Final phase III trial analysis on VR-CAP versus R-CHOP for newly-diagnosed MCL patients

On 19 October 2018, Robak Tadeusz from the Medical University of Lodz, Poland, and colleagues, published in The Lancet Oncology the final survival outcomes of the LYM-3002 phase III trial (NCT00722137). This open-label, randomized trial compared the efficacy and safety of frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), in newly-diagnosed mantle cell lymphoma (MCL) patients.

Frontline R-CHOP is the current standard of care (SoC) for transplantation- or chemotherapy-ineligible MCL patients aged ≥ 65 years. Nevertheless, the survival outcomes of those patients can still be greatly improved. Since bortezomib is an approved proteasome inhibitor for MCL treatment both in the US and Europe, the large phase III clinical trial LYM-3002 was established to further evaluate the suitability of this regimen and its potential superiority to R-CHOP. The findings of the primary analysis of this trial were published in the New England Journal of Medicine in 2015, and revealed that although VR-CAP was more effective than R-CHOP in newly-diagnosed MCL patients it also led to significantly higher haematological toxicity. In this study, the final overall survival (OS) and safety profile of VR-CAP versus R-CHOP in transplantation-ineligible MCL patients was reported.

Study design

• Eligible patients had histologically confirmed, newly diagnosed, previously untreated stage II, III or IV mantle cell lymphoma and were ineligible for stem cell transplantation
• Patients were randomly assigned 1:1 to six or eight cycles (21-day cycles) of R-CHOP or VR-CAP
  • R-CHOP dosing: intravenous 375 mg/m² rituximab, 750 mg/m² cyclophosphamide, 50 mg/m² doxorubicin, and 1.4 mg/m² [maximum 2 mg] vincristine on Day 1 of each cycle, plus oral 100 mg/m² prednisone on Days 1–5
  • VR-CAP dosing: intravenous 1.3 mg/m² bortezomib on Days 1, 4, 8, and 11 of each cycle, followed by rituximab plus cyclophosphamide, doxorubicin, and prednisone, all at the same doses with R-CHOP
• Between 2008 and 2011, N = 487 MCL patients were enrolled and randomly assigned to R-CHOP (n = 244) or VR-CAP (n = 243). Of those, n = 482 patients were included in the safety analysis (VR-CAP: n = 240; R-CHOP: n = 242), and n = 268 in the follow-up analysis (VR-CAP: n = 140; R-CHOP: n = 128)
• In the follow-up analysis group, n = 32 (23%) patients in the VR-CAP arm discontinued due to death versus n = 51 (40%) in the R-CHOP arm

Results

• Median follow-up for both arms = 82.0 months
  • Median follow-up in the VR-CAP arm = 82.5 months
  • Median follow-up in the R-CHOP arm = 81.5 months
• Median OS in the VR-CAP arm = 90.7 months (95% CI, 71.4−not estimable)
• Median OS in the R-CHOP arm = 55.7 months (95% CI, 47.2−9) was significantly lower than VR-CAP median OS (HR = 0.66 [95% CI, 0.51–0.85]; P = 0·001)
• Four-year OS for VR-CAP was 67.3% versus3% for R-CHOP (point difference = 13%)
• Six-year OS for VR-CAP was 56.6% versus0% for R-CHOP (point difference = 14.6%)
• During the entire 9 years of the study, n = 255 (52%) received subsequent therapies, with n = 104 (43%) in the VR-CAP arm and n = 151 (62%) in the R-CHOP group

Safety

• In the final analysis, 42% of patients in the VR-CAP and 57% in the R-CHOP, died mainly due to progressive disease (VR-CAP: 26% versus R-CHOP: 13%)
• Eighteen patients (7%) in each arm died from adverse events (AEs)
  • VR-CAP: infections and infestations and respiratory, thoracic, and mediastinal disorders
  • R-CHOP: cardiac disorders, infections and infestations, and respiratory, thoracic, and mediastinal disorders
• Patients who died from treatment-emergent AEs (TEAEs) were n = 9 (4%) in the VR-CAP and n = 10 (4%) in the R-CHOP arm
• Second primary malignancies were reported in n = 10 patients in each arm throughout the study
  • VR-CAP: basal cell carcinoma, gastric cancer, hepatocellular carcinoma, lung adenocarcinoma, malignant lung neoplasm, malignant melanoma, myelodysplastic syndrome, non-small-cell lung cancer, rectal adenocarcinoma, and small intestine adenocarcinoma (all in one patient each)
  • R-CHOP: acute leukemia, clear cell renal cell carcinoma, gastric cancer, lung adenocarcinoma, malignant melanoma, and squamous cell carcinoma (all in one patient each), myelodysplastic syndrome (n = 2), and prostate cancer (n = 3)

The final follow-up findings of the phase III LYM-3002 trial provided further support on the superiority of VR-CAP to R-CHOP for the treatment of newly-diagnosed MCL patients, who are transplantation-ineligible. The  long-term outcome of this trial indicated that VR-CAP presents with a manageable safety profile, while extending the survival of these patients. The investigators further stated that this is the first study to demonstrate that VR-CAP treatment leads to long-term survival improvement when compared to the current SoC, R-CHOP.