantly longer than the median OS of 55.7 months in the R-CHOP group (HR, 0.66; 95% CI, 0.51-0.85;P= .001).

OS at 4 years was 67.3% in the VR-CAP group and 54.3% in the R-CHOP group. At 6 years, OS was 56.6% in the VR-CAP group and 42.0% among R-CHOP patients. “[This suggests] consistent improvements in survival outcomes in patients receiving VR-CAP compared with those receiving R-CHOP,” the authors wrote.

At final analysis, 103 of 243 patients (42%) in the VR-CAP group had died, compared with 138 of 244 (57%) in the R-CHOP group. Progressive disease was the main cause of death in both groups. In the VR-CAP group, 64 of 243 patients succumbed to progressive disease, while 92 of 244 did in the R-CHOP group.

The authors reported that 18 patients (7%) in each group died from adverse events (AEs). Fatal adverse events in the VR-CAP group included 7 patients with infections and 5 patients with respiratory, thoracic, and mediastinal disorders. Leading causes of fatal AEs in the R-CHOP group included 8 patients with respiratory, thoracic, and mediastinal disorders and 6 patients each with cardiac disorders and infections. The authors also found that 4% of the patients in each group died of treatment-related AEs (VR-CAP n = 9; R-CHOP n = 10).

Three new AEs were reported following the primary analysis cutoff. In the VR-CAP group, 1 patient developed grade 4 lung adenocarcinoma and 1 patient developed grade 4 gastric cancer. In the R-CHOP group, 1 patient had grade 2 pneumonia.

The authors also found in a post-hoc exploratory subgroup analysis that VR-CAP was associated with significantly improved OS compared with R-CHOP in Ki-67-positive patients (Ki-67 expression in >10% tumor cells) regardless of Ki-67 expression level. No OS gains were seen in Ki-67-negative patients or in patients in low MIPI risk categories.

When the authors stratified their findings according to MIPI risk category, they found that VR-CAP was associated with significantly improved OS compared with R-CHOP in the low-risk and intermediate-risk categories, but not in the high-risk category.

References:

  1. Robak T, Jin J, Pylypenko H, et al. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study.Lancet Oncol2018; 19:1449—58. Published Online October 19, 2018.http://dx.doi.org/10.1016/
  2. Robak T, Huang H, Jin J, et al. Bortezomib-Based Therapy for Newly Diagnosed Mantle-Cell Lymphoma.N Engl J Med2015; 372:944-953. DOI: 10.1056/NEJMoa1412096.